[Federal Register: April 28, 2004 (Volume 69, Number 82)]
[Notices]
[Page 23409-23414]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr28ap04-107]
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Part VI
Department of Health and Human Services
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Food and Drug Administration
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Exocrine Pancreatic Insufficiency Drug Products; Draft Guidance for
Submitting New Drug Applications; Notices
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2003N-0205]
Exocrine Pancreatic Insufficiency Drug Products
AGENCY: Food and Drug Administration.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing that all
exocrine pancreatic insufficiency drug products are new drugs and is
announcing the conditions for continued marketing of these drug
products. Manufacturers who wish to continue to market exocrine
pancreatic insufficiency drug products must submit new drug
applications (NDAs); manufacturers who contend that a particular drug
product is not subject to the new drug requirements of the Federal
Food, Drug, and Cosmetic Act (the act) should submit a citizen
petition. FDA has determined that prescription exocrine pancreatic
insufficiency drug products are medically necessary and, accordingly,
is allowing manufacturers 4 years to obtain approved applications.
DATES: This notice is effective April 28, 2004.
A citizen petition claiming that a particular drug product is not
subject to the new drug requirements of the act should be submitted no
later than June 28, 2004.
After April 28, 2008, any prescription exocrine pancreatic
insufficiency drug product introduced or delivered for introduction
into interstate commerce without an approved application, unless found
by FDA not to be subject to the new drug requirements of the act in
response to a citizen petition submitted for that product, will be
subject to regulatory action.
ADDRESSES: All communications in response to this notice should be
identified with Docket No. 2003N-0205 and directed to the appropriate
office listed in section III of this document. References described in
section V of this document are available for public examination in the
Division of Dockets Management (HFA-305), Food and Drug Administration.
FOR FURTHER INFORMATION CONTACT: Mary E. Catchings, Center for Drug
Evaluation and Research (HFD-7), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-2041.
SUPPLEMENTARY INFORMATION:
I. Background
This notice covers pancreatic enzyme preparations containing the
ingredients pancreatin and pancrelipase. Both ingredients are extracted
mainly from hog pancreas and contain principally amylase, protease, and
lipase. Pancrelipase differs from pancreatin mainly in that it has a
higher lipase concentration than does pancreatin.
Pancreatic extract drug products are indicated as replacement
therapy to treat conditions associated with exocrine pancreatic
insufficiency, including cystic fibrosis, chronic pancreatitis,
pancreatic tumors, or pancreatectomy. Under normal circumstances, the
pancreas secretes a sufficient amount of enzymes into the intestine to
aid in the digestion process. When the pancreas is not functioning
properly or is partially removed surgically, lesser amounts of
pancreatic digestive enzymes (i.e., lipase for fat digestion, protease
for protein digestion, and amylase for starch digestion) are released
into the intestine. Because the pancreas has a large functional reserve
capacity, malabsorption, due to insufficient digestion, does not occur
until the pancreatic enzyme output level is reduced by more than 90
percent. When this level of reduction occurs, the pancreatic
insufficiency can usually be detected by the increased fat content in
the stools, and treatment with pancreatic enzymes taken by mouth may be
necessary (56 FR 32282 at 32283, July 15, 1991).
Pancreatic extract drug products have been marketed in the United
States for many years. Marketing of some of these products predates the
1938 passage of the act. Over the years, other pancreatic extract drug
products have entered the market. Until recently, none of these drug
products were marketed under approved NDAs.
As part of the OTC drug review, FDA evaluated the safety and
effectiveness of drug products used to treat exocrine pancreatic
insufficiency. In the Federal Register of December 21, 1979 (44 FR
75666), FDA published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)),
an advance notice of proposed rulemaking to establish a monograph for
OTC exocrine pancreatic insufficiency drug products. The proposed
rulemaking included the recommendations of the Advisory Review Panel on
OTC Miscellaneous Internal Drug Products (the Panel), which was the
advisory review panel responsible for evaluating data on the active
ingredients in this drug class. Interested persons were invited to
submit comments on the proposed rulemaking.
In the Federal Register of November 8, 1985 (50 FR 46594), FDA
published a notice of proposed rulemaking to establish a monograph for
OTC exocrine pancreatic insufficiency drug products based on the
Panel's recommendations and the agency's response to comments submitted
following publication of the advance notice of proposed rulemaking (the
November 1985 proposed rule). In the November 1985 proposed rule, the
agency accepted the Panel's recommendation that exocrine pancreatic
insufficiency drug products be available as OTC drug products and
proposed the conditions under which these drug products would be
generally recognized as safe and effective and not misbranded.
Interested persons were invited to submit new data, written comments,
objections, or requests for oral hearing on the proposed rulemaking.
Based on new information submitted in response to the tentative
final monograph and other available information that came to its
attention, the agency reconsidered the approach proposed in the
November 1985 proposed rule. Mainly because of bioavailability problems
associated with use of pancreatic extract drug products and other
problems reported with the products manufactured as enteric-coated
tablets and encapsulated enteric-coated microspheres, FDA concluded
that an OTC drug monograph would not be sufficient to adequately
regulate these drug products. FDA concluded that preclearance of each
product to standardize enzyme bioactivity would be necessary. FDA also
determined that continuous physician monitoring of patients is a
collateral measure necessary to the safe and effective use of
pancreatic enzyme drug products, requiring such products to be
available by prescription only. Thus, in the Federal Register of July
15, 1991 (56 FR 32282), FDA proposed a rule (the July 1991 proposed
rule) that would declare that OTC drug products used to treat exocrine
pancreatic insufficiency are not generally recognized as safe and
effective and are misbranded. Accordingly, FDA withdrew the November 8,
1985, proposed rule. In the preamble to the July 1991 proposed rule,
FDA also stated that it considers all exocrine pancreatic insufficiency
drug products, whether currently marketed on an OTC or a prescription
basis, to be new drugs for which approved applications will be required
for marketing. The final rule, which affected only OTC products, was
published in the Federal Register of
[[Page 23411]]
April 24, 1995 (60 FR 20162) (the April 1995 final rule).
This notice reiterates the agency's determination that all
pancreatic extract drug products are new drugs under section 201(p) of
the act (21 U.S.C. 321(p)), requiring approved NDAs for marketing, and
states the conditions for marketing the products.
II. Summary of Data Supporting New Drug Finding
In the July 1991 proposed rule and the April 1995 final rule, the
agency discussed its review of the scientific data that provide the
basis for the agency's decision to require approval of pancreatic
extract drug products through the new drug approval process under
section 505 of the act (21 U.S.C. 355).
Those data, including in vitro and in vivo studies, demonstrated
variations in bioactivity among pancreatic extract drug products that
were labeled as containing the same enzyme activity (Refs. 1 through
9). This notice discusses those data and the most recent data received
by the agency.
An early study compared 16 commercially available pancreatic
extract products (tablets, capsules, and enteric-coated tablets) in
vitro. The study demonstrated a wide range of lipase activity (from 10
to 3,600 United States Pharmacopeia (U.S.P.) units of lipase activity
per dosage unit) (Ref. 3). The study also evaluated the effectiveness
of an enteric-coated tablet product with and without the enteric
coating and observed greater effectiveness for the product lacking the
enteric coating.
One in vitro study of various commercial pancreatic enzyme products
demonstrated the variations in lipase activity and release rates among
the products (Ref. 4). The study tested three main types of dosage
forms, i.e., simple pancreatic enzyme preparations (uncoated tablets
and powder-filled capsules), enteric-coated tablets, and encapsulated
enteric-coated microspheres. The products were analyzed for amylase,
lipase, and protease activity before being subjected to a simulated
gastric fluid. The lipase activity of each product was then reanalyzed.
The results showed that when subjected to a simulated gastric fluid,
the simple dosage form products lost all of the original lipase
activity. The enteric-coated tablet dosage form retained all of the
original lipase activity under these conditions; the three encapsulated
enteric-coated microsphere dosage form products retained 54.0, 90.7,
and 99.9 percent, respectively, of their original lipase activity under
these conditions. The study also investigated the release rate of the
enzyme and the hydrogen-ion concentration (pH) level at which release
begins. The enteric-coated tablets showed negligible release of enzymes
in the pH range of 4.0 to 6.0. All of the enteric-coated microsphere
products released their enzymes in the pH range of 5.5 to 6.0.
Variation in effectiveness among various dosage forms also has been
observed. Several studies in patients with severe pancreatic
insufficiency and with cystic fibrosis indicate that the encapsulated
enteric-coated microsphere dosage form of pancreatic enzymes has
improved effectiveness over other formulations in treating pancreatic
insufficiency (Refs. 5 through 9).
A number of studies that compared the lipase activity and
effectiveness of various products also showed variations among
encapsulated enteric-coated microsphere products from different
manufacturers (Refs. 1, 4, 7, and 9). For example, an in vivo study of
19 cystic fibrosis patients that compared 1 tablet form product and 3
encapsulated enteric-coated microsphere form products showed fewer
gastrointestinal symptoms and increased fat absorption with 2 of the
encapsulated enteric-coated microsphere products. The tablet and the
third encapsulated enteric-coated microsphere product gave less
satisfactory results, although the enzyme content of the latter was
similar to the two more successful encapsulated enteric-coated
microsphere products.
In its review, the agency reported that the wide range of enzyme
activity, the variety of dosage forms, and the apparent uneven quality
of the enteric coatings among pancreatic extract drug products have
resulted in instances of underdosing and overdosing with pancreatic
extracts. In one study reviewed by the agency, three patients whose
pancreatic insufficiency had been controlled using one encapsulated
enteric-coated microsphere dosage form experienced therapeutic failure
when a similar product was substituted. The products were labeled as
containing the same enzyme activity. Analyses of the products used in
the study showed that most of the products contained greater lipase
activity than labeled.
Review of the data identified other safety problems associated with
the use of high doses of pancreatic extracts, for example,
hyperuricosuria, hyperuricemia, obstipation, and intestinal
obstruction. FDA has received several reports of intestinal stricture
and blockage in cystic fibrosis patients using higher potency
pancreatic enzymes in delayed release microtablets and microspheres
(Refs. 10 through 17).
In February 2001, FDA received correspondence from the Cystic
Fibrosis Foundation reporting apparent therapeutic failures associated
with the use of pancreatic enzymes when ``generic'' versions of the
drug products were substituted for ``brand name'' products. The adverse
events reported included abdominal pain, intestinal obstruction,
increased incidence of steatorrhea, increased episodes of rectal
prolapse, and increased number of stools. In view of the information
provided, however, no direct link between the 14 cases of insufficient
therapeutic effect and the substitution of pancrelipase products
reported here can be established. No information on adherence to dose
and dose regimen has been provided. Also lacking are data on the
clinical severity of cystic fibrosis in these patients, which is known
to vary widely. Even with good compliance, some patients may not
respond promptly or well to the suggested low starting doses of the
pancreatic enzymes. Further, no information was provided to demonstrate
that the patients with an inadequate therapeutic effect of the
substituted ``generic'' version were administered equivalent units of
the ``brand name'' product. Nonetheless, the substitution of
pancrelipase appears to be somehow involved and raises additional
concerns that should be addressed by FDA's requirement for new drug
approval (Ref. 18).
Based on a review of all available data, including the studies and
adverse reports referenced above, FDA concluded that the safe and
effective use of pancreatic enzyme drug products requires that the
products be marketed by prescription only and that the products be
approved through the new drug approval process to standardize enzyme
activity. FDA determined that bioactivity must be shown to correlate
with the stated potency of each product, particularly for newer
formulations that include microspheres and high-potency levels of
pancreatic enzymes.
III. Office Contacts
All communications in response to this notice should be directed to
the appropriate office as follows:
Applications under section 505 of the act: Central Document Room,
Center for Drug Evaluation and Research, Food and Drug Administration,
5901-B Ammendale Rd., Beltsville, MD 20705-1266.
Citizen petitions (see Sec. 10.30 (21 CFR 10.30)) contending that
a particular drug product is not subject to the new drug
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requirements of the act: Division of Dockets Management (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852.
Requests for an opinion on the applicability of this notice to a
specific product: Division of New Drugs and Labeling Compliance (HFD-
310), Center for Drug Evaluation and Research, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857.
Inquiries regarding procedures for obtaining approval of NDAs:
Division of Gastrointestinal and Coagulation Drug Products (HFD-180),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, 301-827-7310.
Inquiries regarding procedures for obtaining approval of
abbreviated new drug applications (ANDAs): Office of Generic Drugs
(HFD-600), Center for Drug Evaluation and Research, Food and Drug
Administration, 7500 Standish Pl., Rockville, MD 20855.
IV. Legal Status
Pancreatic enzyme drug products containing the ingredients
pancreatin and pancrelipase are used as replacement therapy in
conditions in which the exocrine secretions of the pancreas
(principally, amylase, lipase, and protease) are either absent or
deficient. The goal of therapy in pancreatic enzyme replacement is to
control the consequences of exocrine pancreatic insufficiency, namely
maldigestion and malabsorption of fats, protein, and carbohydrates and
resulting nutritional deficiencies. Individualization of treatment is
needed for optimal therapeutic effect (50 FR 46594 at 46597, November
8, 1985).
Various dosage forms of pancreatic enzyme drug products are
currently marketed: Uncoated tablets, powders, capsules, enteric-coated
tablets, and encapsulated enteric-coated microspheres. Significant
variations in bioavailability have been shown both among the various
dosage forms and among products from different manufacturers of the
same dosage form. These variations in bioavailability can affect both
safety and effectiveness of the products. Subpotent doses of pancreatic
enzyme products may result in patients experiencing steatorrhea,
malnutrition, and consequent nutritional deficiencies. High doses of
these products have been associated with hyperuricosuria,
hyperuricemia, and other severe complications such as colonic
strictures and intestinal blockage in patients using high-potency
dosage preparations.
Available data have shown that the formulation, dosage, and
manufacturing process of pancreatic enzyme drug products have a
critical effect on the safe and effective use of these drugs. The
bioavailability of the enzymes present in these products depends on the
process used to manufacture the drug products. Standardization of the
enzyme bioactivity is necessary to avoid serious safety problems
resulting from too little or too much supplementation.
FDA has approved an NDA for one pancreatic enzyme product (Cotazym,
manufactured by Organon, Inc.). This product is not currently being
marketed. No currently marketed pancreatic enzyme product has been
shown to demonstrate consistent enzyme bioactivity that results in
predictable safety and effectiveness. The approval of the NDA for
Cotazym does not equate to general recognition of safety and
effectiveness for pancreatic enzyme products as a class. Because
bioactivity relates to product-specific formulation and manufacturing
issues, each pancreatic enzyme product must be shown to be safe and
effective based upon the specific characteristics of the drug product.
Therefore, no currently marketed unapproved pancreatic enzyme drug
product is generally recognized as safe and effective. Accordingly,
pancreatic extract drug products used to treat exocrine pancreatic
insufficiency are new drugs under section 201(p) of the act and are
subject to the requirements of section 505 of the act. The submission
of an NDA is necessary to provide FDA with information on the product's
formulation, manufacture, quality control procedures, and the
effectiveness of the marketed formulation to ensure, among other
things, that a company has the ability to manufacture a consistently
bioactive pancreatic enzyme formulation.
If a manufacturer of a pancreatic enzyme drug product contends that
the particular drug product is not subject to the new drug requirements
of the act, this claim should be submitted in the form of a citizen
petition under Sec. 10.30 and should be filed to Docket No. 2003N-0205
no later than June 28, 2004. Sixty days is the time allowed for such
submissions in similar proceedings. (See Sec. 314.200(c) and (e) (21
CFR 314.200(c) and (e)).) Under Sec. 10.30(e)(2), the agency will
provide a response to each petitioner within 180 days of receipt of the
petition. A citizen petition that contends that a particular drug
product is not subject to the new drug requirements of the act should
contain the quality and quantity of data and information set forth in
Sec. 314.200(e). Note especially that a contention that a drug product
is generally recognized as safe and effective within the meaning of
section 201(p) of the act is to be supported by the same quantity and
quality of scientific evidence that is required to obtain approval of
an application for the product. (See Sec. 314.200(e)(1).)
Conditions for Approval and Marketing
Manufacturers who wish to continue marketing pancreatin or
pancrelipase drug products must submit applications as required by
section 505 of the act and part 314 (21 CFR part 314). At this time,
FDA expects to receive only NDAs, including section 505(b)(2)
applications, for these products. For the reasons described below, the
agency has determined that pancreatic extract drug products currently
are not likely to be appropriate subjects for ANDAs.
For a pancrelipase or pancreatin product to be submitted as an
ANDA, the proposed drug product would have to be shown to contain the
same active ingredient(s) as an approved reference listed drug. Because
of the complexity of pancreatic extract products, it is unlikely that
currently available physiochemical and biological analytical tools
would be able to demonstrate that the active ingredients in pancreatic
extract products from two different manufacturers are the same.
Therefore, the agency has concluded that manufacturers currently are
unlikely to obtain approval of pancreatic extract products under
section 505(j) of the act.
Manufacturers interested in submitting ANDAs for pancreatic extract
products are strongly advised to contact the Office of Generic Drugs
(HFD-600) (see section III of this document) to discuss the feasibility
of such an application.
FDA discussed the requirements for approval of a full NDA in the
July 1991 proposed rule (56 FR 32282 at 32283). An NDA must include
adequate and well-controlled clinical studies of the product's
effectiveness, i.e., evidence of human bioactivity in normal volunteers
or patients to demonstrate that the enzymes are active in vivo on
ingested fats, proteins, and carbohydrates. The bioactivity must be
shown to correlate with the stated potency of each product. The studies
need to comply with the requirements of part 314. An application must
also include information on the drug product's formulation,
manufacture, and quality control procedures to ensure that the
applicant has the ability to manufacture a consistently bioactive
formulation. Elsewhere in this issue of the Federal
[[Page 23413]]
Register, FDA is announcing the availability of a draft guidance for
industry entitled ``Exocrine Pancreatic Insufficiency Drug Products--
Submitting NDAs.'' This draft guidance, when finalized, will aid
sponsors of exocrine insufficiency drug products in submitting NDAs for
the drug products.
Inquiries regarding procedures for obtaining approval of NDAs
should be directed to the Division of Gastrointestinal and Coagulation
Drug Products (HFD-180) (see section III of this document).
Pancreatic enzyme products are medically necessary because they are
used to treat exocrine pancreatic insufficiency, a condition in which
symptoms are due to deficient secretion of pancreatic enzymes (i.e.,
lipase, protease, amylase) essential for normal digestion and
absorption. Exocrine pancreatic insufficiency associated with cystic
fibrosis, chronic pancreatitis, and other pancreatic diseases causes
maldigestion and malabsorption of fats, protein, and carbohydrates, and
poor absorption of fat-soluble vitamins, iron, folic acid, and other
micronutrients. These nutritional deficiencies lead to steatorrhea,
diarrhea, and malnutrition in cystic fibrosis and chronic pancreatitis,
and also growth retardation in children, adolescents, and adults with
cystic fibrosis. The severity of the conditions varies from patient to
patient as does the dosage requirement of pancreatic enzyme replacement
therapy needed to relieve the symptoms of pancreatic insufficiency. The
dosage, including the relative amounts of enzymes (lipase for fat
digestion, protease for protein digestion, and amylase for starch
digestion), should be individualized for each patient and adjusted when
clinically indicated. In recommended doses, pancreatic extracts are
virtually free of adverse effects.
There are safety issues associated with the continued marketing of
unapproved pancreatic enzyme products. As discussed previously in this
document, there are safety problems associated with high doses of
pancreatic extracts. The most common adverse effects are
gastrointestinal in nature, specifically diarrhea, nausea, stomach
cramps, or pain. Excessive doses of pancreatic extracts have been
associated with hyperuricosuria, hyperuricemia, obstipation, and
intestinal obstruction. It appears that these side effects have been
addressed to some extent in the labeling for a number of the currently
marketed products. Continuous physician monitoring is also recommended
to help minimize these problems. Cases of intestinal stricture and
obstruction have been observed in one adult and one child without
cystic fibrosis treated for prolonged periods with high concentrations
of pancreatic enzymes. Intestinal stricture and obstruction have also
been observed in children with cystic fibrosis treated with various
concentrations of pancreatic enzymes or with pancreatic enzyme
preparations containing high lipase concentrations. Whether there is a
relationship between the use of these products and intestinal stricture
needs further investigation.
Despite the risks associated with use of unapproved pancreatic
enzyme products, no alternative drug is relied upon by the medical
community to treat the lack of lipase, protease, and amylase caused by
exocrine pancreatic insufficiency. Pancreatic enzyme supplements are a
daily requirement for patients with exocrine pancreatic insufficiency
and are needed for survival for many of these patients, e.g., cystic
fibrosis patients.
To meet the needs of patients requiring pancreatic enzyme
replacement therapy, pancreatic extract drug products in varying dosage
forms, enzyme content, and activity are currently being marketed.
According to FDA records, there are 23 manufacturers and 26 repackers/
private label distributors marketing 38 formulations. Pancreatic enzyme
products, including some of the currently marketed products, have been
marketed for years. Only one product, Cotazym, sponsored by Organon,
Inc., is the subject of an approved NDA and that product is not
currently being marketed. However, there is a need for a range of
products to remain available for patient use. The dosage requirements
of patients vary, and the appropriate daily dose of pancreatic enzyme
supplements must be individualized and adjusted when clinically
indicated. Furthermore, physicians have identified and stabilized their
patients on currently available products with different ratios of
lipase, protease, and amylase that meet the patients' needs. Thus, to
meet the dosing requirements and to maintain compliance with treatment,
pancreatic supplements are needed with varied concentrations of lipase,
protease, and amylase.
Accordingly, FDA will permit currently marketed pancreatic enzyme
products to be marketed without approved applications until April 28,
2008, to give manufacturers time to conduct the required studies and to
prepare and submit applications, and to allow time for review of and
action on these applications. This provision for continuation of
marketing, which applies only to pancreatic enzyme products marketed on
or before the publication of this document, is consistent with the
order in Hoffmann-LaRoche, Inc. v. Weinberger, 425 F. Supp. 890 (D.D.C.
1975), as amended, reprinted in the Federal Register of September 22,
1975 (40 FR 43531), and March 2, 1976 (41 FR 9001), because pancreatic
enzyme products are medically necessary drug products.
After April 28, 2008, any pancreatic enzyme drug product that is
introduced or delivered for introduction into interstate commerce
without an approved application will be subject to regulatory action,
unless there has been a finding by FDA, under a citizen petition
submitted for that product as described above, that the product is not
subject to the new drug requirements of the act.
This notice is issued under the Federal Food, Drug, and Cosmetic
Act (secs. 502, 505 (21 U.S.C. 352, 355)) and under authority delegated
to the Associate Commissioner for Policy and Planning (21 CFR 5.20).
V. References
The following references have been placed on display in the
Division of Dockets Management (see the ADDRESSES section of this
document) and may be seen by interested persons between 9 a.m. and 4
p.m., Monday through Friday.
1. Hendeles, L. et al., ``Treatment Failure After Substitution
of Generic Pancrelipase Capsules: Correlation with In Vitro Lipase
Activity,'' Journal of the American Medical Association, 263:2459-
2461, 1990.
2. Regan, P. T. et al., ``Comparative Effects of Antacids,
Cimetidine and Enteric Coating on the Therapeutic Response to Oral
Enzymes in Severe Pancreatic Insufficiency,'' New England Journal of
Medicine, 297:854-858, 1977.
3. Graham, D. Y., ``Enzyme Replacement Therapy of Exocrine
Pancreatic Insufficiency in Man: Relation Between In Vitro Enzyme
Activities and In Vivo Potency in Commercial Pancreatic Extracts,''
New England Journal of Medicine, 296:1314-1317, 1977.
4. Fatmi, A. A. and J. A. Johnson, ``An In Vitro Comparative
Evaluation of Pancreatic Enzyme Preparations,'' Drug Development and
Industrial Pharmacy, 14:1429-1438, 1988.
5. Graham, D. Y., ``An Enteric-Coated Pancreatic Enzyme
Preparation that Works,'' Digestive Diseases and Sciences, 24:906-
909, 1979.
6. Mischler, E. H. et al., ``Comparison of Effectiveness of
Pancreatic Enzyme Preparations in Cystic Fibrosis,'' American
Journal of Diseases of Children, 136:1060-1063, 1982.
7. Littlewood, J. M. et al., ``In Vivo and In Vitro Studies of
Microsphere Pancreatic Supplements,'' Journal of Pediatric
Gastroenterology and Nutrition, 7 (Supplement 1):S22-S29, 1988.
[[Page 23414]]
8. Dutta, S. K., V. S. Hubbard, and M. Appler, ``Critical
Examination of Therapeutic Efficacy of a pH-Sensitive Enteric-Coated
Pancreatic Enzyme Preparation in Treatment of Exocrine Pancreatic
Insufficiency Secondary to Cystic Fibrosis,'' Digestive Diseases and
Sciences, 33:1237-1244, 1988.
9. Beverley, D. W. et al., ``Comparison of Four Pancreatic
Extracts in Cystic Fibrosis,'' Archives of Disease in Childhood,
62:564-568, 1987.
10. Cystic Fibrosis Foundation Results of a Survey of 114 Cystic
Fibrosis Care Centers in the United States, Patient Registry 1992
Annual Data Report, Bethesda, MD, October 1993, in OTC Vol. 17BFR,
Docket No. 79N-0379, Division of Dockets Management.
11. Smyth, R. L. et al., ``Strictures of Ascending Colon in
Cystic Fibrosis and High-Strength Pancreatic Enzymes,'' Lancet,
343:85-86, 1994.
12. Oades, P. J. et al., ``Letter to the Editor,'' Lancet,
343:109, 1994.
13. Campbell, C. A., J. Forrest, and C. Musgrove, ``Letter to
the Editor,'' Lancet, 343:109, 1994.
14. Briars, G. L. et al., ``Letter to the Editor,'' Lancet,
343:600, 1994.
15. Mahony, M. J. and M. Corcoran, ``Letter to the Editor,''
Lancet, 343:599-600, 1994.
16. Knabe, N. et al., ``Letter to the Editor,'' Lancet,
343:1230, 1994.
17. Taylor, C. J., ``Colonic Strictures in Cystic Fibrosis,''
Lancet, 343:615-616, 1994.
18. Letter dated February 14, 2001, from P. W. Campbell, III,
Cystic Fibrosis Foundation, to L. Talarico, FDA.
Dated: April 5, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-9652 Filed 4-27-04; 8:45 am]
BILLING CODE 4160-01-S