[Federal Register: August 5, 2003 (Volume 68, Number 150)]
[Rules and Regulations]
[Page 46363-46402]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr05au03-14]
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Part III
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 172
Food Additives Permitted for Direct Addition to Food for Human
Consumption; Olestra; Final Rules
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 172
[Docket No. 2000F-0792]
Food Additives Permitted for Direct Addition to Food for Human
Consumption; Olestra
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the food
additive regulations to remove the requirement for the label statement
prescribed specifically for savory snack products that contain olestra.
This action is in response to a petition filed by the Procter and
Gamble Co.
DATES: The regulation is effective August 5, 2003. Submit written
objections and requests for a hearing by September 4, 2003.
ADDRESSES: Submit written objections to the Division of Dockets
Management (HFA-305), Food and Drug Administration, rm. 1061, 5630
Fishers Lane, Rockville, MD 20852. Submit electronic objections to
http://www.fda.gov/dockets/ecomments.
FOR FURTHER INFORMATION CONTACT: Mary D. Ditto, Center for Food Safety
and Applied Nutrition (HFS-255), Food and Drug Administration, 5100
Paint Branch Pkwy., College Park, MD 20740-3835, 202-418-3102.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Subject of Petition
II. Background
A. Basis for Requiring the Label Statement--1996 Decision
1. Legal Authority for the 1996 Label Statement
2. GI Issues Associated With Olestra
3. Nutritional Issues Associated With Olestra
B. Opportunity for Comment and Consideration of New Data
1. Request for Comments on Label Statement Required by the 1996
Final Rule
2. P&G's Commitment To Further Studies
3. FDA's Commitment to Convene an FAC Meeting
4. P&G's Petition To Remove the Requirement for the Label
Statement
5. Comments Received
III. Data and Information Since the 1996 Final Rule
A. Introduction
B. Surveys and Postmarket Passive Surveillance Regarding GI
Effects
1. Telephone Surveys Regarding GI Complaints
a. P&G
b. CSPI
2. Postmarket Passive Surveillance by P&G
3. Postmarket Surveillance Reports From CSPI
4. Comments Regarding Consumer Reports
C. Studies Regarding GI Effects
1. Rechallenge Study
2. Acute Consumption Study
3. Home Consumption Study
4. Stool Composition Study
5. Comments Regarding the GI Studies
D. A Study Regarding Nutritional Effects--Active Surveillance
1. Active Surveillance Study by P&G
2. Comments Regarding the Active Surveillance Study
E. Consultations and Literature Review Regarding Nutritional
Effects
F. Consumer Perception Studies of the Label Statement
1. 1996 Consumer Studies
2. 1999 Consumer Studies
G. 1998 FAC Discussion of the Label Statement
IV. FDA's Conclusions
A. The Applicable Legal Standard
B. FDA's Conclusions Regarding Gastrointestinal Effects
1. Basis of the 1996 Final Rule--GI Effects
a. Abdominal cramping
b. Loose stools
2. Data in the Current Petition--GI Effects
a. Abdominal cramping
b. Loose stools
C. FDA's Conclusions Regarding Nutritional Effects
1. Basis of the 1996 Final Rule--Nutritional Effects
2. Data in the Current Petition--Nutritional Effects
V. Response to Comments on the Label
A. Label Statement for GI Effects
B. Label Statement for Nutritional Effects
C. Labeling for Special Populations
D. Label Statement in Its Entirety
E. Data and Information Considered in this Rulemaking
F. Safety of Olestra
G. Allergenicity of Olestra or Olestra-Containing Foods
H. Nutrition Labeling and Claims
I. Appearance of the Label Statement
J. Labeling for Single-Serving Packages
K. 1995 and 1998 FAC Meetings
VI. Summary
VII. Environmental Impact
VIII. Inspection of Documents
IX. Objections
X. References
I. Subject of Petition
In a notice in the Federal Register of March 3, 2000 (65 FR 11585-
11586), FDA announced that a food additive petition had been filed by
the Procter & Gamble Co., 6071 Center Hill Ave., Cincinnati, OH 45224
(P&G, the petitioner) proposing that the food additive regulations be
amended in Sec. 172.867 Olestra (21 CFR 172.867) to remove the
requirement for the label statement prescribed in Sec. 172.867(e).
II. Background
In the Federal Register of January 30, 1996 (61 FR 3118, ``the 1996
final rule'') FDA announced the approval of olestra for use as a fat
substitute in prepackaged ready-to-eat savory snacks. Olestra is the
common name for a mixture of substances formed by chemical combination
of sucrose with six, seven, or eight fatty acids. The fatty acids,
bound to sucrose by ester bonds, are derived from edible fats and oils.
Olestra is essentially not absorbed or metabolized and passes
unchanged through the gastrointestinal (GI) system (61 FR 3118 at 3125-
3127). Therefore, olestra has the potential to affect GI physiology and
function. Additionally, because of olestra's physical properties, fat-
soluble nutrients present in olestra-containing foods \1\ or other
foods in the GI tract at the same time as olestra can partition into
olestra and pass through the GI tract without being absorbed by the
body. Therefore, FDA required the addition of fat-soluble vitamins A,
D, E, and K, to savory snacks containing olestra to compensate for any
inhibition of absorption by olestra (Sec. 172.867(d)).
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\1\ Olestra has only been approved for use as a fat substitute
in savory snacks. Throughout this document, we refer to olestra-
containing foods to include those savory snacks made with olestra as
well as other olestra-containing foods used in the preapproval
studies for olestra.
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At the time of the 1996 final rule, FDA concluded that, to avoid
being misbranded within the meaning of sections 201(n) and 403(a)(1) of
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(n)
and 343(a)(1)), olestra-containing foods would need to bear a label
statement to inform consumers about possible effects of olestra on the
GI system. The label statement also would clarify that the added
vitamins were present to compensate for any nutritional effects of
olestra, rather than to provide enhanced nutritional value. Therefore,
the 1996 final rule required that foods containing olestra be labeled
with the following statement in a boxed format: ``THIS PRODUCT CONTAINS
OLESTRA. Olestra may cause abdominal cramping and loose stools. Olestra
inhibits the absorption of some vitamins and other nutrients. Vitamins
A, D, E, and K have been added.'' (Sec. 172.867(e)(1)). FDA included
the term ``other nutrients'' because any nutrient that is as lipophilic
as these vitamins would also be affected, although there was no known
basis for adding such nutrients back. The agency also required that the
statement be made in a standardized format that specifies, among other
things, type style and type size, and that
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the label statement be surrounded by a box to ensure proper prominence.
This requirement was established under section 409(c)(3)(B) of the act
(21 U.S.C. 348(c)(3)(B)), which prohibits approval of a food additive
if the proposed use would result in misbranding of food (61 FR 3118 at
3160). The legal authority and scientific basis that underlaid the
requirement for this label statement are reviewed in detail in the next
section of this document.
A. Basis for Requiring the Label Statement--1996 Decision
1. Legal Authority for the 1996 Label Statement
Under section 403(a)(1) of the act, a food is deemed to be
misbranded if its labeling is false or misleading in any particular.
Section 201(n) of the act amplifies what is meant by ``misleading.''
Section 201(n) of the act states that in determining whether labeling
is misleading, the agency shall take into account not only
representations made or suggested about the product, but also the
extent to which the labeling fails to reveal facts material in light of
such representations or material with respect to consequences which may
result from use under the conditions of use prescribed in the labeling
or under such conditions of use as are customary or usual (see 21 CFR
1.21). Thus, the omission of such material fact from the label or
labeling of a food causes the product to be misbranded within the
meaning of sections 201(n) and 403(a)(1) of the act.
2. GI Issues Associated With Olestra
As noted, olestra is not digested or absorbed, and it passes
through the GI tract intact. The petitioner conducted a number of
studies to address issues of potential concern with respect to the
effect of olestra as it passes through the GI tract (61 FR 3118 at
3152-3159). For example, during studies designed primarily to assess
potential effects of olestra on absorption of fat-soluble dietary
components present in the gut at the same time, the petitioner also
assessed the potential for olestra to elicit GI symptoms such as
cramping, bloating, loose stools, and diarrhea-like symptoms by
collecting reports from participants in the studies. In two human
nutritional studies \2\ (88 and 100 subjects respectively), the entire
diet of the subjects was controlled during the length of an 8-week
study period. The studies were parallel, double-blind, and placebo-
controlled, with olestra dosages of 0 (placebo), 8, 20, and 32 grams
per day (g/d).\3\ The diets were formulated so that the total
digestible fat (triglyceride) content was the same for all treatment
groups. Triglyceride was added into the diets in the form of butter,
margarine, or vegetable oil to compensate for the amount of fat
replaced by olestra in the olestra-containing foods. Olestra was added
to various food items by substituting olestra for triglyceride in
recipes or in cooking oils. Therefore, the total amount of lipid-like
material (digestible triglyceride plus olestra) increased with
increasing olestra dose. Each meal contained olestra or the
corresponding placebo (triglyceride). Subjects were questioned daily
about changes in their health, including GI symptoms. To facilitate
collection of GI symptom data, a questionnaire provided a list of
common GI symptoms along with general definitions of each and was
completed by each subject to capture data about the type, severity, and
duration of symptoms experienced. As noted in the 1996 final rule (61
FR 3118 at 3152), the petitioner stated that the two 8-week studies
were not intended to examine GI symptoms under real-life consumption
conditions where snacks are not consumed every day with every meal and
where people may moderate intake if they experience GI symptoms.
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\2\ In evaluating olestra's nutritional effects, the petitioner
conducted two 8-week clinical studies, the 8-week clinical dose
response study (8-week DR), and the 8-week clinical vitamin
restoration study (8-week VR)(61 FR 3118 at 3133-3134). In this
document, when discussing the combined results of these studies,
they will be called the two 8-week studies.
\3\ By comparison, FDA concluded that the estimated lifetime-
averaged daily intake at the 90th percentile of olestra consumption
would be 7.0 grams per person per day (g/p/d) (61 FR 3118 at 3124).
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FDA's analysis of the data from the two 8-week studies (61 FR 3118
at 3152-3154) showed that there was a dose-response effect for olestra
with respect to two endpoints, reported diarrhea/loose stools and fecal
urgency. Reporting of diarrhea was based on subjects' perception of
diarrhea. FDA found no evidence that study subjects experiencing
olestra-related symptoms described as ``diarrhea'' also experienced
significant fluid or significant electrolyte loss. The effect of
olestra on stool consistency is similar to that produced by liquid
petrolatum, which softens fecal contents. FDA recognized that the
effect observed was not diarrhea in the clinical sense, but used that
term in the 1996 final rule, and is using that term here, because it is
the term used in the study report. FDA also found that these GI
symptoms cease soon after olestra is no longer consumed.
The petitioner also conducted a study, the Fecal Parameters Study,
designed to examine fecal composition of stools from subjects who
reported diarrhea when consuming olestra (61 FR 3118 at 3155). The
study consisted of two phases, a screening phase and a study phase. The
screening phase was conducted to identify subjects who reported GI
symptoms from olestra consumption. During the study phase, the
identified subjects ate different amounts of olestra, and GI symptoms
were recorded and fecal measurements were made. From the initial
screening phase, eighteen subjects reported an increase in the
frequency, severity, or duration of GI symptoms during the olestra
period, relative to the placebo period. These 18 subjects were selected
to take part in the study phase, and 15 completed the study. The study
phase was a crossover, placebo-controlled, single-blind (subject)
design with three treatment groups, 0, 10, and 20 g/d olestra. Each
subject received each treatment for 7 days. The treatment periods were
separated by 7-day washout periods. Subjects ate all treatment meals
under supervision at the clinical site, and ate their habitual diets at
home during the washout periods. Study subjects recorded GI symptoms
daily. Total fecal collections were made the last 3 days of each
treatment period. Daily stool collections were measured for wet weight,
volume, and density, and the pooled three day samples were analyzed for
water concentration, dry weight, olestra content, sodium (Na),
potassium (K), chloride (Cl), total and individual bile salts, free
fatty acids, triglycerides, and total lipids.
Measurements of the concentration of stool water and electrolytes
(Na, K, and Cl) suggested that these parameters did not differ in the
stools of persons reporting ``diarrhea'' during the olestra 20 g/d
period from those in the nondiarrheal stools (during the placebo
period) of the same persons. However, it was not possible to analyze
stool electrolyte values by individual stools or by individual days
because the stools were pooled from the 3-day collection period, as is
normally done when measuring fecal parameters. FDA noted that there
appeared to be an increased weight of stools in those subjects
reporting ``diarrhea'' when eating 20 g/d olestra that is not
completely accounted for by the presence of olestra in the stools. FDA
concluded that the results of this study indicated that there is no
difference in stool composition (e.g., water and electrolyte content)
when subjects consumed olestra versus placebo (61 FR 3118 at 3155).
FDA found that the number of subjects in the Fecal Parameters Study
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who reported diarrhea increased with increasing dose of olestra (i.e.,
3 subjects (20 percent) in the placebo, 6 subjects (40 percent) who
consumed 10 g of olestra, and 11 subjects (69 percent) who consumed 20
g of olestra). In addition, both the mean number of reported diarrheal
bowel movements per subject reporting any diarrhea, and the severity of
the reported diarrhea, increased with increasing olestra consumption.
Although there was an increase in the number of subjects reporting
loose stools with increasing olestra dose, this increase was not
statistically significant. FDA concluded that these results were
qualitatively similar to the results of the 8-week studies.
The agency concluded, based upon its evaluation of the data and
information available at the time, that consumption of olestra causes
GI effects such as loose stools, abdominal cramping, and diarrhea-like
symptoms. Additionally, the agency concluded that while olestra caused
these GI symptoms, there was no evidence that these effects represented
adverse health consequences.
At the time of approval, the agency did not have information about
the potential GI effects from usual or customary consumption of olestra
in savory snacks. Nonetheless, FDA considered it prudent to rely on the
available data in deciding whether a label statement about olestra's
potential effects on the GI tract was necessary. Olestra had the
potential to be consumed in relatively large quantities by every
segment of the U.S. population. Additionally, because olestra had never
before been available in the marketplace, consumers had no experience
with it and were not familiar with it or its potential to cause GI
effects. The agency believed that providing consumers label information
about olestra's GI effects would preclude unnecessary concerns about
the origin of GI effects, were they to be observed, and might also
prevent unnecessary or inappropriate medical treatment of those
symptoms (61 FR 3118 at 3161). Based on the weight of the evidence
about olestra's potential to cause GI effects, as well as the agency's
belief that consumers lacked familiarity with olestra and its potential
to cause such effects, FDA concluded at the time of olestra's approval
that the relationship between GI symptoms and consumption of foods
containing olestra is a fact that is material in light of the
consequences of consuming olestra, and therefore a label statement was
required.
3. Nutritional Issues Associated With Olestra
FDA concluded that olestra inhibits the absorption of the fat-
soluble components of the diet when these components are present in the
GI tract simultaneously with olestra (61 FR 3118 at 3132-3147). Such
components include the fat-soluble vitamins A, D, E, and K, and the
lipophilic carotenoids. Based on the data from the nutritional studies,
FDA concluded that addition of the four fat-soluble vitamins (A, D, E,
K) to foods containing olestra would compensate for any decreased
absorption due to the action of olestra, thus ensuring that consumption
of an olestra-containing food would not alter the amount of vitamin
available for absorption (61 FR 3118 at 3144-3147). The amounts of the
vitamins to be provided are prescribed to ensure safe use (Sec.
172.867(d)). As required under section 403(i) of the act, these
vitamins are declared in the ingredient listing.
The added vitamins were not to be considered in determining
nutrient content of the food for the nutritional label or for any
nutrient claims, expressed or implied. This is because the added
vitamins simply compensate for the transient impaired absorption of
vitamins A, D, E, and K, i.e., they are added to ensure no change
(neither increase nor decrease) in vitamin availability. Thus, the
vitamins added to olestra do not contribute significant amounts of
these nutrients to the diet (61 FR 3118 at 3161).
Labeling may be considered misleading not only if it fails to
reveal facts that are material in light of consequences that may result
from use of a food, but also if the labeling fails to reveal facts that
are material in light of representations made. Therefore, to set the
context for why vitamins A, D, E, and K were added, FDA required a
label statement providing information both that vitamins A, D, E, and K
had been added and that olestra inhibits the absorption of vitamins.
Because FDA believed that consumers who see vitamins A, D, E, and K in
the ingredient listing might incorrectly believe that the food was
fortified with these vitamins, the agency required an explanatory
statement on the label of olestra-containing foods to inform consumers
that olestra-containing foods were not an enhanced source of vitamins
A, D, E, and K. The statement indicated that olestra inhibits the
absorption of vitamins and other nutrients to explain why they were
added. FDA included the term ``other nutrients'' because any nutrient
that is as lipophilic as these vitamins would also be affected,
although FDA concluded that there was no basis for adding back
nutrients other than vitamins A, D, E, and K. In this way, FDA sought
to make clear to consumers the reason for the presence of vitamins A,
D, E, and K in the ingredient listing.
Carotenoids are fat-soluble components in the diet, the majority of
which are derived from fruits and vegetables. Data from the
petitioner's two 8-week studies demonstrated that consumption of
olestra inhibits absorption of carotenoids as measured by a decrease in
serum carotenoid levels (61 FR 3118 at 3147-3149). Co-consumption of
olestra and a carotenoid-containing food allows the greatest
interaction between olestra and the carotenoid, thereby maximizing the
potential for interfering with absorption of the carotenoid from the GI
tract.
Beta-carotene is a provitamin A carotenoid that is a dietary source
of vitamin A; provitamin A carotenoids are converted in the body into
vitamin A. At the time of the 1996 final rule, FDA concluded that
supplementing olestra-containing foods with vitamin A would compensate
for olestra's effects on the provitamin A function of carotenoids.
In evaluating whether there is a scientific basis to require the
addition of any carotenoids to olestra-containing foods, FDA consulted
with scientists at the National Cancer Institute of the National
Institutes of Health (NIH) and the National Eye Institute (NEI) of the
NIH (61 FR 3118 at 3148-3149), and the agency's Food Advisory Committee
(FAC) (61 FR 3118 at 3121). At the 1995 FAC meeting on olestra, experts
with a range of views discussed whether carotenoids themselves have
beneficial health effects, or whether it is some other substance in
fruits and vegetables that provides the claimed health effects, in
which case the carotenoids are serving solely as markers for fruit and
vegetable consumption. Five different conferences or reviewing groups
preceding the 1995 FAC meeting had examined the relationship between
carotenoids and disease. All of these groups had concluded that there
was insufficient evidence to recommend consumption of carotenoids,
except to encourage the consumption of fruits and vegetables (61 FR
3118 at 3148). Although epidemiological studies showed an association
between diets rich in fruits and vegetables (including those that
contain carotenoids) and decreased cancer risk, there was no direct
evidence that carotenoids themselves were responsible for or
contributed in a significant way to that protective benefit. Therefore,
at the time of the approval of olestra, the agency
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concluded that the available data did not establish any identifiable
nutritional or prophylactic benefits for carotenoids, either
individually or collectively, aside from the provitamin A function (61
FR 3118 at 3147-3149).
Thus, FDA found no scientific basis for requiring the addition of
any carotenoid to olestra-containing foods. The agency also found that
the actual magnitude of olestra's effects on carotenoid absorption was
likely to be within the range of the normal variation of such
absorption due to diet and bioavailability, providing additional
assurance that the effect of olestra on the absorption of carotenoids
did not raise concern. Accordingly, FDA concluded that there was no
basis for requiring a statement about carotenoids on the label of
olestra-containing food.
B. Opportunity for Comment and Consideration of New Data
1. Request for Comments on the Label Statement Required by the 1996
Final Rule
Because section 409 of the act prohibits, among other things,
approval of a food additive if doing so would cause misbranding, the
agency concluded that the olestra label statement should be imposed as
a requirement as part of the food additive petition process (Sec.
172.867(e)). The agency acknowledged, however, that the specific
wording had not been tested or subject to an opportunity for comment.
Thus, the agency requested comments on the label statement from
interested persons on such issues as the need for labeling, the
adequacy of its content, and the agency's current word choices (61 FR
3118 at 3160).
After the publication of the 1996 final rule, the agency received
timely comments on the label statement,\4\ as well as objections to the
1996 final rule.\5\
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\4\ The comments received by April 1, 1996, included the results
of P&G's consumer focus group studies on the label statement. Frito-
Lay also submitted consumer perception studies on the olestra label
statement. These studies are discussed in section III.F.1 of this
document. The agency continued to receive comments on the label
statement after April 1, 1996. In this document, FDA addresses
comments received on the label statement regardless of whether the
comments were received by April 1, 1996.
\5\ Timely objections were to be filed by February 29, 1996.
FDA's response to these objections and requests for hearing is
published elsewhere in this issue of the Federal Register.
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2. P&G's Commitment To Further Studies
In a letter to the agency dated January 24, 1996, the petitioner
stated its intention to conduct focus group testing of the required
olestra label statement, to establish a postmarket surveillance system,
to conduct additional studies of olestra exposure (both amounts
consumed and patterns of consumption), and to conduct additional
studies regarding the effects of olestra consumption (61 FR 3118 at
3160 and 3168). FDA responded that P&G was to conduct the studies it
had identified in its letter to FDA, consistent with the timetables
identified in that letter (61 FR 3118 at 3168).
P&G did carry out the surveillance and studies outlined in its
letter of commitment, and performed additional studies not mentioned in
the January 1996 letter. After the publication of the 1996 final rule,
P&G carried out its commitment to establish a system of passive
surveillance to collect spontaneous reports of possible effects that
consumers associated with the consumption of olestra-containing snacks.
This system included establishing an outside panel of medical experts
to review reports, followup on reports of serious illness, and provide
FDA information about reports received.
P&G also carried out its commitment to conduct studies on the
exposure and effects of olestra. The active surveillance program that
P&G sponsored was designed to examine the impact of olestra consumption
on endpoints such as serum concentrations of carotenoids and vitamins,
olestra consumption patterns (including frequency and amounts), and GI
symptoms.
These data and information were presented to the FAC in June 1998,
and were eventually incorporated into the petition that is the subject
of this rulemaking.
3. FDA's Commitment To Convene an FAC Meeting
In the 1996 final rule, FDA committed to review and evaluate any
new data and information bearing on the safety of olestra and to
present such information to the agency's FAC within 30 months of the
approval of the use of olestra in savory snacks (61 FR 3118 at 3168-
3169; Sec. 172.867(f)).
FDA convened a meeting of its FAC within 30 months of the approval
of the use of olestra in savory snacks. At an open public meeting, held
June 15-17, 1998, new data and information concerning olestra, obtained
since the 1996 approval were presented (Ref. 1). These new data, which
comprise the majority of material that P&G subsequently submitted in
its petition, are discussed in section III of this document. FDA, P&G,
the Center for Science in the Public Interest (CSPI), and other
interested members of the public made presentations to the Committee.
After presentation of the new data, the FAC discussed the label
statement specified in Sec. 172.867(e). The complete set of
transcripts of the June 1998 FAC meeting (``the transcript'' or
``transcript'') is publicly available through FDA's Division of Dockets
Management and through FDA's Internet site.\6\
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\6\ The Internet site is located at http://www.fda.gov/ohrms/dockets/ac/cfsan98t.htm#Food
Advisory Committee (choose June 15, 16,
and 17).
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4. P&G's Petition To Remove the Requirement for the Label Statement
P&G submitted a food additive petition, dated December 1, 1999, to
amend the food additive regulations in Sec. 172.867 Olestra by
removing the requirement for the label statement prescribed in Sec.
172.867(e). This petition incorporated the studies and information that
were performed after the publication of the 1996 final rule. As noted,
much of that material was discussed by the FAC in 1998.
5. Comments Received
FDA received approximately 80 letters, each containing one or more
comments, on the olestra label statement.\7\ \8\ Some of the comments
were submitted in response to FDA's request in the 1996 final rule for
comments on the olestra label statement. Other comments were submitted
in response to the January 24, 1996, announcement of the approval of
olestra for use in savory snacks. Because all of these comments
addressed P&G's original petition, which was granted in 1996, in this
document FDA refers to these comments as comments ``to the 1996 final
rule.'' Comments were also submitted in response to publication in the
Federal Register of the filing notice for the current petition (65 FR
11585, March 3, 2000); in this document, FDA refers to these comments
as comments ``to the current petition.''
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\7\ FDA notes that one of the objections submitted by CSPI
concerns the label statement required by the 1996 final rule.
\8\ Although not part of the petition being considered in the
current rulemaking, FDA reviewed comments regarding labeling that
were addressed to the 1998 FAC. These comments raised no substantive
issue that was not already considered as part of the current food
additive petition.
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Comments were submitted by P&G, Frito-Lay, Inc. (Frito-Lay), and
other members of the food industry, as well as from individual
consumers, consumer organizations, academia, trade associations, and a
member of Congress. Several comments were filed by CSPI. Several
parties, including Frito-Lay and
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CSPI, submitted comments to both the 1996 final rule and the current
petition.
Although section 409 of the act establishes no comment period for
food additive petitions, and the agency generally does not solicit
comments in notices announcing the filing of a food additive petition,
it is FDA's practice to consider any relevant comments submitted prior
to the agency's decision on a petition.\9\ In this document, FDA
separately discusses data from telephone surveys and passive
surveillance regarding GI effects, new studies regarding GI effects,
and active surveillance and other information regarding nutritional
effects of olestra. As part of its discussion of these areas, FDA
describes and responds to comments relevant to the topic. FDA discusses
and responds to comments on other topics (such as the wording of the
label statement, the prominence and placement of the label statement,
and the need for a label statement) in a separate section (see section
V of this document). In responding to the submitted comments, FDA has
considered all of the data and information available in the record that
bear on the olestra label statement, including the data and information
in the 1996 final rule as well as the new information in the current
petition.
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\9\ See discussion of comments in the filing notice for this
petition (65 FR 11585-11586, March 3, 2000).
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III. Data and Information Since the 1996 Final Rule
A. Introduction
Olestra-containing snacks were introduced into test markets in
April 1996, and national marketing began in February 1998. P&G
established a system of passive surveillance to collect reports of
possible effects that consumers associated with eating olestra-
containing snacks. This surveillance system was in place when test
marketing began. P&G has submitted reports to the agency, as well as
analyses of such reports. P&G also established its program for active
surveillance to monitor, among other things, possible nutritional
impacts of olestra consumption.
P&G conducted studies concerning possible GI effects from consuming
olestra-containing snacks in ``real-life'' situations. Specifically,
P&G conducted four controlled studies concerning possible GI effects in
humans and submitted reports about those studies to FDA.\10\ The four
controlled studies are described as follows:
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\10\ A copy of the petition submitted by P&G, as well as copies
of the studies, surveys, and other supporting materials listed here,
can be found at the Division of Dockets Management, Docket No. 00F-
0792.
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[sbull] An Acute Consumption Study,
[sbull] A Six-Week Consumption Facilitated Ad Lib Study (also
called the Home Consumption Study),
[sbull] A Rechallenge Study, and
[sbull] A Stool Composition Study.
In the current petition, P&G also submitted the following data and
information:
[sbull] Reports and analyses of data collected through consumer
focus group and perception studies,
[sbull] Surveys regarding GI symptoms,
[sbull] Updated literature reviews on carotenoids and disease, and
[sbull] A report and analysis of the first year of data collected
in an Active Surveillance Study.
CSPI also submitted reports from individuals who attributed an
effect to the consumption of an olestra-containing food (Docket No.
87F-0179). In some cases, CSPI obtained medical records from consumers
and forwarded them to FDA for analysis.
Below, FDA describes in detail the studies and information
submitted in support of this petition, comments to the 1996 final rule
that discuss the labeling of olestra-containing foods, comments to the
current petition, and other relevant information.
B. Surveys and Postmarket Passive Surveillance Regarding GI Effects
1. Telephone Surveys Regarding GI Complaints
a. P&G. P&G sponsored two telephone surveys to investigate the
frequency and severity of GI complaints, to investigate the frequency
of consumption of foods that consumers believe cause GI symptoms, and
to determine knowledge about reported GI symptoms from olestra-
containing foods. Both of these surveys were performed before olestra-
containing foods were available for sale in those markets. The first
survey was done in February 1997 in Indiana (in Marion County, where
Indianapolis is located), which was later a test-market for olestra-
containing foods. This survey also served as a pilot study for the
second survey, which was a national survey of the U.S. population
completed in September 1997. National marketing of olestra-containing
foods began in February 1998.
The petitioner acknowledged limitations in the design of the first
survey completed in Indiana. For example, because the first survey was
also the pilot study, the study instrument had not yet been
validated.\11\ Also, the sample size was small and not shown to be
representative of the general population surveyed. Despite these
limitations, the petitioner concluded from the survey that GI symptoms
were very common among the adult respondents polled. Asked about the
previous three month period, respondents reported most frequently the
GI symptoms of gas (34.6 percent), diarrhea (33.2 percent), and
abdominal cramps (25.8 percent). Of those respondents who experienced
one or more GI symptoms, 14 percent reported seeking medical attention
because of the symptom. More than half of those who experienced a GI
symptom said it was of moderate to severe intensity. The other result
noted by the petitioner in this study was that there are a number of
common foods (e.g., beans, onions, spicy foods) that respondents said
caused them to have GI symptoms, but more than 80 percent of these
respondents said they continued to eat these foods. Approximately half
of the respondents had heard of olestra and among that group, 18 to 28
percent associated olestra with a GI symptom such as abdominal cramping
or diarrhea.
---------------------------------------------------------------------------
\11\ Data obtained from the first survey was used to validate
the study instrument for use in the second survey.
---------------------------------------------------------------------------
The second survey was a larger, national survey that was designed
with a reliability check, and a portion of the survey was designed to
be a truly random sample of respondents. In this survey, 40.5 percent
of respondents reported having one or more GI symptoms in the previous
month. Of those respondents reporting a GI symptom, 21.8 percent had
abdominal pain or discomfort, and 26.9 percent reported diarrhea or
loose stools. More than 65 percent of respondents rated each of their
symptoms as moderate to severe in intensity, and 14 percent consulted
physicians about their symptoms. When asked about specific foods,
respondents reported having GI symptoms after eating foods such as
beans (22 percent) or spicy foods (34.4 percent). Despite symptoms,
approximately 80 percent continued to consume these foods. The
petitioner also found that women were more likely than men to report GI
symptoms, and that abdominal pain, discomfort, and bloating were more
commonly reported by women. There was little difference between males
and females for reports of diarrhea. More than half the respondents in
this study had heard of olestra, and of those, a varying number
associated olestra with different GI
[[Page 46369]]
symptoms (diarrhea (33 percent), loose stools (4 percent), cramps (11
percent), other GI problems (23 percent)).
FDA notes that in both these surveys, the percent of individuals
reporting a GI symptom was high. FDA also notes that while the great
majority of respondents in both surveys indicated that they consumed
foods that caused them GI symptoms, the survey did not obtain
information about the severity of these symptoms (Ref. 2).
b. CSPI. In 1996, CSPI commissioned a telephone survey in cities
where olestra-containing foods were test marketed (Cedar Rapids, IA,
Eau Claire, WI, and Grand Junction, CO), and submitted a report of the
results to FDA.\12\ The purpose of CSPI's survey was to determine how
many people in the test market had tried olestra-containing snacks, and
of those who had eaten olestra-containing snacks, how many had
experienced GI symptoms. A random digit dialing sampling system was
used, until a total of 506 telephone interviews were conducted in June
and July 1996. CSPI said that 27 percent of individuals surveyed had
tried the newly marketed olestra-containing chips, and of those, 20
percent reported experiencing GI symptoms characterized by CSPI as an
adverse GI effect. Respondents characterized these events as mild (58
percent), moderate (23 percent), or severe (9 percent). CSPI also found
that the majority of respondents (78 percent) had seen negative reports
in the press about olestra, although only 28 percent said they were
concerned about these possible effects. Based on this telephone survey,
CSPI predicted that a large number of adverse events would be caused by
the national marketing of olestra-containing foods. CSPI performed a
separate survey of the original respondents who had not eaten olestra-
containing chips but ate other chips to assess the frequency of GI
events associated with consumption of conventional savory snacks and
found that only 0.5 percent associated an adverse GI effect with eating
a triglyceride savory snack.
---------------------------------------------------------------------------
\12\ CSPI submitted this report to Docket No. 87F-0179.
---------------------------------------------------------------------------
CSPI commissioned a second survey, which was conducted in April and
May 1997 in the Indianapolis area where olestra-containing foods were
test-marketed. The purpose of the survey was to ascertain the
consumption of olestra-containing foods and possible rate of adverse
effects. CSPI submitted a report of the results to FDA.\13\ CSPI
reported that the majority of respondents said they had eaten savory
snacks in the past 8 weeks (68.8 percent), and that a smaller portion
of respondents (32.7 percent) said they had eaten olestra-containing
foods. CSPI said that when respondents were asked whether they had
eaten a specific brand of chips that contain olestra, they said yes,
but when asked whether they had eaten olestra, these consumers
responded that they had not eaten olestra. Of the group of respondents
who had eaten an olestra-containing food, 8.3 percent reported
experiencing what was characterized as an adverse effect after eating
the olestra-containing food.
---------------------------------------------------------------------------
\13\ CSPI submitted this report to the Docket No. 87F-0179.
---------------------------------------------------------------------------
In its review of the data and information submitted by CSPI, FDA
found that the studies provided information about the prevalence of use
of olestra-containing foods, awareness of GI symptoms associated with
olestra, and sources of information that consumers were using to learn
about GI symptoms associated with olestra. FDA disagreed, however, that
these studies could provide information about the cause of these GI
symptoms. FDA found that the study design was inadequate to determine
the cause of GI symptoms. Additionally, it is known from food-borne
illness outbreaks that attribution biases can influence consumers and
lead to the erroneous attribution of symptoms to a particular food.
CSPI's survey does not allow for the evaluation of erroneous
attribution of GI symptoms to consumption of olestra-containing chips,
i.e., other plausible causes for illness reports were not considered
(Ref. 3).
2. Postmarket Passive Surveillance by P&G
P&G established a system of passive surveillance to collect
consumer reports associated with the consumption of olestra-containing
foods. Passive surveillance refers to the collecting of spontaneous,
voluntary reports about a product. In its petition, P&G presents an
overview of both the utility and limitations of data obtained from
spontaneous, postmarket consumer reports. P&G characterized postmarket
passive surveillance as a means of identifying and characterizing
potential issues, including safety issues, once a product has entered
the marketplace and been utilized by the population at large. The
population experience with a product will be much broader than that
derived during premarket testing because the number of individuals
participating in premarket testing is necessarily limited. A reporting
rate may be calculated based on the total amount of product sold and
the number of reports received. P&G notes, however, that there are a
number of limitations with passive surveillance reporting. For example,
these data do not lend themselves to assessment of causality because of
the lack of controlled conditions and various confounding factors, such
as a high background incidence of reported GI effects. Voluntary
reporting, such as that obtained in P&G's passive surveillance system,
is also subject to a number of biases including the level of attention
the subject is receiving in the news media. Because reporting is
voluntary and subject to interpretation, and because the total number
of ``exposures'' can only be estimated, a true incidence rate cannot be
calculated from passive surveillance.
Reports to P&G under its passive surveillance program for olestra
were, for the most part, collected via calls made by consumers to a
toll-free telephone number displayed on olestra-containing foods. Such
calls were taken directly by P&G via its own toll-free telephone
number. Calls were also forwarded to P&G by other snack food
manufacturers (specifically, Frito-Lay). In some cases, information
from such calls (but not the calls themselves) was forwarded to P&G by
other snack manufacturers. Information was collected from callers as to
the product used, specific product code information (where available),
amount consumed, the nature of the complaint, symptom onset and
duration, recurrence, characteristics and treatment, concomitant
medications, and physician or other health professional involvement.
Where physician contact was involved, or a medically significant event
was reported, the petitioner attempted to obtain more detailed
information including release of medical records for evaluation.
Consumer reports were reviewed by trained medical affairs staff at
P&G. Additionally, the petitioner established a committee (Olestra
Postmarketing Surveillance Committee) of medical experts outside of P&G
whose membership included specialists in GI disease (both adult and
pediatric GI), epidemiology, and pharmacology to review the reports
received, and to make recommendations about the implications, if any,
of these reports on the safety of olestra. The petitioner submitted
reports to FDA of complaints associated with olestra consumption
beginning in April 1996 with the test marketing of snacks made with
olestra.
The petitioner reported that there were peaks in the number of
reports received after the test marketing and
[[Page 46370]]
national introduction of olestra-containing foods. The petitioner found
that while the absolute number of reports increased when olestra-
containing foods were first introduced into test markets, the reporting
rate (reports per amount of product sold) declined over time. The
petitioner also found that over time the absolute number of reports
declined and eventually reached a plateau. The greatest number of
reports the petitioner received over a four month period was 4,951 in
1998 at the national introduction of olestra-containing snacks. The
petitioner stated in its initial reports on passive surveillance that
it is common to receive calls and complaints for products. At the start
of national marketing the reporting rate was one report for
approximately 100,000 servings sold, and 2 years later the reporting
rate was one report for approximately 1 million servings sold.
The petitioner analyzed the data from its passive surveillance
efforts and found no trend toward increased symptoms with increased
consumption; no trend towards increased severity with increased
consumption; and no difference in severity by age group or gender. The
petitioner's Olestra Postmarketing Surveillance Committee reviewed
reports using an algorithm developed to assess the likelihood that an
effect was caused by olestra. Using this algorithm, P&G's committee
concluded that many reports were not likely to be related to olestra
and no serious reports could be attributed to olestra (Docket No. 00F-
0792, submission dated March 3, 2000). Based on the nature of the
complaints received, the petitioner designed subsequent studies to
address, in part, issues arising from consumers' anecdotal reports
after eating olestra-containing foods.
In the 1996 final rule, FDA determined that the use of olestra was
safe based on results from the preapproval safety studies. FDA stated
in the 1996 final rule (61 FR 3118 at 3168) that P&G's plans to
continue to study the consumption and effects of olestra were both
prudent and responsible. FDA expected, based on results of the
preapproval studies, that some reports concerning GI upset, such as
loose stools and abdominal cramping, would be collected through a
system of passive surveillance. FDA also considered that postmarket
passive surveillance had the potential to detect low frequency and
unexpected events because postmarket passive surveillance involves the
entire population that consumes a product.
FDA reviewed the reports of effects attributed to olestra and found
that the majority of reports received concern GI effects such as loose
stools and abdominal cramping. Other symptoms were reported at lower
frequencies.
FDA recognizes that passive surveillance data such as those
collected by P&G have utility but are limited in that they do not allow
for the determination of a causal association between the product
consumed (i.e., olestra-containing foods) and effects reported. Such
reports can, however, lead to hypothesis generation about why specific
effects are occurring. This may then result in the development of
studies used to test these hypotheses (Ref. 4).
FDA reviewed reports of effects associated with ingestion of
olestra that led consumers to seek medical attention. Where possible,
the agency reviewed medical records that were obtained directly from
individuals who reported the effect or that were obtained through P&G
and CSPI (Refs. 5 and 6). At the 1998 FAC meeting, FDA presented its
analysis of the medical reports received up to that time. Among the
reports discussed was a case where a consumer had undergone an
appendectomy and associated this with consuming an olestra-containing
food. The pathology diagnosis at the hospital noted that there were
minimal inflammatory changes. FDA obtained a medical release from the
patient in order to examine the pathology slides from the appendectomy,
which were read independently by four FDA pathologists, all of whom
confirmed the presence of inflammatory cells throughout the wall of the
appendix meriting a diagnosis of acute appendicitis.\14\ In many other
of the medical records reviewed, physicians attributed patient symptoms
to an etiology other than olestra, or did not provide an etiology.
There were cases where physicians did attribute symptoms to olestra,
but the limitations of passive surveillance make it difficult, if not
impossible, to draw definitive conclusions about causality based on the
review of individual medical records.
---------------------------------------------------------------------------
\14\ Transcript, vol. 1, pp. 271-276.
---------------------------------------------------------------------------
3. Postmarket Surveillance Reports From CSPI
CSPI has periodically submitted to FDA reports of effects allegedly
associated with the consumption of olestra (Docket No. 87F-0179). The
complaints were gathered initially in test markets by calls to an
advertised toll-free telephone line, and gathered subsequently through
CSPI's Internet site.
FDA analyzed the reports from CSPI and compared the information and
analysis to the information and analysis of the reports submitted to
FDA by P&G. FDA noted that the reports received by CSPI were very
similar in nature, type of complaint, and amount consumed as the
reports by P&G.\15\ As discussed previously, passive surveillance has
limited utility in determining causality.
---------------------------------------------------------------------------
\15\ Transcript, vol. 1, pp. 258-270.
---------------------------------------------------------------------------
4. Comments Regarding Consumer Reports
FDA received comments about reports of effects that consumers
attributed to olestra. FDA considered these comments and responds in
the following section of this document.
(Comment 1) One comment from an individual consumer to the current
petition reported that a family member who had Addison's disease
suffered gastric cramps and diarrhea, laid down, went into an
Addisonian crisis, and died after consuming olestra-containing potato
chips. The comment did not provide any further information regarding
the death mentioned. CSPI forwarded to the agency the medical record of
an Addison's disease patient who had reportedly consumed olestra-
containing potato chips prior to death. The patient who died was
diagnosed as having Addison's disease (adrenocortical insufficiency)
and hypothyroidism in 1989. FDA believes, based on several factors,
that the comment and medical record provided by CSPI refer to the same
person.
FDA reviewed the medical record forwarded by CSPI. This patient
collapsed suddenly after experiencing a bout of gastroenteritis, and
reportedly consumed olestra-containing chips prior to the bout of
gastroenteritis. An autopsy showed that the adrenal glands could not be
identified and noted a finding of Hashimoto's thyroiditis. The medical
record did not provide any information regarding the gastroenteritis
experienced prior to death.\16\ Due to the lack of information
contained in the medical record, the agency was unable to determine
whether the ingestion of olestra had any role in this patient's illness
or death (Ref. 5).\17\
---------------------------------------------------------------------------
\16\ The Certificate of Death lists acute cardiorespiratory
arrest as the immediate cause of death with autoimmune
adrenocortical deficiency syndrome as the underlying cause leading
to the immediate cause of death. Other significant conditions
contributing to death but not resulting in the underlying cause
include mitral valve prolapse and Hashimoto's thyroiditis.
\17\ FDA investigated the death mentioned in the comment. As
part of the investigation, FDA spoke with the patient's spouse and
the patient's co-workers about the events leading up to the
patient's death.
---------------------------------------------------------------------------
[[Page 46371]]
(Comment 2) A comment from CSPI to the current petition asserted
that FDA has never conducted indepth investigations (beyond reviewing
the medical records of a few individuals) of any of the anecdotal
reports, including those reports involving rectal bleeding,
hospitalization, and death. The comment further asserted that the
agency has ignored all of the anecdotal reports and has said that there
is no proof that any of the reports were due to olestra. The comment
also stated that in some reports, a patient's physician attributed his/
her symptoms to olestra. The comment also quoted FDA review memoranda
(Refs. 6 and 7) stating that olestra may have been responsible for some
of the effects reported.
FDA does not agree that it has ignored anecdotal reports. Nor does
it agree that it must conduct further investigation of the anecdotal
reports. FDA regularly reviews the reports forwarded to the agency by
P&G and CSPI. The reports are analyzed and summarized using criteria
such as sex, age, symptoms reported, duration of symptoms, and amount
of olestra-containing food consumed. The agency also reviews any
medical records forwarded with the reports. CSPI provided no evidence
to support its allegation that anecdotal reports have been ignored. Nor
has CSPI provided any reason to suspect that serious adverse health
effects could have been caused by olestra. The agency will continue to
monitor reports as they are forwarded to the agency.
As stated in the memoranda cited by the comment, some of the
effects reported may have been caused by olestra. These reports were
collected using passive surveillance. As noted previously, passive
surveillance is useful in that it can lead to hypothesis generation
about why specific effects are occurring. These hypotheses can then be
tested in controlled clinical trials. For example, the reports received
from consumers attributing their symptoms to olestra served as a basis
for some of the hypotheses tested in the petitioner's most recent
controlled clinical studies. However, while passive surveillance data
have utility, such data are limited in that they do not allow for the
determination of a causal association between the product consumed and
effects reported. Thus, based on the passive surveillance data alone,
it is not possible to determine whether the effects reported were
caused by consumption of an olestra-containing food.
The agency has reviewed all of the medical records that it has
received from CSPI and P&G about consumers who saw a physician for an
effect attributed to the consumption of an olestra-containing food. In
fact, FDA has conducted an investigation into the death mentioned in
the previous comment. FDA has also obtained and examined the pathology
slides of a patient who had undergone an appendectomy that the patient
associated with consumption of an olestra-containing food. The agency
has not found sufficient evidence to conclude that olestra is likely to
have caused the symptoms that led the consumers to see a physician.\18\
---------------------------------------------------------------------------
\18\ Ref. 5 and Transcript, vol. 1, pp. 271-276.
---------------------------------------------------------------------------
(Comment 3) A comment from CSPI to the current petition stated that
letters and electronic mail messages sent to P&G describing GI symptoms
have not been included in reports that P&G submitted to the agency;
therefore, the agency has not received all of the symptom-related
reports. The comment recommended that the agency investigate whether it
had received all reports.
FDA recognizes that not every report from a consumer will provide
enough information for FDA to determine whether an effect was possibly
related to olestra and that some judgement is needed in compiling data.
In light of this limitation, the agency recognizes that P&G may not
forward all reports it receives, such as those reports containing
incomplete information, to the agency. While this may mean that less
than 100 percent of reports are collected, the agency has no reason to
believe that the complaints not forwarded to the agency constitute a
unique data set or raise an issue not previously considered. Indeed,
the reports gathered and forwarded independently to the agency by P&G
and CSPI are consistent in terms of the nature of the complaints and
the amounts of olestra consumed. CSPI's comment provides no specific
information that would lead the agency to conclude that it has not
received an accurate and representative sample of the effects reported
to P&G or that such reports raise an issue not already considered.
Thus, the agency finds that there is no basis for concluding that it
should obtain and evaluate each and every report that P&G receives.
(Comment 4) A comment from CSPI to the current petition stated that
the agency should obtain and disclose to the public the number of
consumers (without identifying any particular individuals) who
attributed their symptoms to olestra and reached an out-of-court
settlement with the petitioner. The comment also asked for the number
of consumers who, after attributing their symptoms to olestra, received
or were offered reimbursement for their medical expenses. The comment
requested that the agency consider this information in its rulemaking.
FDA does not agree that it should obtain and disclose to the public
the number of consumers who attributed their symptoms to olestra and
reached an out-of-court settlement with the petitioner. Importantly,
the comment does not demonstrate the relevance of the requested
information to the question at issue: i.e., whether FDA should continue
to require special labeling for olestra-containing foods. Moreover,
settlement of lawsuits may be reached for a variety of reasons,
including improved public relations or avoidance of unnecessary
conflict, and do not address any factual issues regarding whether
olestra is capable of causing the effects claimed.
C. Studies Regarding GI Effects
1. Rechallenge Study
The petitioner submitted a report of a study designed to test
whether individuals who complained of a GI effect after consuming
olestra-containing snacks would have the same experience with
subsequent exposure (Refs. 8 and 9). This test was designed to show
whether the GI effect is consistently associated with consumption of
the olestra-containing snack. The petitioner's study was a randomized,
double-blind, placebo-controlled, four-period, within-subject crossover
study. Subjects were recruited from consumers who had voluntarily
called the snack manufacturer and reported GI symptoms associated with
consumption of olestra-containing snacks. Each subject made four visits
to the study site, at least 1 week apart, and was provided with 2
ounces (oz) of either potato chips containing olestra (olestra chips)
or potato chips containing conventional triglyceride \19\ (triglyceride
chips). At each visit, subjects were to consume as much as they could
of the 2 oz serving. Each participant was randomly assigned to receive
olestra chips at two visits and triglyceride chips at two visits.
Participants were contacted after each visit and asked whether they had
[[Page 46372]]
experienced any GI symptoms within the week after eating the potato
chip product.
---------------------------------------------------------------------------
\19\ In the various reports submitted by the petitioner, the
terms triglyceride, full-fat, regular, and conventional were all
used to describe the oil used in savory snacks. These terms mean the
same thing. For consistency in this document, we use the word
triglyceride.
---------------------------------------------------------------------------
The study was completed with 98 participants, the majority of whom
had initially called to report that they had experienced diarrhea,
loose stools, and/or abdominal cramping (61 percent, 16 percent, and 64
percent respectively). Approximately 48 percent of the participants
described the symptoms that prompted their original call as severe. For
nearly three-quarters of the participants, the amount of olestra chips
consumed in the study was comparable to, or greater than, the amount
associated with their initial call.
The petitioner found that during the study there were no
significant differences following consumption of olestra chips,
compared with consumption of triglyceride chips, in the frequencies of
abdominal cramping (12 percent with olestra, 9 percent with
triglyceride), diarrhea or loose stools (11 percent with olestra, 15
percent with triglyceride), gas (7 percent with olestra, 5 percent with
triglyceride), or any other GI symptom (28 percent with olestra, 26
percent with triglyceride). Overall symptom severity ratings for all
subjects were similar after consumption of olestra and triglyceride
chips. The petitioner concluded that this study provided evidence that
an episode that was initially reported to be an olestra-related effect
was in all likelihood not olestra-related, and that there was no
evidence of a population or subpopulation with a sensitivity to
olestra. The petitioner suggested that these results indicate that
initial calls made to the toll-free telephone line may reflect false
attribution of symptoms to products made with olestra.
FDA found this study was adequately representative of the
population who called the postmarketing surveillance system in terms of
severity of initial symptoms and amount of olestra reportedly consumed
prior to the initial symptom episode. FDA noted that while 98
participants were enrolled in the study, only 92 completed all 4
visits. The six dropouts were unrelated to olestra-related effects.
Based on an analysis of the data in the study, FDA concluded that under
the conditions of the study (two exposures of up to 2 oz of olestra-
containing chips separated by at least a week), subjects eating
olestra-containing chips were no more likely to report having had loose
stools, abdominal cramps, or any other GI symptom compared to subjects
eating an equivalent amount of triglyceride chips (Refs. 10 and 11).
2. Acute Consumption Study
P&G sponsored \20\ a study to determine whether there was a
difference in the nature or frequency of GI symptoms experienced by
subjects eating olestra chips compared to those eating triglyceride
chips, ad libitum on a single eating occasion (Ref. 12). The study was
a randomized, placebo-controlled, double-blind study in which 1,092
adults and teenagers who were provided with a 13 oz bag of potato chips
(either olestra chips or triglyceride chips) in a plain, unlabeled
white bag, consumed as many chips as they desired while viewing a
movie. Participants were also provided a 32-oz soft drink of their
choice. Participants were told prior to the test that they might
experience temporary dry mouth, thirstiness, or digestive symptoms
(such as gas, cramping, or loose stools), as they might with salty or
high fiber foods.
---------------------------------------------------------------------------
\20\ The principal investigator for the study was Dr. L.
Cheskin, Dept. of Gastroenterology, Johns Hopkins School of
Medicine.
---------------------------------------------------------------------------
Participants were instructed to be seated in the theater at least
one seat apart from other participants, to eat and drink as much or as
little of their chips and beverage as they desired, and not to share
with anyone else. The theaters were monitored by several study staff
during the movies. At the conclusion of the movie, participants clipped
their bags of chips shut; noted the approximate amount of beverage
consumed; and completed a brief questionnaire about product acceptance,
satiety, and sensory attributes. Participants turned in the completed
questionnaires and bags with uneaten chips and were given a toll-free
telephone number to call if they had any questions or problems. Bags of
chips were subsequently weighed to determine the amount consumed by
each subject.
Trained telephone interviewers contacted study participants and
administered a recall questionnaire to collect information on any
effect experienced since the movie. All subjects were specifically
asked if they had experienced any GI symptoms during or since the
movie, and to specify those symptoms including the severity and timing
of any such symptoms. The study protocol specified that participants be
contacted within 2 to 4 days of viewing the movie. The petitioner
reported that 85 percent were contacted within 2 to 4 days and a total
of 97 percent were contacted within a week of viewing the movie.
The petitioner reported that the median consumption of olestra
chips was approximately 2.1 oz (approximately 16 g of olestra) \21\
compared to about 2.7 oz of triglyceride chips. Overall chip
consumption was similar across age groups, but males generally consumed
more chips than females (median of 2.8 versus 2.1 oz, p<0.01). The
overall palatability of the triglyceride chips was rated slightly
higher than the olestra chips, with a mean score of 6.4 versus 5.6 on a
9-point preference scale (p<0.01). Regarding satiety, there were no
significant differences between the groups as indicated by mean satiety
scores of 5.9 versus 5.7 for triglyceride chips and olestra chips,
respectively, on a 9-point scale, with 9 being ``extremely full''
(p=0.07). Nor were any differences seen in beverage consumption, choice
of beverage, or time since last meal prior to the movie between the two
groups.
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\21\ In 1996, FDA estimated the probable life-time averaged
intake of olestra at the 90th percentile to be 7.0 g/p/d. To
evaluate subchronic conditions, FDA estimated that a ``high'' acute
consumer of olestra (everyday for 12 weeks) would consume 20 g/p/d,
equivalent to eating a 2 oz bag of potato chips every day, and the
99th-percentile single-day intake of olestra for the group consuming
the highest level of savory snacks to be 45 g/d (61 FR 3118 at
3124).
---------------------------------------------------------------------------
The petitioner attributed the lower chip consumption in the olestra
group to the slightly lower preference for olestra chips reported by
study participants. The petitioner stated, however, that the median
consumption (2 oz) was more than a typical single-serving snack size
bag of chips, and that approximately 100 participants ate more than 4
oz of olestra chips (approximately 32 g of olestra).
The petitioner reported that the proportion of subjects who
reported GI symptoms after consuming olestra chips was not different
from that after consuming triglyceride chips (15.8 percent and 17.6
percent respectively). There were no differences between the olestra
and triglyceride groups in the frequencies for 14 different self-
reported GI symptoms (gas, diarrhea, pain, cramping, upset stomach,
loose stools, nausea, bloating, indigestion, aftertaste, eructation,
constipation, vomiting, bloody stool), overall symptom severity for any
GI event, nor time to onset or duration of symptoms. The petitioner
also reported that consumption levels did not correlate with the rate
of symptom reporting in either the olestra or triglyceride group.
The petitioner planned to have 1,400 participants in the study and
anticipated symptom reporting to be 10 percent for the triglyceride
group and 15 percent for the olestra group. Using these assumptions,
the study would provide 80 percent power for detecting
[[Page 46373]]
a 5 percent difference in the proportions of symptoms between the
olestra and triglyceride groups. The final number of participants to
complete the study was 1,092,\22\ which was fewer than planned. The
rate of symptom reporting in the triglyceride group was 17.6 percent,
which was higher than planned. Given the actual number of participants,
and the actual rate of reports of symptoms in the triglyceride control
group, FDA found that the study had an 80 percent chance of detecting a
7 percent difference between the test groups (p=0.05) (Ref. 13).
---------------------------------------------------------------------------
\22\ Of the 1,742 individuals originally enrolled for the study,
1,123 kept their appointments. Thirty-one individuals could not be
contacted for followup, leaving a total of 1,092 evaluable subjects.
---------------------------------------------------------------------------
FDA observed that 962 participants completed a post-movie interview
within the 2 to 4 days goal of the study. Of the remaining 130
participants who were contacted, 124 participants were contacted in 5
to 10 days, 3 on the day of the movie, 1 within a day, and 2 within 23
days. FDA noted that P&G included data from these 130 participants in
its analysis to enhance the sensitivity of its analysis.
FDA noted that in both the olestra and triglyceride groups, the
most frequently reported GI symptoms were abdominal pain, diarrhea, and
flatulence. These symptoms are also the symptoms most commonly reported
to P&G's passive surveillance program. FDA agrees with the petitioner
that in this study, there was no difference in the rate or severity
reported for loose stools or abdominal cramps between subjects who ate
olestra-containing chips and subjects eating triglyceride chips. FDA
examined the percent of subjects reporting at different levels of chip
consumption and found that reports of diarrhea increased for both the
olestra and triglyceride groups with increasing consumption of chips,
but there was no difference in the rate of reporting between the groups
(Refs. 10 and 13).
3. Home Consumption Study
The Home Consumption Study \23\ was designed to measure, under
market use conditions, the effect of eating chips made with olestra on
GI symptoms in adults and children over an extended period of time
(Ref. 14). This double-blind placebo-controlled trial represented 1,138
households (3,181 individuals, ages 2 to 89) randomly assigned to
either the olestra group or the control group. To be enrolled, at least
half the members of the household had to have eaten corn or potato
chips at least four times in the previous month and all members of the
household had to be willing to participate in the 6-week long study. A
contact for each household was identified and was required to return to
the study site once a week for 6 consecutive weeks. During each visit,
the contact could choose from a selection of potato chips and tortilla
chip products labeled as containing either olestra or triglyceride. The
selection of snacks used in the study were products available in the
marketplace presented in typical packaging. To encourage snack
consumption, up to eight bags of chips (varying in weight from 5.5 to 9
oz) could be selected each week. For the households in the olestra
group, the olestra-labeled packages contained olestra chips, but for
the control group, the olestra-labeled packages contained triglyceride
chips. For both groups, the triglyceride-labeled packages contained
triglyceride chips. All olestra-labeled products displayed the olestra
label statement.
---------------------------------------------------------------------------
\23\ Dr. R. Sandler, Professor of Medicine, University of North
Carolina, Chapel Hill, was the principal investigator for this
study.
---------------------------------------------------------------------------
At each weekly visit, the contact would also provide daily records
kept by each member of the household regarding GI symptoms. The
household contact assisted and/or completed the form for children. The
record consisted of a check list of eight specific GI symptoms \24\ as
well as a field to write in any other symptoms. On each day a GI
symptom was recorded, the subject was to rate the effect of those
symptoms on daily activity using a scale ranging from ``noticed but did
not affect'' to ``missed all day at work/school.'' Medication use and
physician visits were also to be recorded.
---------------------------------------------------------------------------
\24\ The list of GI symptoms include the following descriptions:
(1) Heartburn or indigestion, (2) nausea or queasiness, (3)
vomiting, (4) gas, (5) bloating, (6) abdominal cramping or pains,
(7) more frequent bowel movements, and (8) looser stool.
---------------------------------------------------------------------------
There were 1,620 subjects from 568 households in the olestra group
and 1,561 subjects from 570 households in the control group. The groups
were similar with respect to age, sex, and race. Subjects ate chips
frequently throughout the study. The median number of days on which a
subject consumed an olestra-labeled chip was 20 days of a possible 42
days for the olestra group and 21 of a possible 42 days for the control
group. The length of the study and the large number of individuals per
group resulted in a collective period of more than 30,000 ``eating''
days, making it possible to detect small differences in the reporting
of GI symptoms. The median total amount of olestra-labeled chips eaten
over the course of the study by the olestra group (25.2 oz) was
slightly less than that eaten in the control group (27.6 oz). During
the 42-day study, subjects whose consumption was in the top 10 percent
of the olestra group ate more than 59 oz of chips, while in the control
group, the top 10 percent of the group ate more than 70 oz of chips.
The petitioner presented data to show that the rates of olestra
consumption achieved were beyond customary snacking by comparing the
intake of olestra at the 90th percentile of consumption in this study
(13.3 g/d) to Market Research Corp. of America (MRCA) preapproval
estimates (6.4 g/d), and to data collected regarding ``real-world''
olestra consumption in the Active Surveillance Study (2.1 g/d). The
petitioner concluded that the rates of consumption achieved in this
study for both the olestra and triglyceride groups were higher than
usual snack consumption.
The petitioner reported that for its original planned analysis for
the study, which examined the percentage of eating days where GI
symptoms were reported within 2 days, olestra-containing chips resulted
in an increase (p<0.05) in the GI symptoms of more frequent bowel
movements, loose stools, and gas. There was no increase in reports of
abdominal cramping or any of the other individual or total GI symptoms.
The petitioner decided that this analysis could not be clearly
interpreted because olestra labeled chips were eaten on numerous days
of the study and therefore a particular GI event would be associated
with 2 or 3 eating days.
The petitioner presented data from an analysis that compared the
occurrence and frequency of GI symptoms between the olestra and control
groups. The primary response variable was the percentage of individuals
reporting a GI event. For all subjects who consumed olestra-labeled
products, the petitioner found that there was no difference in the
total percentage of subjects reporting a GI symptom between the olestra
and control groups. Of the eight GI symptoms evaluated, the only
difference was an increased number of reports of nausea for the control
group. For those subjects who reported a GI event, the number of
symptom days was also compared. When the petitioner examined the data
by days on which subjects reported symptoms, there was a small increase
in the olestra group in the number of days when more frequent bowel
movements were reported (3.7 days for olestra compared to 2.8 days for
controls; p=0.04). The petitioner calculated that this increase was
about one symptom day out of the 42 days of the study. The petitioner
reported that
[[Page 46374]]
subjects' self assessments showed little or no impact of GI symptoms on
subjects' daily life, and there was no increase in the percentage of
reported severe impacts in the olestra group compared to the control
group.
The petitioner also examined whether there were differences in the
incidence of reported GI symptoms among the different age groups. The
petitioner reported that there were no significant differences in total
or specific GI symptoms between the olestra and triglyceride groups for
children (2 to 12 years; n=885), teens (13 to 17 years; n=227), or the
elderly (65 to 89 years; n=402), even among the highest consumers. This
analysis showed that for adults (18 to 64 years; n=1667), there was an
increased percentage in reporting the GI symptom gas in the olestra
group compared to the control group. There was also an increase in the
number of GI symptom days, and an increase in the number of more
frequent bowel movement symptom days, among adult subjects eating
olestra of approximately one symptom day out of the 42 days of the
study.
Among adult females in the olestra group, compared to adult females
in the control group, there was an increase of approximately one
symptom day out of 42 days of the study with regard to more frequent
bowel movements, gas, and any GI symptom. The only difference regarding
reports of abdominal cramping was an increase in the control compared
to the olestra group for adult males.
The petitioner concluded, based on the subjects' self assessments,
that none of these reported increases in the number of symptom days
were meaningful because there was no impact on subjects' daily
activities. Based on its comparison of the percent of subjects who
reported one or more GI events during the course of the study, P&G
concluded that there were no meaningful or serious GI effects
associated with eating olestra-containing chips.
At the end of the 6-week study, P&G asked participants which kind
of chips they thought they were eating from the olestra-labeled bags.
P&G reported that the percentage of subjects reporting GI symptoms was
greater (approximately 50 percent) in those who believed they were
eating chips made with olestra compared to those who thought they were
eating triglyceride chips. This was true regardless of whether the
participant was actually eating olestra or triglyceride chips.
FDA employed a number of statistical approaches to best address the
different questions to be answered by the study, and while such
differing approaches may yield different answers, this varied approach
provides a more complete picture of the study results. FDA analyzed
both the temporal relationship between consumption and symptoms, and
summation data for the study (Refs. 15 and 16).
Examination of temporal data is important for evaluating an
association between olestra intake and GI symptoms. Such an analysis is
also important because in a study of this length, subjects can modify
their eating behavior based on their experience with a product. FDA
found that subjects in both the olestra and triglyceride groups
modified their intake of chips as a result of experiencing more
frequent bowel movements. FDA was able to conclude that consumers
modify their behavior based on their experience with olestra chips by
examining the amount of chips consumed the day before, the day of, and
the day after a report of more frequent bowel movements. Chip
consumption decreased after experiencing more frequent bowel movements,
although consumption of chips did not cease.
In order to understand the temporal relationship between olestra
consumption and GI symptoms, FDA examined the frequency of GI symptoms
for numerous different patterns of olestra consumption over a period of
several days.\25\ In all these analyses, FDA found that for men,
olestra consumption resulted in an increase in any GI symptom, gas, and
more frequent bowel movements, and a decrease in nausea. For women,
olestra consumption resulted in an increase in any GI symptom, gas,
looser stools, and more frequent bowel movements. On the day that chips
were eaten, the difference in the percentage of occasions that more
frequent bowel movements were reported for the olestra chips compared
to the triglyceride chips was 1.6 percent for males and 1.2 percent for
females. These effects were seen on days of consumption of olestra
chips but not on subsequent days on which olestra-containing chips were
not eaten. When olestra chips were consumed on consecutive days there
was some cumulative effect for the reports of these GI symptoms. This
was particularly true for males. For example, the difference in the
percentage of occasions that a report was made in the category ``any GI
symptom'' for the olestra chips compared to the triglyceride chips
increased from 0.9 percent on the first day to 1.7 percent on the
second day, to 2.6 percent on the third consecutive day that chips were
eaten and a complaint was recorded. There was also a trend for more
frequent and recent consumption of olestra to result in a GI symptom.
While increasing consumption of olestra and triglyceride chips both
resulted in more symptoms, the effect of olestra was greater compared
to triglyceride chips at all doses.
---------------------------------------------------------------------------
\25\ These included determining the percent of occasions for
which GI symptoms occurred on the same day and the following 2 days
of eating an olestra-labeled chip; comparing the frequency of
occurrence of GI symptoms on days that olestra-labeled chips were
eaten to days that chips were not eaten to determine a ``same day of
eating effect''; determining the percent of days on which GI
symptoms were reported for all non-eating days in order to evaluate
possible delayed or continuing effects of olestra; comparing the
percent of days on which GI symptoms were reported to the number of
consecutive days eating olestra-labeled chips in order to examine
possible cumulative effects; for various GI symptoms analyzing the
pattern of consumption of olestra-labeled chips for the days prior
to the GI symptom in order to examine how the most recent day of
eating and the frequency of eating is related to the GI symptom; for
various GI symptoms, determining the amounts of olestra-labeled
chips consumed on the day the GI symptom occurred (Ref. 16).
---------------------------------------------------------------------------
In examining the effect of olestra consumption on different age
groups, FDA found that GI symptoms were primarily seen in the 18 to 64
age group. There were no olestra-related effects in the groups over 65
years or younger than 18 years.
In a separate statistical analysis, FDA focused on the sum total of
symptom days and consumption of olestra-labeled chips over the course
of the 42-day study (summation data). FDA analyzed the data for each GI
symptom for both the entire study population, and for a population
divided based on age and gender.
In the statistical analysis of the sum total of symptom days over
the course of the 42-day study, FDA first examined the relationship
between the reporting of particular GI symptoms and the consumption of
olestra-containing foods by comparing the olestra group and the
triglyceride group. FDA found that for all study subjects (males and
females) over the course of the 42 day study, there was an increase of
0.28 more frequent bowel movement symptom days in the olestra group
compared to the triglyceride group. FDA then examined the relationship
between the reporting of particular GI symptoms and the consumption of
olestra-containing foods by analyzing the olestra group and the
triglyceride group separately by gender. FDA found for females in the
olestra group, there was an increase in ``any GI symptom'' of 0.5 mean
symptom days compared to the females in the triglyceride control. It
was also observed that for females in the olestra group, there was an
increase of 0.3 symptom days in more frequent bowel
[[Page 46375]]
movements over the course of the 42 day study compared to females in
the triglyceride group. For males in the olestra group, the analysis
showed an increase of 0.24 more symptom days for more frequent bowel
movements compared to males in the triglyceride group.
FDA then examined the relationship between the amount of product
consumed and symptoms reported for all study subjects (males and
females), and found there were associations between olestra consumption
and reports of ``any GI symptom'' (p=0.03), loose stools (p=0.006), and
more frequent bowel movements (p=0.002). No such associations were
observed between the consumption of the control chips (triglyceride
chips labeled as olestra) and any measured symptom. When analyzed
separately by gender, both sexes showed trends for an association
between the consumption of olestra and loose stools (males p=0.001,
females p=0.018), and more frequent bowel movements (males p=0.001,
females p=0.042), but only males also showed a trend for an association
between the consumption of olestra and ``any GI symptom'' (p=0.001).
FDA examined the relationship between the consumption of olestra-
containing foods and reports of abdominal cramping. FDA found no
difference in the frequency of reported abdominal cramping between the
olestra group and the triglyceride group. FDA analyzed the olestra and
triglyceride groups separately by gender for reports of abdominal
cramping and found no difference between males or females in the
olestra group as compared to the triglyceride group. FDA agrees with
the petitioner that there was no observed difference in the incidence
or association of reported abdominal cramps between the olestra group
and the triglyceride group (Ref. 10).
4. Stool Composition Study
The Stool Composition Study was sponsored \26\ by the petitioner as
a followup to the preapproval Fecal Parameters Study (discussed
previously in section II.A.2 of this document). The study was designed
to establish whether consumption of olestra-containing foods is
associated with changes in clinical measures of diarrhea (water and
electrolyte loss), effects which may be harmful, or stool consistency
alone, which may result from adding bulk to the stool and which is not
harmful. In addition, the study was designed to determine the
relationship between objective measures of clinical diarrhea (e.g.,
stool water output and bowel movement (BM) frequency) and subjective
reports of ``diarrhea'' from study subjects. The effects of olestra
were compared to a placebo, triglyceride chips, and to sorbitol, an
osmotically active sugar alcohol that was chosen as a positive control
to ensure that the study methodology was adequately sensitive to detect
increases in stool water output.
---------------------------------------------------------------------------
\26\ The GI consultant to the study was Dr. R. Gianella,
University of Cincinnati.
---------------------------------------------------------------------------
The study was a single-site, randomized, double-blind, placebo-
controlled parallel clinical trial. Sixty-six subjects, ages 18 to 74,
were housed on a metabolic ward for 12 days and consumed meals ad
libitum. The meals conformed to the American Heart Association Step I
diet guidelines (no more than 30 percent of calories from fat).
Beverages were available ad libitum. All study subjects had to consume
5 oz of potato chips eaten as two afternoon snacks. A serving of potato
chips was either olestra (test) or triglyceride (placebo). All subjects
were also required to consume 1.5 oz of candy made either with sorbitol
(test) or sucrose (placebo) as a morning snack. The first two days
(study days 1 and 2) were a lead-in period during which subjects were
acclimated to the living conditions and the diet, and consumed placebo
snacks (triglyceride potato chips and sucrose candies). Stool samples
were not collected during the lead-in period. The next 4 days (study
days 3 to 6) comprised the baseline period, in which subjects continued
to consume placebo snacks, and all stool samples, BM ratings, and GI
symptoms were collected. For the final 6 days (study days 7 to 12),
subjects consumed snacks according to their randomly assigned treatment
group, and all stool samples, bowel movement ratings, and GI symptom
reports were collected. There were two olestra test groups (20 g and 40
g olestra) and two control groups (positive control of 40 g sorbitol
and placebo). The placebo group consumed two servings of placebo
(triglyceride) potato chips and placebo (sucrose) candy. The positive
control group consumed two servings of placebo potato chips and test
candy (40 g sorbitol). The 20 g olestra test group consumed one serving
of test potato chips (olestra), one serving of placebo potato chips,
and placebo candy. The 40 g olestra group consumed two servings of test
chips and placebo candy.
The petitioner noted that in the study the doses of olestra were
threefold to sixfold more than the estimated daily intake, and 10 to 20
times more than the observed intake at the 90th percentile level in the
Active Surveillance Study (see section III.D.1 of this document). The
high dose, 40 g/d, was higher than the highest dose used in the
preapproval nutrition studies (32 g/d) described previously in section
II.A.3 of this document, in which the high dose group experienced an
increase in GI symptoms, specifically in reported diarrhea/loose
stools. In that preapproval study, FDA concluded that the reported
diarrhea was not diarrhea in the medical sense because there was no
evidence of subjects experiencing significant fluid or electrolyte loss
(hemoconcentration, electrolyte imbalance; 61 FR 3118 at 3152-3154).
The petitioner concluded that with regard to the critical
parameters that are medically relevant in defining diarrhea, the
objective measures showed that olestra did not meaningfully change
either the total stool output or stool water output, while sorbitol
produced large effects on both parameters. Compared to baseline, mean
stool water output increased 9 g/d and 37 g/d for the 20 and the 40 g/d
olestra groups respectively, and 325 g/d for the 40 g/d sorbitol group.
Stool water output decreased 28 g/d for placebo. The measured mean
stool water content for the sorbitol group was nearly 10 times greater
than the group consuming the highest level of olestra and the number of
watery BMs was 140 in the sorbitol group, one in the 40 g/d olestra
group, none in the 20 g/d, and one in placebo. While sorbitol
significantly increased the severity of abdominal cramping compared to
placebo, olestra did not. The petitioner found that olestra consumption
did not result in any clinically meaningful increases in objective
measures of diarrhea, namely, total stool output, bowel movement
frequency, and stool water and electrolyte output. The mean number of
BMs for the olestra 40 g/d group was increased compared to placebo but
was not increased compared to the olestra 20 g/d group. Subject reports
of ``watery, difficult to control diarrhea'' did not necessarily
correlate with measured viscosity of the stool. Olestra did increase
stool weight in proportion to the amount eaten, and daily consumption
of olestra gradually softened stool in a dose-responsive manner. The
sponsor found that there was increased reporting of ``diarrhea'' in the
olestra treatment groups during the treatment phase without an increase
in total water output outside the normal range, i.e., the range
observed during the baseline period and in the placebo group.
P&G concluded, based upon the study results, that the consumption
of olestra
[[Page 46376]]
does not cause diarrhea, but simply adds bulk and softening to the
stool.
FDA reviewed the data from this study and agrees with the
petitioner's analysis, although some of the agency's analytical
strategies differed from those of the sponsor (Ref. 17). FDA concludes
that both comparisons of the mean after treatment and of changes from
baseline showed dose responsive increases in stool characteristics
(total output, water output, consistency, frequency and increases in
water content) that were not clinically significant (Ref. 18).
Using a 7-point scale to rate consistency of bowel movements (1 =
watery, diarrhea; 4 = normal; 7 = hard, constipation), subjective
ratings of stool consistency showed that subjects who ate 40 g/d
olestra perceived their stools to be looser (mean rating 2.4) compared
to those who ate 20 g/d olestra (mean rating 3.1). By comparison,
placebo subjects had a mean score of 3.9 whereas those subjects in the
40 g/d sorbitol group had a mean score of 1.5 (mean scores determined
for days subjects consumed snacks according to their randomly assigned
treatment group). When stool consistency was measured by peak force
value for extrusion, both olestra groups had a lower mean stool
consistency than placebo and the 40 g/d olestra group was lower than
the 20 g/d group. These dose responsive findings seen among subjects
eating olestra resulted from gradual stool softening effects observed
after several consecutive days of olestra consumption. Although
subjects characterized these viscosity changes as ``diarrhea,'' the
changes were not associated with an increase in stool water.
FDA examined the percentage of symptom days for cramping and found
that although the 40 g/d olestra group reported an increased incidence
of abdominal cramping compared to those in the 20 g/d olestra group
(35.8 percent compared to 9.8 percent), this difference did not rise to
statistical significance. The percentage of subjects reporting
abdominal cramping in the 20 g/d olestra group appeared to decrease
when compared to baseline or placebo (9.8 percent compared to 20.5
percent or 18.3 percent). The 40 g/d sorbitol group had the highest
percentage (69.8 percent) of reports of cramping. Subjects rated
symptom severity on a scale of 0 to 5, with 0 representing none and 5
extreme. The severity of cramps reported by subjects in the olestra 40
g/d group was less severe than that reported by subjects in the 40 g/d
sorbitol group (0.72 compared to 2.3). No significant olestra effects
were found for GI symptom severity, although one individual in the 20
g/d olestra group reported severe urgency at a rating higher than any
other report in any of the other groups (Refs. 10 and 18).
5. Comments Regarding the GI Studies
FDA received comments about the new GI studies. FDA considered
these comments and responds in the following paragraphs. Comments
regarding the label statement for GI effects will be discussed in
section V of this document.
(Comment 5) A comment from CSPI to the current petition criticized
the Rechallenge Study. The comment stated that the study subjects were
not screened for sensitivity to olestra, as was done in the preapproval
Fecal Parameters Study. The comment also asserted that the Rechallenge
Study contained a strong likelihood of bias because only 10 percent of
those contacted agreed to participate in the rechallenge and those that
did participate consumed olestra on only 2 days, at least 1 week apart,
which reduced the sensitivity of the study. CSPI asserted that the
Rechallenge Study also assumed that those sensitive to olestra would
respond to it 100 percent of the time. The comment contended that those
experiencing adverse reactions may only do so under certain
circumstances, not 100 percent of the time.
FDA does not agree that the selection of study subjects biased the
Rechallenge Study nor does CSPI provide such evidence. FDA has
determined that the subjects who participated in the Rechallenge Study
were adequately representative of those persons who contacted the
postmarketing surveillance system in terms of severity of initial
symptoms and amount of olestra reportedly consumed prior to the initial
symptom episode (Ref. 11). Further, CSPI provided no basis for its
assertion that additional subject screening is necessary to accomplish
the objectives of the Rechallenge Study.
CSPI states that the sensitivity of the Rechallenge Study was
reduced because participants consumed olestra on only 2 days, at least
1 week apart. The conditions of the study were designed to be similar
to the conditions under which the subjects originally reported effects
that they attributed to consuming an olestra-containing snack. FDA
found that for nearly three-quarters of the subjects, the amount of
olestra consumed in the study was comparable to, or greater than, the
amount associated with their initial symptom episode (Ref. 11). In
addition, more than three-quarters of the subjects reported that their
initial symptom episode occurred after a single eating occasion.
Therefore, subjects were challenged with 2 oz of olestra chips on two
occasions separated by a week, providing a dose and number of exposures
comparable to, or greater than, those associated with many of the
subjects' initial symptom episodes.
CSPI's comment did not reference where FDA or the petitioner
assumed that those sensitive to olestra would respond to it 100 percent
of the time, nor is FDA aware of anyone who has put forth such a
position. Indeed, FDA agrees that even if an individual experiences a
reaction to olestra, that individual may not experience such reaction
after every exposure. The Rechallenge Study shows that subjects exposed
to olestra containing-chips were no more likely to report GI symptoms
than when exposed to an equal amount of triglyceride chips. Thus, the
study subjects' reactions to olestra containing-chips are not so
frequent that they can be distinguished from their reactions to regular
chips under the conditions of the test.
(Comment 6) A comment from CSPI to the current petition criticized
the Acute Consumption Study. CSPI's comment relies on its published
letter \27\ commenting on a published study (Ref 12.) that reports data
from the Acute Consumption Study. CSPI stated that the study may have
failed to detect the true incidence of GI effects due to a lack of
statistical power or inadequate controls. For example, with the
incidence of ``any GI event'' of about 15 percent, 550 subjects in each
group would have provided only about a 50 percent probability of
detecting a 5 percent actual increase in the treatment group. Along the
same lines, diarrhea and loose stools were increased less than 1
percent in the olestra group compared to baseline levels of 2.6 percent
and 1.1 percent, respectively. The comment asserted that maintaining 80
percent power to detect a 1 percent increase over a 2 percent baseline
requires about 4,000 subjects per group. The comment also contends that
the darkened movie theater may potentially cause exposure
misclassification (some ``olestra eaters'' may have eaten few or none
of their chips; some ``non-olestra eaters'' may have eaten friends'
olestra chips). The comment also stated that it took up to 10 days
after consumption to assess symptoms. CSPI also pointed out that non-
olestra eaters consumed one-third more chips than the olestra eaters.
---------------------------------------------------------------------------
\27\ CSPI's published letter was included in the comment as an
attachment (Ref. 19).
---------------------------------------------------------------------------
The criticism by CSPI of the Acute Consumption Study does not
negate the
[[Page 46377]]
conclusion that FDA reached in its analysis of the study. The Acute
Consumption Study was conducted to provide information relevant to
whether olestra-containing foods should bear a label statement that
informs consumers about the potential GI effects associated with
olestra. FDA points out that the Acute Consumption Study was only one
of several studies under consideration in this petition, and that the
agency's decision on the petition is based on the totality of evidence
in the record.
While the petitioner's Acute Consumption Study did not achieve the
statistical power that P&G originally desired (80 percent power to
detect a 5 percent difference between treatment groups), the study
still provides meaningful information concerning the effect of olestra-
containing foods on the GI system. FDA's scientific review determined
that the study does have 80 percent power to detect a 7 percent
difference between treatment groups (Ref. 13). The study showed that
there was no difference in the rate or severity of loose stools or
abdominal cramps between subjects who ate olestra-containing chips
compared to those who ate triglyceride-containing chips.
The comment provides no evidence that the darkened theater or the
method used to collect symptom data affected the outcome of the study.
As discussed previously, the study protocol was designed to minimize
the possibility of inaccurate measurements or subjects' sharing of
chips. For example, study participants were instructed to be seated in
the theater at least one seat away from other participants and not to
share their chips or beverage with anyone else. The theaters were also
monitored by several staff during the movie.
Similarly, the comment did not explain the effect on the study
results, if any, from the 10-day period used to assess symptoms. After
the movie, trained telephone interviewers contacted study participants
and administered a recall questionnaire to collect information on any
effects experienced since the movie. The study protocol specified that
participants be contacted within 2 to 4 days of viewing the movie. The
petitioner reported that 85 percent of study subjects (962 of the
1,092) were contacted within 2 to 4 days of viewing the movie, an
additional 124 subjects were contacted in 5 to 10 days.\28\
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\28\ Of the remaining subjects, three were contacted on the day
of the movie, one within a day, and two within 23 days (Ref. 13).
---------------------------------------------------------------------------
FDA agrees that the median chip consumption for the control group
was greater than that for the olestra group. As discussed previously,
the Acute Consumption Study was designed to be an ad libitum study,
allowing the investigators to examine the effects of customary or usual
consumption. As an ad libitum study, it is possible that one group of
subjects may consume more chips than the other. For example, the median
consumption of chips made with olestra was 2.1 oz compared to 2.7 oz
for chips made with conventional triglycerides. CSPI did not explain
how the fact that one group of subjects ate more chips than the other
affects the conclusions drawn from this study regarding the need for
special labeling.
(Comment 7) A comment from CSPI to the current petition criticized
the Home Consumption Study. CSPI's comment relies on its published
letter \29\ commenting on a published study that reports data from the
Home Consumption Study (Ref. 14). The comment raises five issues: (1)
The comment stated that some of the data relating to the highest decile
of olestra consumers were overlooked; (2) the comment argued that it is
important to focus on the small number of heavier consumers because
most subjects ate relatively few olestra-containing chips; (3) the
comment stated that in the highest decile of olestra consumers the
incidence of more frequent bowel movements and loose stools was twice
that of controls; (4) the comment stated that olestra consumers in the
highest decile had symptoms on 18 percent of person-days, compared to
12 percent of person-days in the control group (table 4 in Ref. 14);
and (5) the comment pointed out that olestra consumers missed some or
all of their activities on 0.4 percent of days, compared to 0.2 percent
in the control group.
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\29\ CSPI's published letter was included in its comment as an
attachment (Ref. 20).
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Prior to publication of the article concerning the Home Consumption
Study (Ref. 14), FDA conducted its own indepth analysis of the raw data
from the Home Consumption Study (Refs. 15 and 16) and described this
analysis at the 1998 FAC meeting in which CSPI participated. FDA's
analysis included an estimate of the extra symptom-days experienced by
subjects in both the 90th and 95th percentile of olestra-containing
chip consumption (Ref. 15). Subjects at the 90th percentile ate 64 oz
of olestra-containing chips over the course of the study while those at
the 95th percentile ate 83 oz of olestra-containing chips over the
course of the study. Although CSPI alleges that the subjects in the
study ate relatively few olestra-containing foods, the petitioner
presented data to show that, in fact, the rates of olestra consumption
achieved in the study were beyond usual snack consumption.
As part of the Home Consumption Study, the investigators considered
the effect of GI symptoms on subjects' daily activities. In its
comment, CSPI points out that olestra consumers missed some or all of
their activities on 0.4 percent of days, compared to 0.2 percent in the
control group, implying that this is significant. FDA disagrees.
CSPI does not explain how it calculated the percentage of days on
which subjects missed some or all of their activities, nor does CSPI
provide statistical analyses to assess whether these differences
occurred by random chance (e.g., illness unrelated to olestra). FDA was
able to replicate the numbers that CSPI presented and performed tests
of statistical significance on the data. The actual number of days on
which subjects in the highest decile missed some or all of their
activities is very small (9 of 2,226 days in the olestra group versus 5
of 2,646 days in the control group). Five subjects in the olestra group
and four subjects in the control group missed some or all activities at
least 1 day. The number of subjects missing activities and the number
of days missed by these subjects are comparable for the olestra and
control groups, except for one subject in the olestra group who missed
some or all activities on 4 days (Ref. 21).\30\ From these data, it
cannot be concluded that for the highest decile of consumers olestra
consumption resulted in an increase in days in which consumers missed
some or all activities. FDA believes that the Home Consumption Study,
designed to examine the effects of ``real life'' olestra consumption,
provides useful information relevant to the labeling of olestra-
containing foods. CSPI does not show how their analysis would change
FDA's conclusions.
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\30\ Sophisticated statistical models are impractical for such a
small number of cases. However, a Fisher's Exact test showed that
the proportion of subjects in the olestra group who missed some or
all activity at least 1 day was not significantly different (p-value
of 0.73) from the proportion of subjects in the control group who
missed some or all activity at least 1 day.
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(Comment 8) A comment from CSPI to the current petition criticized
the petitioner's Stool Composition Study. The comment stated that this
study does not negate and should not supersede the two preapproval 8-
week studies or the preapproval Fecal Parameters Study. In its comment,
CSPI cites a 1995 FDA memorandum discussing the Fecal Parameters Study
(Ref. 22) and asserts that the memorandum says that several
[[Page 46378]]
subjects in the study experienced high rates of water loss through
their stool. The comment also stated that the definition of diarrhea
used in the Stool Composition Study was too narrow and is not
consistent with the definition used by the Centers for Disease Control
and Prevention (CDC; three or more loose stools in a 24 hour period).
The comment asserted that self-reporting is usually considered
sufficient to conclude that people experience diarrhea regardless of
demonstrated loss of electrolytes.
In contrast to the Acute Consumption Study, the Home Consumption
Study, and the Rechallenge Study, the Stool Composition Study was
designed to extend the understanding of olestra's effect on stool
characteristics that would potentially represent a safety concern. For
this reason, the Stool Composition Study was conducted under conditions
most likely to elicit GI effects. The highest dose of olestra provided
in the Stool Composition Study (40 g/d) was greater than the 32 g/d
used in the preapproval 8-week studies which was shown to cause an
increase in GI symptoms (specifically in reported diarrhea/loose
stools) and was twice as high as the highest dose given in the
preapproval Fecal Parameters Study (20 g/d). Additionally, subjects'
stool samples were collected for all 6 days of the treatment period in
the Stool Composition Study, compared to only three days of the 7-day
treatment periods in the Fecal Parameters Study. The Stool Composition
Study does not negate the preapproval studies, but the results of the
preapproval studies must be considered in light of those from the Stool
Composition Study.
The results of the Stool Composition Study show that olestra
consumption does not result in any clinically meaningful increases in
the objective measures of diarrhea. Importantly, the Stool Composition
Study assessed the effects of olestra consumption using objective
parameters such as total stool output, bowel movement frequency,\31\
and stool water and electrolyte output rather than a subject's
subjective assessment of whether he or she experienced diarrhea. The
use of objective measures of diarrhea is necessary to assess whether
the ``diarrhea'' experienced by study subjects represents a safety
concern.
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\31\ FDA notes that the mean bowel movement frequencies in the
olestra-consuming groups were less than three bowel movements per
day. The mean bowel movement frequencies were 1.6 +/- 0.2 BM/d (mean
+/- standard error) in the 20 g/d olestra group and 2.0 +/- 0.2 BM/d
(mean +/- standard error) in the 40 g/d olestra group (Ref. 18).
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FDA was concerned with the potential for olestra to cause diarrhea
because diarrhea of medical significance is associated with excessive
water loss and electrolyte loss, which may raise safety concerns. The
Fecal Parameters Study memorandum cited by the comment states that the
stool water concentration of subjects who reported having diarrhea
during the olestra 20 g/d period did not differ from that of their
nondiarrheal stools during the placebo period. The memorandum also
states that although the percent of water in the stools may not have
differed, it is possible that absolute water loss was greater in
subjects reporting olestra-associated diarrhea because of the greater
mass (weight) of stool passed. FDA concluded in the 1996 final rule
that the loose stools experienced in the preapproval clinical studies
were not diarrhea in the medical sense because they were not associated
with loss of water or electrolytes (61 FR 3118 at 3159). The agency
also stated that even those subjects in the 8-week studies who
experienced loose stools or diarrhea continuously for several weeks
during olestra consumption did not show any evidence of fluid loss such
as hemoconcentration or electrolyte imbalance. Thus, the agency
determined that olestra-related GI effects were not adverse health
effects (61 FR 3159). The results of the Stool Composition Study
confirm the agency's 1996 decision that the GI effects resulting from
olestra consumption do not represent adverse health effects, regardless
of the terminology (diarrhea or otherwise) used to describe these
effects.
D. A Study Regarding Nutritional Effects--Active Surveillance
As discussed previously in section II of this document, olestra is
neither digested nor absorbed, and as such, passes intact through the
digestive tract where it can interact with fat-soluble dietary
components present in the gut at the same time. Fat-soluble nutrients
and components tend to partition or dissolve into the olestra, thereby
reducing the absorption efficiency of these substances (61 FR 3118 at
3144-3149). Olestra does not interfere with the absorption of macro-
nutrients (protein, carbohydrates, and fats) or water-soluble nutrients
(61 FR 3118 at 3149-3152). The clinical studies conducted in support of
the 1996 final rule examining the effect of olestra on fat-soluble
components of the diet were performed under conditions that maximized
the interaction of olestra with these dietary components, i.e., olestra
was incorporated into foods eaten at every meal. These studies were not
designed to examine effects from the usual or customary consumption of
savory snacks made with olestra (see section II.A.3 of this document).
To compensate for the effect of olestra on the absorption of the
fat-soluble vitamins A, D, E, and K, FDA required that these vitamins
be added to olestra-containing foods. The level of addition was chosen
to ensure that there would be neither a reduction in the absorption of
fat-soluble vitamins from the diet, nor an increase in vitamin levels
due to the presence of the added vitamins in the olestra-containing
foods (see section II.A.3 of this document). Although FDA noted that
olestra interferes with the absorption of carotenoids, FDA found no
scientific basis for requiring the addition of any carotenoid to
olestra-containing foods (61 FR 3118 at 3147-3149).
As outlined by the petitioner in its January 24, 1996, letter to
the agency, P&G established a program of active surveillance. A report
of this surveillance with results and analysis from the first year at
the sentinel site was submitted to the agency on April 15, 1998.
Additionally, the agency has continued to review and evaluate new data
and information that bear on the safe use of olestra, such as new data
and information on the health significance of carotenoids.
1. Active Surveillance Study by P&G
The petitioner provided funding to investigators at the Fred
Hutchinson Cancer Research Center in Seattle, WA, to design and
implement a multi-year, Active Surveillance Study to monitor patterns
of use of olestra-containing savory snack products and to collect blood
samples to measure nutrient status (Ref. 23). The study had three
specific goals: (1) To monitor adoption and patterns of use of olestra-
containing savory snack products in representative samples of the U.S.
population; (2) to assess the association between the introduction of
olestra-containing savory snacks and serum concentrations of
carotenoids and fat-soluble vitamins in representative cross-sectional
samples of the U.S. population; and (3) to assess the long-term
association between consumption of olestra-containing savory snacks and
serum concentrations of carotenoids and fat-soluble vitamins among a
cohort of olestra consumers.
The study has three components corresponding to the three specific
aims. The first component, called the population cross-section, was a
telephone survey used to monitor the prevalence and patterns of
olestra-containing savory snack consumption,
[[Page 46379]]
fruit and vegetable consumption, and triglyceride savory snack food
consumption by consumers. Demographic information was collected as
well. A telephone survey was conducted in each of the study sites
before olestra-containing snacks were marketed. Subsequent yearly
surveys were completed after olestra-containing snacks were introduced
to the market.
A random sample of participants in each telephone cross-section
sample was recruited into the second component, a clinical cross-
section. The clinical cross-section was an investigation of the
relationships among nutrient intake, olestra consumption, and serum
nutrients. Study participants visited a clinic to provide further
information, including dietary information, medical histories, and
blood samples. Followup telephone interviews included questions about
usual fruit, vegetable, and snack food use during the previous month, a
24-hour dietary recall to measure co-consumption of fruits and
vegetables with savory snacks, health symptoms and status, and a short
household food inventory.
Within the clinical cross-section, information on olestra intake
was used to select olestra users from non-users to be recruited into
the third component of the Active Surveillance Study, i.e., the
clinical cohort study. The clinical cohort study was an investigation
of the relationships among nutrient intake, olestra consumption, and
changes in serum nutrients over time. Participants in the clinical
cohort are a subset of those people who participated in the Year 0
clinical cross-section and were monitored annually over the course of
the Active Surveillance Study. The clinical cohort was designed to have
an over-representation of consumers of olestra-containing snack food.
The design for the clinic visit and the information gathered is the
same as for the clinical cross-section.
The study was conducted in four U.S. cities. As of the publication
of this document, data are available only from the sentinel site,
Marion County, IN, where test marketing began in 1997.\32\ The study
began one year later in the other cities, because national marketing of
olestra-containing foods in those areas began later.
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\32\ The other three cities in the Active Surveillance Study
were Baltimore, MD, San Diego, CA, and Minneapolis, MN.
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The first component of the active surveillance is the population
cross-section. A random-digit-dial telephone survey of Marion County,
IN, residents was completed before olestra-containing foods were
marketed in that area (February 1997). This survey (Year 0) included
1,962 adults, aged 18 years and over. The second telephone survey was
completed after olestra-containing foods were introduced to the local
market (between August 1997 and January 1998). This survey (Year 1)
included 1,525 adults, aged 18 years and over. Based on the Year 1
data, which are weighted to be representative of the Marion County
population, 15.5 percent of adults reported eating olestra-containing
snacks one or more times per month with the median frequency being
three times per month. Ninety percent of adults reported eating one or
more servings of fruits and vegetables per day, thus providing a basis
for assessment of any effects on dietary carotenoid absorption. Intake
of fruits and vegetables and intake of total snacks did not change in
the population cross-section between Year 0 and Year 1. Olestra-
containing snack food introduction was not associated with an overall
increase in savory snack consumption or with a decrease in fruit and
vegetable intakes. There was a modest decrease in consumption of
reduced- and non-fat savory snacks at Year 1 compared to Year 0.
Blood sera from study subjects, in both the cross-sectional and
clinical cohorts, were analyzed for vitamins A, D, E, and K, total
cholesterol, high density lipoprotein (HDL) and triglycerides, and the
six major carotenoids that represent more than 90 percent of the
circulating carotenoids (alpha and beta carotene, lycopene, lutein,
zeaxanthin, and beta-cryptoxanthin). The study investigators then
compared these serum measures based on olestra intake. Four olestra
consumption groups were defined: (1) None; (2) low (less than 0.4 g/d
of olestra, which is less than the 60th percentile of consumption); (3)
medium (between 0.4 and 2.0 g/d of olestra, which is between the 60th
and 90th percentiles of consumption); and (4) high (greater than 2 g/d,
which is greater than the 90th percentile of consumption).
Results from the cross-sectional study comparing 1,252 subjects in
year 0, and 1,164 subjects in year 1, show that with increasing olestra
intake, there were significant trends for an increase in vitamin K
levels (p = 0.013) and a decrease in serum cholesterol (p = <0.05).
There were no significant differences or trends found for other
vitamins or for total carotenoid or individual carotenoids that could
be associated with olestra consumption.
For the clinical cohort (477 study participants), the sponsor
reported that for the entire cohort from year 0 to year 1, there was a
decrease in mean serum concentrations of total carotenoids, as well as
in concentrations of retinol, 25-OH vitamin D, lycopene, lutein, and
zeaxanthin, and an increase in beta-cryptoxanthin. Tests of association
between olestra consumption and changes in serum concentrations of fat-
soluble vitamins and carotenoids were based on regression models that
included variables to characterize the four levels of olestra
consumption. However, these changes were not related to the amount of
olestra consumed. A trend was observed for increased vitamin K, but the
change did not reach statistical significance (p = 0.087). There were
no changes observed for the other vitamins.
The petitioner cautioned that the results discussed previously
reflect data from only the first year that olestra products were
marketed, and that data were available from only a single site. With
these caveats, the petitioner reached the tentative conclusion that it
appeared that the consumption of olestra-containing foods in the
marketplace had little, if any, effect on the status of fat-soluble
vitamins and nutrients as measured by serum concentration.
FDA notes that survey results show that the co-consumption of
savory snacks (made with or without olestra) with a fruit or vegetable
was relatively rare. Overall, less than 15 percent of total carotenoids
were consumed with any savory snack. Olestra's effect on the absorption
of fat-soluble carotenoids is greatest when co-consumed with the source
of the carotenoid. Interference with absorption of carotenoids
diminishes and then disappears as the time between eating an olestra-
containing food and a carotenoid-containing product increases.\33\
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\33\ The precise length of time olestra interferes with
absorption varies with the dose of olestra, and also varies somewhat
from individual to individual, as GI transit time is variable among
individuals (61 FR 3118 at 3144).
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In the clinical cross-sectional sample, 217 of 947 individuals
reported eating at least one olestra-containing food in the previous
month with a median intake of 8.1 g of olestra per month. The 90th
percentile consumption level was 64 g of olestra per month. Of the 402
clinical cohort participants who were considered consumers of olestra,
only 139 reported eating any olestra-containing foods in the previous
month. The median frequency of eating olestra-containing foods for this
group of consumers was 1.01 times per month with a median intake of
11.9 g of olestra per month. The 90th percentile
[[Page 46380]]
frequency of eating olestra-containing foods was six times per month
with a 90th percentile intake total of 70.6 g of olestra per month.
FDA notes the infrequent and small olestra ingestion reported in
the study. These