[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