[Federal Register Volume 76, Number 245 (Wednesday, December 21, 2011)]
[Notices]
[Pages 79196-79198]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-32551]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2011-N-0842]
Gluten in Drug Products; Request for Information and Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; request for information and comments.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
establishment of a docket to obtain information and comments that will
assist the Agency in its deliberations about ways to help individuals
with celiac disease avoid the presence of gluten in drug products. In
particular, FDA is interested in information on ingredients present in
human drug products marketed in the United States that are currently
derived from wheat, barley, or rye.
DATES: Submit either electronic or written information and comments by
March 20, 2012.
ADDRESSES: Submit electronic information and comments to http://www.regulations.gov. Submit written information and comments to the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Identify both
electronic and written comments and any supporting documents with the
docket number in brackets in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Yana R. Mille, Center for Drug
Evaluation and Research, Food and Drug Administration, Bldg. 51, rm.
4152, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, (301)
796-1577.
SUPPLEMENTARY INFORMATION:
I. Background
A. Celiac Disease
Celiac disease (also known as celiac sprue and gluten-sensitive
enteropathy) is an immune-mediated chronic inflammatory disorder
affecting primarily the small intestine in genetically susceptible
individuals (Refs. 1 and 2). In these individuals, the symptoms of
celiac disease are triggered by the ingestion of wheat grain proteins
collectively known as glutens (Ref. 3). The consumption of wheat gluten
and similar proteins in barley and rye stimulates the production of
antibodies and inflammatory cells, resulting in an abnormal immune
response. The resultant immediate inflammatory reaction damages the
tiny, fingerlike protrusions called ``villi'' that line the small
intestine and absorb nutrients from food (Refs. 4 and 5). In addition,
over time, continued dietary exposure to gluten from wheat, barley, or
rye can lead to impaired absorption of nutrients and a variety of other
serious health problems (Ref. 4). For the purposes of this notice, the
phrase ``wheat, barley, or rye'' includes wheat, barley, and rye, as
well as the crossbred hybrids of these grains.
The prevalence of celiac disease in the United States is estimated
to range from about 0.4 percent to about 1 percent of the population
(Refs. 1 and 6). Celiac disease may go undetected in some individuals
for years before they develop symptoms that cause them to seek medical
attention (Refs. 7 and 8).
The standard treatment of celiac disease is the elimination of
gluten-containing products from the diet (Ref. 1). Over time, strict
avoidance of gluten from wheat, barley, or rye sources can resolve the
symptoms, mitigate and possibly reverse intestinal damage, and reduce
the health risks associated with celiac disease (Ref. 4). For some
individuals with celiac disease, over time, failure to avoid
consumption of gluten from wheat, barley, and rye can lead to severe
and sometimes life-threatening complications (Refs. 9 to 11).
B. Gluten and Grains of Concern for Individuals With Celiac Disease
Technically, ``gluten'' is the storage protein of wheat that is
composed of alcohol-soluble gliadins and insoluble glutenins (Ref. 2).
Gliadins have been most closely studied and have been found to be the
main antigen in celiac disease; however, glutenins also have been
implicated in the disease (Refs. 12 and 13). The storage proteins of
rye (secalins) and barley (hordeins) are similar in amino acid sequence
to wheat gluten proteins and may trigger the same inflammatory
response. For these reasons, the term ``gluten'' has been adopted to
mean any proteins implicated in celiac disease (Ref. 2). In this
notice, the term ``gluten'' is used to refer to the antigenic proteins
of wheat, barley, and rye implicated in celiac disease.
The grains that contain gluten that can cause harm to individuals
who have celiac disease are as follows: Wheat (including durum wheat,
spelt wheat, and kamut), barley, rye, and crossbred hybrids of these
grains (e.g., triticale, which is a cross between wheat and rye) (Refs.
14 and 15). While there is no general agreement among experts about the
extent to which oats may present a hazard for individuals who have
celiac disease (Refs. 16 to 18), it is generally believed that moderate
amounts of oats can be ingested safely by the majority of individuals
with celiac disease (Ref. 4).
C. Determination of Tolerable Daily Intake
The extent of risk posed to celiac patients by ingestion of trace
amounts of gluten is uncertain. The majority of current data is from
retrospective studies or nonrandomized, prospective, nonblinded studies
without a placebo challenge group, limiting the conclusive evidence on
safe thresholds for gluten intake. In the context of an ongoing
rulemaking to define criteria for voluntary ``gluten-free'' claims on
food,
[[Page 79197]]
FDA's Office of Food Safety in the Center for Food Safety and Applied
Nutrition undertook a health hazard assessment for gluten exposure in
individuals with celiac disease.
The assessment, which is available for public review (Ref. 19),
included a description and characterization of available prospective
dose-effect data, as well as a safety assessment derived from
prospective gluten challenge data from individuals with celiac disease.
The assessment specifically examined morphological and clinical adverse
effects that are reflective of celiac disease. These reactions were
subsequently placed into subgroups identifying whether they occurred
after acute, subchronic, or chronic exposures. The no observable
adverse effect level and lowest observable adverse effect level were
determined for each study considered. Uncertainty factors were applied
to account for limitations in data, variability in response between
patients, and other potential gaps, and from this information tolerable
daily intake levels of exposure were derived. Based on this health
hazard assessment, a conservative tolerable daily intake level for
gluten in individuals with celiac disease is 0.4 milligrams (mg) gluten
per day for adverse morphological effects and 0.015 mg gluten per day
for adverse clinical effects.
D. Ingredients at Issue
The Agency believes that wheat is not used to a significant extent
in the production of drug ingredients and that barley and rye are used
either rarely or not at all. FDA is aware, however, that certain
ingredients in drug products may be derived from wheat. For the
purposes of this notice, the phrase ``drug products'' refers to all
FDA-regulated human drug products marketed in the United States. These
include prescription, nonprescription, biologic, and homeopathic drug
products. The National Formulary includes a monograph for wheat starch.
Some monographs in the National Formulary and the U.S. Pharmacopeia
include statements that wheat or wheat starch may be used as source
materials. Other monographs include statements that starch may be used
as a source material without specifying the plant source of the starch.
This request for information and comment includes information on
all drug ingredients that may be derived from wheat, barley, or rye--
whether or not they are the subject of a compendial monograph. Examples
of such ingredients that FDA is aware of include: Wheat starch,
modified starch, pregelatinized starch, pregelatinized modified starch,
sodium starch glycolate, dextrates, dextrin, caramel, dextrimaltose,
malt, maltodextrin, gamma cyclodextrin, and wheat bran. Certain flavor
ingredients also may be derived from wheat, barley, or rye.
This notice does not request information relating to the possible
presence of gluten from wheat, barley, or rye in drug products at trace
levels that may result from accidental contamination.
II. Discussion and Approaches
A. Discussion
FDA is considering ways to help individuals with celiac disease
avoid the presence of gluten in drug products. In 2008, the Agency
received a citizen petition from an individual asking that the Agency
prohibit the addition of wheat gluten to drug products (Ref. 20). FDA
has heard from other individuals and organizations in recent years
asking that the Agency do more to provide assurance to individuals who
have celiac disease that drug products will not harm them.
Currently, the possible presence of gluten in drug products
presents a difficult challenge for individuals who have celiac disease.
Ingredient information provided on drug labels and information
available to pharmacists and physicians may not indicate whether
certain drug products contain gluten. Faced with uncertainty, some
patients may forego important treatment.
The possible presence of gluten in drug products presents a
challenge to individuals who have celiac disease that is different from
the challenges associated with dietary gluten. For example, medication
is sometimes needed on an urgent basis, not leaving time for an
investigation into the drug's gluten content. In some cases, a patient
with celiac disease may be unable to confirm the gluten-free status of
a drug product and may have difficulty obtaining a product known to be
manufactured without gluten.
B. Approaches
The Agency is evaluating various approaches for helping patients
with celiac disease avoid the presence of gluten in drug products.
While the Food Allergen Labeling and Consumer Protection Act of 2004
(Pub. L. 108-282, Title II) specifies the creation of a standard for
voluntary ``gluten free'' labeling for foods (see 72 FR 2795, January
23, 2007; 76 FR 46671, August 3, 2011), other options may be preferable
for drugs, given the distinct considerations they present. FDA is
particularly interested in understanding what impact would result if
the use of drug ingredients derived from wheat, barley, or rye were
completely discontinued in human drugs. If interested stakeholders do
not identify reasons why certain ingredients must be derived from
wheat, barley, or rye--or why the flexibility to use these grains as
ingredient sources is important--discontinuing use of such ingredients
may be attractive for its simplicity and effectiveness in addressing
the issue.
III. Requested Information and Comments Regarding FDA-Regulated Human
Drug Products Marketed in the United States
Interested persons are invited to provide detailed comment on all
aspects of this issue with respect to prescription, nonprescription,
biologic, and homeopathic drug products. FDA is particularly interested
in responses to the following questions.
A. Current Practice
1. What inactive ingredients used in drug products marketed in the
United States today are derived from wheat, barley, or rye? Please
identify specific ingredients derived from any of these sources.
2. Please provide any available information on the number of drug
products that contain inactive ingredients derived from wheat, barley,
or rye. What is the general prevalence of such inactive ingredients in
the human drug supply?
3. To what extent are active ingredients derived from wheat,
barley, or rye used in drug products?
4. Are certain ingredients derived from wheat, barley, or rye
processed in a way that removes gluten? Please provide information
concerning the certainty with which processing methods may remove or
destroy gluten and identify any test methods used to confirm the
absence of gluten. The Agency's interest extends to ingredients that
may be derived from a variety of starch sources if they are sometimes
derived from wheat. Sugar alcohols such as sorbitol, xylitol, maltitol,
and mannitol may fall into this category.
5. Do manufacturers routinely test ingredients or drug products to
determine whether gluten is present? If so, what test methods are used
and what is their sensitivity?
B. Flexibility and Consequences
6. What negative consequences, if any, would arise from
discontinuing the use of ingredients derived from wheat, barley, or rye
in drug products? Are
[[Page 79198]]
there certain applications for which an ingredient (inactive or active)
must be derived from one of these grains for reasons related to
physical properties, performance characteristics, safety, efficacy,
availability, or reformulation burden, as well as other reasons?
C. Exposure Estimate
7. Is it possible to determine, with a high level of assurance,
that certain drug ingredients derived from wheat, barley, or rye are
free of gluten or would contribute only very dilute, insignificant, and
nonharmful quantities of gluten to a drug product? If so, what
scientific evidence supports such a determination?
D. Routes of Administration
8. FDA believes that the use of ingredients derived from wheat,
barley, or rye in drugs administered orally presents a particular risk
to individuals who have celiac disease, as compared to use of these
ingredients in drugs dispensed in dosage forms intended for other
routes of administration. FDA welcomes comments in this area. Are
ingredients derived from wheat, barley, or rye presently used in drugs
that are intended for nonoral routes of administration, such as
topical, injectable, or ano-rectally administered drugs? Please submit
any data or information on risks to celiac patients associated with
nonoral exposure to ingredients derived from wheat, barley, or rye.
E. Incidental Addition of Gluten
9. FDA is primarily interested in ingredients derived from wheat,
barley, or rye that are intentionally added to and intended to remain
in the drug product. However, the Agency welcomes responses to the
following question: Are processing aids or production aids (e.g.,
filtration media or fermentation media) derived from wheat, barley, or
rye used today that could introduce gluten into a drug product at
nontrivial levels?
IV. Submission of Information and Comments
Interested persons may submit information and comments responsive
to this request to the Division of Dockets Management (see ADDRESSES)
in electronic or written form. It is no longer necessary to send two
copies of mailed comments. Identify comments with the docket number
found in brackets in the heading of this document. Except for data and
information prohibited from public disclosure under 21 U.S.C. 331(j) or
18 U.S.C. 1905, submissions may be seen in the Division of Dockets
Management between 9 a.m. and 4 p.m., Monday through Friday, and on the
Internet at http://www.regulations.gov.
V. References
The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Fasano, A., and C. Catassi, ``Current Approaches to Diagnosis and
Treatment of Celiac Disease: An Evolving Spectrum,''
Gastroenterology, vol. 120, pp. 636-651, 2001.
2. National Institutes of Health (NIH), ``NIH Consensus Development
Conference Statement on Celiac Disease, June 28-30, 2004,''
Gastroenterology, vol. 128, pp. S1-S9, 2005.
3. Jabri, B., D.D. Kasarda, and P.H.R. Green, ``Innate and Adaptive
Immunity: The Yin and Yang of Celiac Disease,'' Immunological
Reviews, vol. 206, pp. 219-231, 2005.
4. Molberg, O., N.S. Flaete, T. Jensen, et al., ``Intestinal T-Cell
Responses to High-Molecular-Weight Glutenins in Celiac Disease,''
Gastroenterology, vol. 125, pp. 337-344, 2003.
5. Farrell, R.J. and C.P. Kelly, ``Celiac Sprue,'' The New England
Journal of Medicine, vol. 346, pp. 180-188, 2002.
6. Fasano, A., I. Berti, T. Gerarduzzi, et al., ``Prevalence of
Celiac Disease in At-Risk and Not-At-Risk Groups in the United
States: A Large Multicenter Study,'' Archives of Internal Medicine,
vol. 163, pp. 286-292, 2003.
7. West, J., R.F.A. Logan, P.G. Hill, et al., ``Seroprevalence,
Correlates, and Characteristics of Undetected Coeliac Disease in
England,'' Gut, vol. 52, pp. 960-965, 2003.
8. Green, P.H.R. and B. Jabri, ``Coeliac Disease,'' Lancet, vol.
362, pp. 383-391, 2003.
9. Rubio-Tapia, A., R.A. Kyle, E.L. Kaplan, et al., ``Increased
Prevalence and Mortality in Undiagnosed Celiac Disease,''
Gastroenterology, vol. 137, pp. 88-93, 2009.
10. Catassi, C., I. Bearzo, and G.K.T. Holmes, ``Association of
Celiac Disease and Intestinal Lymphomas and Other Cancers,''
Gastroenterology, vol. 128, pp. S79-S86, 2005.
11. Corrao, G., G.R. Corazza, V. Bagnardi, et al., ``Mortality in
Patients With Coeliac Disease and Their Relatives: A Cohort Study,''
Lancet, vol. 358, pp. 356-361, 2001.
12. Waga, J., ``Structure and Allergenicity of Wheat Gluten
Proteins--A Review,'' Polish Journal of Food and Nutrition Sciences,
vol. 13, pp. 327-338, 2004.
13. Vader, W., Y. Kooy, P. Van Veelen, et al., ``The Gluten Response
in Children With Celiac Disease Is Directed Toward Multiple Gliadin
and Glutenin Peptides,'' Gastroenterology, vol. 122, pp. 1729-1737,
2002.
14. Kieffer, M., P.J. Frazier, NW.R. Daniels, et al., ``Wheat
Gliadin Fractions and Other Cereal Antigens Reactive With Antibodies
in the Sera of Coeliac Patients,'' Clinical and Experimental
Immunology, vol. 50, pp. 651-660, 1982.
15. Sturgess, R.P., H.J. Ellis, and P.J. Ciclitira, ``Cereal
Chemistry, Molecular Biology, and Toxicity in Coeliac Disease,''
Gut, vol. 32, pp. 1055-1060, 1991.
16. Lundin, K.E.A., E.M. Nilsen, H.G. Scott, et al., ``Oats Induced
Villous Atrophy in Coeliac Disease,'' Gut, vol. 52, pp. 1649-1652,
2003.
17. Janatuinen, E.K., T.A. Kemppainen, R.J.K. Julkunen, et al., ``No
Harm From Five Year Ingestion of Oats in Coeliac Disease,'' Gut,
vol. 50, pp. 332-335, 2002.
18. Haboubi, N.Y., S. Taylor, and S. Jones, ``Coeliac Disease and
Oats: A Systematic Review,'' Postgraduate Medicine Journal, vol. 82,
pp. 672-678, 2006.
19. Office of Food Safety, Center for Food Safety and Applied
Nutrition, Food and Drug Administration, ``Health Hazard Assessment
for Gluten Exposure in Individuals With Celiac Disease:
Determination of Tolerable Daily Intake Levels and Levels of Concern
for Gluten,'' May 2011.
20. Citizen Petition submitted by Michael Weber, June 2008, Docket
No. FDA-2008-P-0333.
Dated: December 15, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-32551 Filed 12-20-11; 8:45 am]
BILLING CODE 4160-01-P