[Federal Register Volume 60, Number 78 (Monday, April 24, 1995)]
[Rules and Regulations]
[Pages 20162-20165]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-10078]
[[Page 20161]]
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Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 310
Exocrine Pancreatic Insufficiency Drug Products for Over-The-Counter
Human Use; Final Rule
Federal Register / Vol. 60, No. 78 / Monday, April 24, 1995 / Rules
and Regulations
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[[Page 20162]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 310
[Docket No. 79N-0379]
RIN 0905-AA06
Exocrine Pancreatic Insufficiency Drug Products for Over-The-
Counter Human Use
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
establishing that over-the-counter (OTC) exocrine pancreatic
insufficiency drug products (drug products used to treat pancreatic
enzyme deficiency) are not generally recognized as safe and effective
and are misbranded. FDA is issuing this final rule after considering
public comments on the agency's notice of proposed rulemaking and all
new information on OTC exocrine pancreatic insufficiency drug products
that has come to the agency's attention. This final rule is part of the
ongoing review of OTC drug products conducted by FDA.
EFFECTIVE DATE: October 24, 1995.
FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug
Evaluation and Research (HFD-810), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5000.
SUPPLEMENTARY INFORMATION:
I. Background
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, together with 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 by April 21,
1980. Reply comments in response to comments filed in the initial
comment period could be submitted by May 21, 1980.
In accordance with Sec. 330.10(a)(10), the data and information
considered by the Panel were placed on public display in the Dockets
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,
12420 Parklawn Dr., Rockville, MD 20857, after deletion of a small
amount of trade secret information. Only five comments were submitted
in response to the publication of the advance notice of proposed
rulemaking.
The agency's proposed regulation, in the form of a tentative final
monograph, for OTC exocrine pancreatic insufficiency drug products was
published in the Federal Register of November 8, 1985 (50 FR 46594).
That proposal constituted FDA's tentative adoption of the Panel's
conclusions and recommendations on OTC exocrine pancreatic
insufficiency drug products as modified on the basis of the comments
received and the agency's independent evaluation of the Panel's report
and information available at that time. In that document, 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 file by January 7, 1986, written
comments, objections, or requests for oral hearing before the
Commissioner of Food and Drugs (the Commissioner) regarding the
proposal, and by March 10, 1986, to file comments on the agency's
economic impact determination. New data could have been submitted until
November 10, 1986, and comments on the new data until January 8, 1987.
New information submitted in response to the tentative final
monograph caused the agency to reconsider the approach proposed in that
document. In vivo and in vitro studies of various commercial pancreatic
enzyme preparations had demonstrated variations in lipase activity and
release rates among the products. These variations in pancreatic
extract drug products occurred both among various dosage forms and
among products from different manufacturers of the same dosage form. In
addition, problems had been reported with pancreatic extract products
manufactured as tablets with enteric coatings and as encapsulated
enteric-coated microspheres. As a result of the wide range of enzyme
activity in these products, the variety of dosage forms marketed, and
the apparent uneven quality of the enteric coatings among pancreatic
extract drug products, instances of underdosing and overdosing with
pancreatic extract products have occurred. The agency determined that
preclearance of each product in order to standardize enzyme bioactivity
was necessary to avoid serious safety problems resulting from too
little or too much enzyme supplementation. The agency tentatively
concluded that an OTC drug monograph would not be sufficient to
adequately regulate these drug products. The agency discussed these
problems in the Federal Register of July 15, 1991 (56 FR 32282 at 32286
and 32287).
In that notice, FDA proposed to classify OTC drug products to treat
exocrine pancreatic insufficiency as not generally recognized as safe
and effective, as being misbranded, and as new drugs within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act)
(21 U.S.C. 321(p)). FDA proposed to amend part 310, subpart E by adding
new Sec. 310.543 (21 CFR 310.543) for OTC exocrine pancreatic
insufficiency drug products. The agency also withdrew its proposed rule
(part 357, subpart E) issued on November 8, 1985. Interested persons
were invited to file by November 12, 1991, written comments,
objections, or requests for oral hearing on the proposed regulation
before the Commissioner, and to file comments on the agency's economic
impact determination by November 12, 1991. Final agency action occurs
with the publication of this final rule on OTC exocrine pancreatic
insufficiency drug products.
In the Federal Register of March 11, 1992 (57 FR 8586), the agency
reopened the administrative record and announced that a workshop would
be held on April 23, 1992, to discuss testing procedures that will be
required as part of new drug applications (NDA's) for all exocrine
pancreatic insufficiency drug products. Relevant data and notice of
participation were to be submitted by April 10, 1992. The
administrative record remained open until July 23, 1992, to receive
comments regarding matters raised at the workshop.
In response to the announcement of the workshop, eight notices of
participation and three comments were submitted. Copies of the
comments, notices received, and information coming to the agency's
attention after the workshop are also on public display in the Dockets
Management Branch (address above). At the conclusion of the workshop,
manufacturers were encouraged to arrange pre-NDA meetings with agency
personnel so that NDA submissions could proceed as quickly as possible
(Ref. 1).
This final rule amends part 310 to include drug products containing
ingredients for the treatment of exocrine pancreatic insufficiency by
adding new [[Page 20163]] Sec. 310.543 to subpart E. The inclusion of
OTC exocrine pancreatic insufficiency drug products in part 310 follows
FDA's established policy for regulations in which there are no
monograph conditions. (See, e.g., Secs. 310.510, 310.519, 310.525,
310.526, 310.532, 310.533, 310.534, and 310.546.) It is the agency's
intent that exocrine pancreatic insufficiency drug products be marketed
by prescription only. However, if, in the future, any ingredient is
determined to be generally recognized as safe and effective for use in
an OTC exocrine pancreatic insufficiency drug product, the agency will
promulgate an appropriate regulation at that time.
FDA no longer uses the terms ``Category I'' (generally recognized
as safe and effective and not misbranded), ``Category II'' (not
generally recognized as safe and effective or misbranded), and
``Category III'' (available data are insufficient to classify as safe
and effective, and further testing is required) at the final rule
stage. In place of Category I, the term ``monograph conditions'' is
used; in place of Category II or III, the term ``nonmonograph
conditions'' is used.
In the proposed rule for OTC exocrine pancreatic insufficiency drug
products (56 FR 32282 at 32283), the agency advised that the final rule
for these drug products would be effective 6 months after the date of
its publication in the Federal Register. Therefore, on or after October
24, 1995, no OTC drug products that are subject to this final rule may
be initially introduced or initially delivered for introduction into
interstate commerce unless they are the subject of an approved
application. The agency is unaware of any OTC exocrine pancreatic
insufficiency drug products that are the subject of an approved
application. Any such drug product in interstate commerce after the
effective date of this final rule that is not in compliance with the
regulation is subject to regulatory action.
In response to the proposed rule on OTC exocrine pancreatic
insufficiency drug products, five drug manufacturers, one foundation,
and three individuals submitted comments. Copies of the comments
received and any additional information that has come to the agency's
attention since publication of the proposed rule are on public display
in the Dockets Management Branch (address above).
Reference
(1) Comment No. MM1, Docket No. 79N-0379, Dockets Management
Branch.
II. The Agency's Conclusions on the Comments
1. Six comments (including the Cystic Fibrosis Foundation and the
American Academy of Pediatrics) agreed with the agency's proposal that
exocrine pancreatic insufficiency drug products should not be marketed
OTC. Three comments opposed the proposal. Two of those comments stated
that increased costs to consumers would include a physician's fee and a
higher markup when sold by prescription. The third comment indicated
that these products are currently reasonably priced as nonprescription
drugs.
The agency appreciates the support of the six agreeing comments and
is finalizing its proposal that all exocrine pancreatic insufficiency
drug products should be available only by a doctor's prescription. The
agency stated in the proposed rule that continuous physician monitoring
of patients appears to be one of several important factors in the
increased survival rates for exocrine pancreatic insufficiency patients
(56 FR 32282 at 32285). Accordingly, such collateral measures necessary
to the use of these drug products require that they be available by
prescription only, as required by section 503(b)(1)(B) of the act (21
U.S.C. 353(b)(1)(B)). The agency acknowledges the cost concerns raised
by the three opposing comments. However, as stated in the proposed rule
(56 FR 32282 at 32285), financial considerations are not among the
statutory criteria for determining whether a drug product should be
restricted to prescription status.
2. Two comments disagreed with the agency's proposal that NDA
approval be required for continued marketing of all exocrine pancreatic
insufficiency drug products. One comment stated that the proposal is
inconsistent with the Panel's and the agency's previous conclusion that
these products have been safely used to treat exocrine pancreatic
insufficiency for many years (50 FR 46594 at 46597). The comment
contended that the July 15, 1991, proposal did not contain any new
evidence showing that the initial conclusion was erroneous. The comment
stated that the agency's concerns are based on a perceived inability of
patients to treat themselves and mentioned that this problem could be
remedied by requiring these products to be available by prescription,
without the need for an NDA for continued safe and effective use. The
comment contended that an NDA requirement would have a devastating
effect on patients who require these products for survival, e.g.,
cystic fibrosis patients. The comment surmised that most manufacturers
would withdraw their exocrine pancreatic insufficiency drug products
from the market if an NDA were required, primarily because of NDA-
associated costs. The comment added that manufacturers would wait until
another manufacturer's application was approved so they could submit an
abbreviated NDA. A third comment made a number of suggestions for the
bioactivity testing requirements, urged that certain products that had
been extensively used and studied be granted approval on the basis of
published reports and in vitro data, and contended that placebo-
controlled safety and effectiveness studies in cystic fibrosis patients
are unethical.
The agency disagrees with the first two comments. The agency's
position on exocrine pancreatic insufficiency drug products changed
between 1985 and 1991. Based on variations in formulations and dosage
forms, e.g., encapsulated microsphere dosage forms, in use in 1991, the
agency determined that final formulation effectiveness testing and
information on the product's formulation, manufacture, and quality
control procedures are necessary to ensure that a company has the
ability to manufacture a proper, bioactive formulation (56 FR 32282 at
32283). Because there are no approved NDA's for any exocrine pancreatic
insufficiency drug products, the agency has no information on the
bioactivity of these products. The agency notes that even if all
products were available only by prescription, variances in bioactivity
of final formulations could pose safety concerns. Additional
information (which an NDA would contain) is needed to assure safe and
effective use of these products. Bioactivity must be shown to correlate
with the stated potency of each proposed product, particularly for
newer formulations that include microspheres and high potency levels of
the pancreatic enzymes.
The agency is not persuaded by the comment's suggestion that
manufacturers would not submit applications for pancreatic enzyme
products and would wait until abbreviated NDA's were possible. The
agency acknowledges that a number of manufacturers are currently
seeking NDA approval for their currently marketed exocrine pancreatic
insufficiency drug products.
The agency has received a number of reports of occurrences of
stricture of the colon in cystic fibrosis patients who had taken higher
potency pancreatic enzymes in delayed release microtablets and
microspheres for varying numbers of months prior to corrective surgery
[[Page 20164]] (Refs. 1 through 8). The agency is concerned that there
may be a relationship between the use of these formulations and
stricture of the colon. The agency needs to evaluate manufacturing
information for these formulations, which would be included in an NDA.
The third comment's suggested bioactivity testing requirements,
support for approval of certain products, and opposition to placebo-
controlled studies are outside the scope of this document. The agency
notes, however, that it is widely believed that demonstration of the
fat digestive actions of various preparations can be done in ethical
human studies. Inquiries relating to these subjects should be directed
to the 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, 301-443-0479.
References
(1) Cystic Fibrosis Foundation Results of a Survey of 114 Cystic
Fibrosis Care Centers in United States, Patient Registry 1992 Annual
Data Report, Bethesda, MD, October 1993, in OTC Vol. 17BFR, Docket
No. 79N-0379, Dockets Management Branch.
(2) Smyth, R. L. et al., ``Strictures of Ascending Colon in
Cystic Fibrosis and High-Strength Pancreatic Enzymes,'' Lancet,
343:85-86, 1994.
(3) Oades, P. J. et al., ``Letter to the Editor,'' Lancet,
343:109, 1994.
(4) Campbell, C. A., J. Forrest, and C. Musgrove, ``Letter to
the Editor,'' Lancet, 343:109, 1994.
(5) Briars, G. L. et al., ``Letter to the Editor,'' Lancet,
343:600, 1994.
(6) Mahony, M. J., and M. Corcoran, ``Letter to the Editor,''
Lancet, 343:599-600, 1994.
(7) Knabe, N. et al., ``Letter to the Editor,'' Lancet,
343:1230, 1994.
(8) Taylor, C. J., ``Colonic Strictures in Cystic Fibrosis,''
Lancet, 343:615-616, 1994.
3. As an alternative to the NDA process, one comment recommended
that a uniform convention be developed for labeling exocrine pancreatic
insufficiency drug products to clearly describe product potency. The
comment urged that labels include the expiration date and rate of loss
of potency, and indicate that proprietary agents are not generally
equivalent.
The agency disagrees with the comment's alternative to the NDA
process. Uniform labeling to describe product potency is important;
however, that alone will not ensure safety and effectiveness of these
products. The comment's labeling suggestions will be considered, based
on data considered in applications, as NDA's for these products are
approved. These issues are outside of the scope of this rulemaking.
4. One comment urged the agency not to issue a final rule for OTC
exocrine pancreatic insufficiency drug products until NDA's for these
products have been approved. Alternatively, the comment asked that the
agency withdraw its proposal and request that NDA's be submitted for
exocrine pancreatic insufficiency drug products. The comment contended
that the latter action would be similar to the agency's action in 1978
regarding potassium iodide. The comment stated that either approach
would guarantee the availability of these products to patients who are
benefitting from them.
The agency disagrees with both of the comment's suggestions. In the
Federal Register of December 15, 1978 (43 FR 58798), the agency
published a notice requesting submission of NDA's for potassium iodide
in oral dosage forms for use as a thyroid-blocking agent in a radiation
emergency. The Commissioner concluded that potassium iodide was safe
and effective under certain specified conditions of use. However, the
Commissioner did not conclude that potassium iodide was generally
recognized as safe and effective (43 FR 58798 at 58799). Therefore,
potassium iodide was regarded as a new drug requiring an approved NDA
as a condition of marketing.
Exocrine pancreatic insufficiency drug products are a similar
situation. These products are safe and effective under specified
conditions of use, but their bioactivity raises both safety and
effectiveness concerns that require agency preclearance under NDA's.
The agency sees no reason to withdraw its proposal because the final
rule resulting from that proposal requires that an NDA be submitted for
any exocrine pancreatic insufficiency drug product marketed OTC.
Manufacturers have known since 1991 that an approved NDA would be
needed for continued marketing of their product(s) on an OTC basis.
While this final rule affects availability of these products when
marketed OTC, it does not affect products marketed on a prescription
basis. The agency intends that exocrine pancreatic insufficiency drug
products marketed by prescription also have an approved NDA. All
manufacturers of prescription exocrine pancreatic insufficiency drug
products will need to have an NDA for their product(s). The agency will
address this subject further in a future issue of the Federal Register.
III. The Agency's Final Conclusions on OTC Exocrine Pancreatic
Insufficiency Drug Products
A number of pancreatic enzyme drug products are currently marketed
OTC, and other products are marketed by prescription. Some of the
prescription products are encapsulated enteric coated microsphere
dosage forms. None of these pancreatic enzyme drug products have
approved applications, i.e, none have been precleared for marketing by
FDA. Some products are produced by different manufacturers and contain
the same active ingredient(s); however, these products have shown
significant differences in bioavailability. The agency finds that these
differences raise a potential for serious risk to patients using these
products.
Based on all available evidence, the agency has determined that the
bioavailability of pancreatic enzymes is dependent on the process used
to manufacture the drug products. Information on this process is not
addressed by an OTC drug monograph. Therefore, the agency has
determined that the safe and effective use of these enzymes for
treating exocrine pancreatic insufficiency cannot be regulated
adequately by an OTC drug monograph. In this final rule, the agency is
declaring that all exocrine pancreatic insufficiency drug products
(whether currently marketed on an OTC or prescription basis) are new
drugs for which approved applications will be required for marketing.
In the Federal Register of November 7, 1990 (55 FR 46914), the
agency published a final rule in part 310 establishing that certain
active ingredients that had been under consideration in a number of OTC
drug rulemaking proceedings were not generally recognized as safe and
effective. That final rule was effective on May 7, 1991, and included
in Sec. 310.545(a)(9) the ingredient hemicellulase, which had been
previously considered under this rulemaking for OTC exocrine pancreatic
insufficiency drug products. In order to avoid duplication in listing
OTC exocrine pancreatic insufficiency active ingredients in more than
one regulation, and for ease in locating these ingredients in the Code
of Federal Regulations, the agency is listing all of these ingredients
in a single regulation in new Sec. 310.543 entitled ``Drug products
containing active ingredients offered over-the-counter (OTC) for human
use in exocrine pancreatic insufficiency.'' Accordingly, the ingredient
hemicellulase, currently listed in Sec. 310.545(a)(9) is now being
listed in Sec. 310.543(d), and Sec. 310.545(a)(9) is being removed and
reserved. The ingredients pancreatin and pancrelipase, covered by this
final rule, are being listed in Sec. 310.543(e). [[Page 20165]]
IV. Analysis of Impacts
An analysis of the costs and benefits of this regulation, conducted
under Executive Order 12291 was discussed in the proposed rule (56 FR
32282 at 32289). Comments received were discussed in part II of this
final rule. Executive Order 12291 has been superseded by Executive
Order 12866.
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the final
rule is not a significant regulatory action as defined by the Executive
Order and, so, is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. This final rule will result in the removal of all
drug products containing the ingredients pancreatin and pancrelipase
from the OTC marketplace. However, only a limited number of OTC drug
products are marketed in this manner and are affected by this final
rule. Accordingly, the agency certifies that the final rule will not
have a significant economic impact on a substantial number of small
entities. Therefore, under the Regulatory Flexibility Act, no further
analysis is required.
The agency has determined under 21 CFR 25.24(c)(6) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
List of Subjects in 21 CFR Part 310
Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
310 is amended as follows:
PART 310--NEW DRUGS
1. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
360b-360f, 360j, 361(a), 371, 374, 375, 379(e); secs. 215, 301,
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.
216, 241, 242(a), 262, 263b-263n).
2. New Sec. 310.543 is added to subpart E to read as follows:
Sec. 310.543 Drug products containing active ingredients offered over-
the-counter (OTC) for human use in exocrine pancreatic insufficiency.
(a) Hemicellulase, pancreatin, and pancrelipase have been present
as ingredients in exocrine pancreatic insufficiency drug products.
Pancreatin and pancrelipase are composed of enzymes: amylase, trypsin
(protease), and lipase. Significant differences have been shown in the
bioavailability of marketed exocrine pancreatic insufficiency drug
products produced by different manufacturers. These differences raise a
potential for serious risk to patients using these drug products. The
bioavailability of pancreatic enzymes is dependent on the process used
to manufacture the drug products. Information on this process is not
included in an OTC drug monograph. Therefore, the safe and effective
use of these enzymes for treating exocrine pancreatic insufficiency
cannot be regulated adequately by an OTC drug monograph. Information on
the product's formulation, manufacture, quality control procedures, and
final formulation effectiveness testing are necessary in an approved
application to ensure that a company has the ability to manufacture a
proper bioactive formulation. In addition, continuous physician
monitoring of patients who take these drug products is a collateral
measure necessary to the safe and effective use of these enzymes,
causing such products to be available by prescription only.
(b) Any drug product that is labeled, represented, or promoted for
OTC use in the treatment of exocrine pancreatic insufficiency is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act (the act), for which an approved
application under section 505 of the act and part 314 of this chapter
is required for marketing. In the absence of an approved application,
such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use in the
treatment of exocrine pancreatic insufficiency is safe and effective
for the purpose intended must comply with the requirements and
procedures governing the use of investigational new drugs set forth in
part 312 of this chapter.
(d) After May 7, 1991, any such OTC drug product that contains
hemicellulase initially introduced or initially delivered for
introduction into interstate commerce that is not in compliance with
this section is subject to regulatory action.
(e) After October 24, 1995, any such OTC drug product that contains
pancreatin or pancrelipase initially introduced or initially delivered
for introduction into interstate commerce that is not in compliance
with this section is subject to regulatory action.
Sec. 310.545 [Amended]
3. Section 310.545 Drug products containing certain active
ingredients offered over-the-counter (OTC) for certain uses is amended
by removing and reserving paragraph (a)(9), and by revising paragraph
(d)(1) to read as follows:
Sec. 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(d) * * *
(1) May 7, 1991, for products subject to paragraphs (a)(1) through
(a)(4), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except as covered by
paragraph (d)(3) of this section), (a)(8)(i), (a)(10)(i) through
(a)(10)(iii), (a)(12)(i) through (a)(12)(iv), and (a)(14) through
(a)(18)(i) of this section.
* * * * *
Dated: April 13, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-10078 Filed 4-21-95; 8:45 am]
BILLING CODE 4160-01-F