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NEWSLETTER
July 2007
Volume 7, Issue 2
fusing science and compliance ©
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James Griffiths, Ph.D.
BOOTH
Traditionally, when a regulator, a consultant,
or an ingredient marketer thought of "claims,"
they pigeon-holed them into two broad categories,
(1) structure / function claims (SFC) or (2) health
claims/qualified health claims (HC/QHC). Dietary
supplement ingredients and food ingredients were
usually thought to be able to use one but not the
other. And for the most part, that has been and
continues to be true. If one takes a look at an oatbased cereal, there will be a bona fide FDA qualified health claim, allowing manufacturers to say
that soluble fiber from whole oats, oat bran, or oat
flour "as part of a low-saturated-fat, lowcholesterol diet, may reduce the risk of heart disease." On the other hand, a bottle of dietary supplement tablets will carry a bona fide structure /
function claim, allowing a glucosamine product to
state that it “helps support healthy cartilage and
joint function." So for most observers, the dichotomy is clear, a food carries a QHC and a dietary
supplement carries a SFC.
But that dichotomy is changing, and with
guidance spelled out in a recent FDA document
(http://www.cfsan.fda.gov/~dms/flguid.html;
http://www.cfsan.fda.gov/~dms/labstruc.html),
structure / function claims will change even faster.
Supplements do not seem to be focused on generating the necessary safety and efficacy data to
broach health claims—but foods are sporting new
and informative SFCs of their own. One popular
yogurt now “helps naturally regulate your digestive system." A claim, interestingly enough, that
the yogurt company did not have to pass by the
FDA, as required for a supplement SFC, or bear
the supplement’s disclaimer that the “…statement
has not been evaluated by the Food and Drug
Administration. This product is not intended to
#3722
EVENTS
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STRUCTURE/FUNCTION CLAIMS &
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CONTENTS
1 Structure / Function Claims - Not Just
for Supplements Anymore
1 Indirect Additive or GRAS Ingredient?
2 In The News…
2 Did You Know?
3 AER Law Takes Effect December 2007
4 Recent Publications
4 Upcoming Events
diagnose, treat, cure or prevent any disease.”
Use of a structure / function claim for a food
does come with three stipulations. The most critical is that all of the ingredients in the food, including whatever ingredient(s) is/are providing the
functionality, MUST be approved food ingredients. The only two paths for a new ingredient are
via a FDA food additive petition (FAP), or
through a Generally Recognized As Safe (GRAS)
determination. In both cases, the approval for a
new food ingredient is based solely upon safety.
When the new food ingredient has jumped
the safety hurdle, and has been approved for use
as a food ingredient, the next requirement, efficacy, is then in play. Because the FDA states that
the claim “must be truthful and not misleading,”
there must be a sufficiently robust and persuasive
human clinical study to provide a truthful SFC.
The study’s protocol design, statistical power,
relevant endpoints, inclusion/exclusion parameters
for the subjects, length of testing, etc., are all
germane to the clinical study, and all may be
modified to generate the final burden of a truthful
claim.
The third and final requirement is that the
claim must derive from the use of the functional
ingredient –contained within the food; that is, the
ingredient upon which the claim is based must
(also) have some utility in the food, i.e., provide
either nutritional value, taste, and/or aroma. This
requirement is to prevent using food simply as a
delivery system for the functional ingredient. This
is important, as back in the mid-1980s, a specific
food—Nutrilab’s “Starch-Blocker”—was ruled
“not a food” because the kidney bean ingredient to
promote the SFC did NOT contribute to the food’s
attributes of “taste, aroma
(Continued on page 3)
George Burdock, Ph.D. and Amy Mozingo, M.S.
The case of Monsanto v. Kennedy forever established the fact that food contact materials (such as
packaging ingredients) obey the Second Law of Thermodynamics, i.e., “the entropy of an isolated system
not in equilibrium will tend to increase over time, approaching a maximum value at equilibrium” – sometimes called the “diffusion principle.” In the circumstance of a food and its wrapper, the Second Law of
Thermodynamics dictates that components of the wrapper become part of food, albeit “indirectly.” However, this act of becoming a part of food, satisfies one of the criteria for classification as a food additive,
as according to the Federal Food Drug and Cosmetic Act (FFDCA)(§201(s))
(Continued on page 3)
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Page 1
Volume 7, Issue 2
Page 2
POSTER PRESENTATION
DID YOU KNOW ?
D-Fumonisin Production is Necessary for Development of the Full
Spectrum of Symptoms Indicative
of Fusarium verticillioides MaizeSeedling Disease and Evidence for
Disruption of Sphingolipid Metabolism as the Proximate Cause
S
L.D. Williams, A.E. Glenn, C.W. Bacon,
M.A. Smith and R.T. Riley
O
POSTER PRESENTATION
D-Ribose has Non-Significant Toxicity in Both
Short and Long Term Supplementation
J.C. Griffiths1 & J. A. St. Cyr2
T
PLATFORM PRESENTATION
Pharmacokinetic and developmental safety
evaluation studies of methylsulfonylmethane
(OptiMSM®) in rats
2
R.A. Matulka & B. Magnuson
0
T O X I C O L O G Y!
C
O N G R A T U L A T I O N S
B URDOCK G ROUP S TUDENT TRAVEL A WARD
RECIPIENTS :
M ICHELLE L A M ERILL , A LISON H EGE ,
J ENIFER P HILLIPS & N ATALIE J OHNSON
TO THE
7
AT BURDOCK GROUP
WE SPEAK YOUR LANGUAGE ©
0
A little fun at the FS3 Annual Meeting.
From the left: Drs. Borzelleca, Doull &
Williams
PSYLLIUM in granular form in over-the-counter (OTC) laxative
drug products are not generally recognized as safe and effective
(GRASE) and are misbranded, according to a FDA final rule. FDA
is issuing this final rule after considering reports of esophageal
obstruction associated with the use of psyllium laxatives. The final
rule becomes effective October 1, 2007 and does not apply to
psyllium laxatives in non-granular dosage forms, such as powders,
tablets, or wafers. (Federal Register, March 29, 2007 (Volume 72,
Number 60)).
OBESITY prevalence more than doubled over 25 years among
adolescent males and females, and the prevalence of obesity quadrupled over 25 years among boys and girls, making obesity the
major health care challenge for the 21st century, according to the
American Obesity Association. www.obesity.org/subs/fastfacts/
obesity_youth.html.
XYLITOL is used as a sugar substitute. The ASPCA Animal Poison Control Center cautions animal owners that xylitol, found in
certain sugar-free chewing gums, candies, baked goods and other
products can potentially cause serious (i.e., liver failure) and even
life-threatening problems for pets. http://www.aspca.org/.
Glycerin is a sweetener commonly used worldwide in liquid overthe-counter and prescription drug products. FDA warned pharmaceutical manufacturers, suppliers, and healthcare professionals of
the importance of assuring that glycerin used in products is not
contaminated with diethylene glycol (DEG), a known poison used
in antifreeze, due to potential fatality. FDA issued guidance to
industry recommending methods of testing glycerin to identify any
contamination with DEG. http://www.fda.gov/OHRMS/
DOCKETS/98fr/E7-8389.pdf.
Insomnia. Relatively healthy individuals who experience sleep
disruptions at night appear to have an increased risk activity of
factors associated with the development of a blood clot
(thrombus). Sleep disruption was initially associated with procoagulant activity in patients with obstructive sleep apnea, and in
patients facing major life stress, according to a recent article in
Chest (March, 2007).
Vitamin D (1,25D3) may sensitize tumor cells to chemotherapy
drugs, thereby providing a more effective therapeutic cancer treatment, according to a recent study (AACR, April 14, 2007).
Bronchiolitis obliterans, a severe lung disease is detected among
food flavoring plant workers as a result of inhaling the chemical
diacetyl, which has been known to cause the same problem among
workers in the microwave popcorn industry, according to CDC
(U.S. Centers for Disease Control and Prevention).
Soy isoflavones may impact LDL-cholesterol levels and soy proteins with or without isoflavones can decrease LDL levels and
increase HDL levels, a result that does impact beneficially on
heart health according to a recent article in the American Journal
of Clinical Nutrition (April 2007, Volume 85, Number 4, Pages
1148-1156).
Estrogen, a recent study, part of the Women's Health Initiative
Memory Study found that women who used any form of estrogen
hormone therapy before the age of 65 were nearly 50% less likely
to develop Alzheimer's disease or dementia (AAN Press Release,
5/2/07).
www.burdockgroup.com
Volume 7, Issue 2
Page 3
(Continued from page 1) “Indirect Additives or GRAS Ingredient?”
by
Ioana G. Carabin, M.D. and Ray Matulka, Ph.D.
The Dietary Supplement and Nonprescription Drug
Consumer Protection Act, also known as the “AER law”,
requires dietary supplement and over-the-counter (OTC) product manufacturers to submit serious adverse event reports (AERs) to the Food and
Drug Administration (FDA) starting December 2007.
Twelve years after the Dietary Supplement Health and Education
Act (DSHEA) was signed into law, the “AER bill” was passed unanimously by the Senate and approved by a two-third majority in the House
in December 2006. The bill was signed into law by President George W.
Bush on December 22, 2006 (Law No. 109-462). The “AER bill” was
originally sponsored by Senators Orrin Hatch (R-Utah), Tom Harkin (DIowa), Dick Durbin (D-Illinois), Michael Enzi (R-Wyoming), and Edward Kennedy (D-Massachusetts), and was introduced in the US Senate
in June 2006 and the US House of Representatives in September 2006.
Effective December 2007, the new amendment to the Federal Food,
Drug and Cosmetic Act (FFDCA) will require supplement labels to
include a telephone number for the reporting of serious adverse events,
and submission of the reports by supplement companies to the FDA
within 15 days. By law, the FDA is required to consolidate multiple
reports of the same incident. Individual states would be precluded from
establishing their own AER systems. Records related to each AER have
to be maintained by the responsible party for six years. Under the AER
law, the reporting of serious adverse events would be a legal requirement, as opposed to the current voluntary Center for Food Safety and
Applied Nutrition (CFSAN) Adverse Event Reporting System (CAERS).
An adverse event is defined in the Act as any “health-related event
associated with the use of a nonprescription drug that is adverse, including an event occurring from an overdose of the drug, whether accidental
or intentional; an event occurring from abuse of the drug; an event occurring from withdrawal from the drug; and any failure of expected
pharmacological action of the drug.”
A serious adverse event is defined as any “health-related event resulting in death, a life-threatening experience, inpatient hospitalization,
persistent or significant disability, congenital abnormality or birth defect,
or any medical or surgical intervention to prevent the above outcomes.”
If a complaint is received on a branded product, the manufacturer of
the product will have the legal responsibility of reporting serious adverse
events in connection with these products. For private label products, the
retailer has the choice to either assign the reporting responsibility to the
manufacturer of their private label products or to report serious adverse
events themselves.
The Act includes language to make it clear that submitting an AER
to the FDA "shall not be construed as an admission that the dietary
supplement involved caused or contributed to the adverse event." The
privacy of individuals reporting adverse events will also be protected.
Additionally, it would be illegal to file a false AER.
While the Act became effective December 22, 2007, the FDA has
until August (270 days from the date of enactment of this Act) to issue
guidance on the minimum data elements that should be included in a
serious AER.
Faced with these time constraints, and prior to the release of the
FDA guidance, manufacturers have already started to develop their plans
for label revisions, call-in centers, the collection and review of reports,
and appropriate submission of the reports to the FDA. Although the
dietary supplement industry does not anticipate many AERs, each manufacturer needs to develop an appropriate plan for handling this complex
process and demonstrate compliance with the law in the event of an
audit.
The term “food additive” means any substance the intended use of which
results or may reasonably be expected to result, directly or indirectly, in its
becoming a component or otherwise affecting the characteristics of any food
(including any substance intended for use in …packing, …packaging, or
holding food…)
Once the issue of the status of the substance was resolved, energies were
refocused on (1) how much of the migrating substance constituted an insignificant or de minimus amount and; (2) because food additive petitions had become
so burdensome, wasn’t there a way to expedite the process?
In the first regard, while the courts avoided identifying a de minimus threshold, the packaging industry initially embraced a threshold of 50 parts per billion
(ppb), below which, a food additive petition would not be required (provided no
heavy metals, carcinogens or substances of known toxicity were present). This
has since been replaced by the concept of Threshold of Regulation (21 CFR
170.39), which embodies the principle that substances in the diet at less than 0.5
ppb are not subject to regulation. The Threshold of Regulation may also be
applied to already approved food additives, if it’s presence as a packaging ingredient in the diet does not exceed 1 percent of the acceptable daily intake for
the substance’s direct addition to food. Lastly, the 0.5 ppb exemption applies to
substances which may contain carcinogenic constituents or impurities with a
TD50 of less than 6.25 mg/kg body weight per day.
In response to the complaint of a too burdensome food additive process ((a)
because of resource limitations of the agency, a food additive petition could
take two to four years and (b) the possibility of performing many costly toxicology studies à la the Redbook criteria), Congress provided some relief with the
Food and Drug Administration Reform Act of 1997 (FDAMA), allowing the
initiation of Food Contact Notification (FCN) program (FFDCA§409(h)). Now
in place, the FCN program (http://www.cfsan.fda.gov/~dms/opa-notf.html)
describes administrative, chemical, toxicological and environmental requirements for a FCN; even the forms to be used for submission are available online. Once the appropriate steps have been taken and the requirements satisfied,
FDA has 120 days to respond to a submission. In the approximately 10 years
since the program’s authorization, nearly 500 FCNs have been approved.
While the FCN program has been of great benefit to an over-burdened
agency, provided relief for the manufacturer and protected the safety of the
consumer, the program will likely be discontinued by October of this year as the
result of budget constraints. While the loss of this program is regrettable,
manufacturers’ looking for renewed relief might consider the other criteria for
defining a food additive; that is, a food additive is something that is “not generally recognized as safe” (GRAS). While GRAS determinations for food contact
substances have not been the most popular method for meeting compliance
requirements, it is likely this process would have a higher degree of appeal to
manufacturers. Further, it would seem that convincing evidence of eligibility
for a determination of GRAS by an Expert Panel, would be embodied in a demonstration that the substance meets the same criteria laid out in the FCN program. Although it is unlikely many GRAS Notifications may be carried out, the
increase in non-notified GRASes will likely be on the increase in the near future
for packaging ingredients.
O
(Continued from page 1). “Structure/Function Claims”
or nutritive value” (http://query.nytimes.com/gst/fullpage.html?
res=9504E5DE173BF933A25753C1A964948260&sec=health&spon=&page
wanted=print).
The market share-driven impetus will be for innovative companies to use
these consumer friendly claims on favored food products. It won’t be long
until that bag of corn chips claims “digestive tract transit time improvement”
because of a taste-modifying prebiotic fiber, or the ice cream with a new tangier flavor note will be provided by probiotic “gut friendly” bacteria, or a sport
beverage sporting a pictogram of a flexing knee joint brought about by a cartilage-healthy nutritive ingredient. However, the entrepreneurial company
should not put that initial investment of venture capital entirely into the design
and conduct of the human clinical studies and end up with depleted capital
and the sudden realization that the safety was ignored. No matter how persuasive the efficacy data are to “Big-Food” and “Big-Beverage,”, and no matter
how tempting the structure / function claim will look on that final food product… “Big-Food/Big-Beverage” will not and cannot plan to commercialize
this amazingly effective ingredient until safety has been addressed.
www.burdockgroup.com
2001 9th Avenue
Suite 301
Vero Beach, FL 32960-6414
fusing science and compliance
WHAT HAS YOUR CONSULTANT PUBLISHED LATELY?
JULY
S E L EC T U PC OM IN G
AND
R E C EN T P U B L IC A TI ON S
G.A. Burdock, I.G. Carabin and J.C. Griffiths (2007). Breaking Down the Barriers to Functional Foods, Nutraceuticals and Claims (2007). Book chapter in “Nutraceuticals and Functional Foods Regulations in the United States and Around the World”, Elsevier. Submitted to
the editor.
I.G. Carabin and J.C. Griffiths. (2007). Functional Foods & Structure/Function Claims. Is
There a Difference Between Sexes? Nutritional Outlook, June issue. In print.
G.A. Burdock and L. Williams. (2007). Nanotechnology and Nanotoxicology of Food Ingredients. Agro Food Industry, July/August issue. In print.
Institute of Food Technologists (IFT)
Chicago, IL
AUGUST
2nd Food Safety Technology Forum 2007
Shanghai, China
NOVEMBER
SupplySide West (SSW)
Las Vegas, NV
J.C. Griffiths. (2007). Sweeteners – Traditional to Cutting Edge, NutraCos, May/June.
G.A. Burdock and I. G. Carabin (2007). Safety assessment of myristic acid as a food ingredient. Food and Chemical Toxicology 45, 517-529.
J.C. Griffiths, J.F. Borzelleca and J. St. Cyr (2007). Sub-Chronic (13 week) Oral Toxicity
Study with D-Ribose in Wistar Rats. Food and Chemical Toxicology 44, 152-155.
J.C. Griffiths, J.F. Borzelleca and J. St. Cyr (2007). Lack of Oral Embryotoxicity/
Teratogenicity with D-Ribose in Wistar Rats. Food and Chemical Toxicology 44, 388-395.
G.A. Burdock and S. Teske (February 2007). The Toxic Potential of Nanotechnology . Functional Foods and Nutraceuticals.
J.C. Griffiths (January/February 2007). SOY– OH BOY! NutraCos.
R. Matulka, O. Noguchi and N. Nosaka (2006). Safety Evaluation of a Medium-and LongChain Triacylgycerol Oil Produced from Medium-Chain Triacylgycerols and Edible Vegetable Oil. Food and Chemical Toxicology 44 (9): 1530-1538.
For a complete list of our publications, visit www.burdockgroup.com/publications.html
AT BURDOCK GROUP WE DO MORE THAN SOLVE
PROBLEMS. WE DESIGN SOLUTIONS.©
This newsletter is prepared by:
Amy Mozingo, Client Relations
and James C. Griffiths, Ph.D.
For inquiries regarding the contents of the newsletter or if you
are interested in receiving an electronic copy, contact us at:
[email protected]
+01-772-562-3900
1-888-6-BURDOCK