[Federal Register Volume 69, Number 82 (Wednesday, April 28, 2004)]
[Notices]
[Pages 23410-23414]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-9652]



[[Page 23409]]

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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Exocrine Pancreatic Insufficiency Drug Products; Draft Guidance for 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

  Federal Register / Vol. 69, No. 82 / Wednesday, April 28, 2004 / 
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

[[Page 23412]]

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[FEDREG][VOL]*[/VOL][NO]*[/NO][DATE]*[/
DATE][NOTICES]