[Federal Register Volume 68, Number 137 (Thursday, July 17, 2003)]
[Proposed Rules]
[Pages 42324-42327]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-17934]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 348

[Docket No. 78N-0301]
RIN 0910-AA01


External Analgesic Drug Products for Over-the-Counter Human Use; 
Reopening of the Administrative Record and Amendment of Tentative Final 
Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is reopening the 
administrative record for the rulemaking for over-the-counter (OTC) 
external analgesic drug products to accept comments and data concerning 
OTC external analgesic drug products that have been filed with the 
Division of Dockets Management, FDA, since the administrative record 
officially closed. FDA is also amending the tentative final monograph 
(TFM) (proposed rule) to clarify the status of patch, plaster, and 
poultice dosage forms for OTC external analgesic drug products. FDA is 
providing for the administrative record to remain open for 90 days to 
allow for public comment on the comments and data being accepted into 
the rulemaking and on the status of patch, plaster, and poultice dosage 
forms for OTC external analgesic drug products. This action is part of 
FDA's ongoing review of OTC drug products.

DATES: Submit written or electronic comments and data by October 15, 
2003. See section IX of this document for the effective date of any 
final rule that may be published based on this proposal.

ADDRESSES: Submit written comments and data to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Gerald M. Rachanow, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2307.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA has on numerous occasions received new data and information 
bearing on OTC drug panel reports and proposed monographs after the 
closing of the administrative record in a rulemaking proceeding. Under 
Sec.  330.10(a)(7)(iii) (21 CFR 330.10(a)(7)(iii)), new data and 
information may be submitted within 12 months after publication of a 
TFM. Within 60 days after this 12-month period ends, comments on the 
new data and information may be submitted (see Sec.  330.10(a)(7)(iv)). 
Under Sec.  330.10(a)(10)(i), the administrative record closes at the 
end of this 60-day period.
    In the Federal Register of February 8, 1983 (48 FR 5852), FDA 
published the TFM on OTC external analgesic drug products for OTC human 
use. The

[[Page 42325]]

administrative record for this TFM closed on April 9, 1984. The 
administrative record for this rulemaking was last reopened on November 
19, 1997 (62 FR 61710) to include safety and effectiveness data on OTC 
vaginal douche drug product ingredients for external analgesic uses 
(e.g., povidone-iodine for the relief of minor vaginal itching and 
irritation) and closed on February 17, 1998. Under Sec.  
330.10(a)(7)(v), new data and information submitted after February 17, 
1998, prior to the establishment of a final monograph (FM), are 
considered a petition to amend the monograph and are to be considered 
only after a FM has been published unless the agency finds that good 
cause has been shown that warrants earlier consideration. Further, 
under Sec.  330.10(a)(10)(ii), FDA shall make all decisions and issue 
all orders under Sec.  330.10 in the FM solely on the basis of the 
administrative record and shall not consider data or information not 
included as part of the administrative record.
    FDA has received new data and information submitted to the external 
analgesic rulemaking after the administrative record closed on April 
19, 1984. In some cases, interested persons submitted a petition to 
reopen the record. In other cases, they submitted new data and 
information to the Division of Dockets Management as comments on the 
TFM. A number of the petitions and comments submitted to the TFM 
contain new data on proposed nonmonograph (Category II and Category 
III) ingredients and on external analgesic active ingredients applied 
in a patch, plaster, or poultice dosage form.

II. Reopening of the Administrative Record

    Because these data are relevant to the final classification of 
these ingredients in the FM, FDA has determined that good cause exists 
to consider these new data and information in developing the FM for 
these products. By this document, FDA announces that it is treating all 
of these submissions, received after the administrative record closed, 
as petitions to reopen the administrative record, and is granting the 
petitions by allowing the new data and information contained therein to 
be included in the administrative record for the rulemaking for OTC 
external analgesic drug products. Accordingly, the agency is reopening 
the administrative record for this rulemaking to accept data and 
information previously submitted to the Division of Dockets Management 
into the administrative record and to provide interested persons an 
opportunity to submit comments on these data and information prior to 
the closing of the record.

III. Status of Patch, Plaster, and Poultice Dosage Forms for OTC 
External Analgesic Drug Products

    After the TFM was published on February 8, 1983, FDA received a 
petition (Ref. 1) to amend portions of the TFM to add poultice or 
plaster dosage forms only for the counterirritant ingredients in 
proposed Sec.  348.12, specifically for the ingredients methyl 
salicylate; camphor; menthol; and capsicum. This petition led FDA to 
review the report of the Advisory Review Panel on OTC Topical 
Analgesic, Antirheumatic, Otic, Burn, and Sunburn Prevention and 
Treatment Drug Products (the Panel) (44 FR 69768, December 4, 1979), 
the TFM for OTC external analgesic drug products, available data, 
marketing history, and the current market for OTC counterirritant 
ingredients in topical drug products used in poultice and plaster 
dosage forms.
    FDA found that the Panel discussed poultices and plasters only in 
its discussion of allyl isothiocyanate (oil of mustard) (44 FR 69768 at 
69791 and 69792) and stated its concern that used as a poultice, the 
inflammatory action caused by allyl isothiocyanate may go beyond 
erythema to vesication. It was the Panel's opinion that although the 
actual number of adverse effects to external use of mustard 
preparations was relatively low, care should be taken to assure that 
safety is maintained through adequate packaging, labeling, and 
application. The low incidence of adverse reactions the Panel discussed 
(44 FR 69768 at 69791) was for an ointment dosage form (Ref. 2) and not 
for a plaster or poultice (a soft, moist mass about the consistency of 
cooked cereal, spread between layers of muslin, gauze, or towels and 
applied hot to a given area in order to create moist local heat or 
counterirritation). The Panel did briefly discuss mustard plaster, 
National Formulary IX , but did not include a plaster dosage form in 
its recommended dosage for this ingredient (44 FR 69768 at 69792).
    The Panel did not discuss plaster or poultice dosage forms for any 
other counterirritants, although articles from standard texts in some 
of the submissions to the Panel indicated that capsicum has been used 
in a plaster dosage form (Ref. 3). There was one submission to the 
Panel for a medicated poultice dressing containing methyl salicylate, 
salicylic acid, and eucalyptus oil as active ingredients (Ref. 4). 
Although the Panel recommended a Category I classification for methyl 
salicylate, it did not discuss the submission related to the use of 
this ingredient as a poultice or plaster. The submission did not 
contain any controlled clinical evaluations to support safety and 
effectiveness of the combination drug product or for the specific 
contribution of the individual active ingredients. The product's safety 
and effectiveness were based on its performance for 80 years. At that 
time, FDA surveyed several standard texts that listed currently 
marketed topical drug products containing counterirritants and did not 
find any plaster or poultice dosage forms listed therein.
    FDA stated (Ref. 5) that in order for poultice and plaster dosage 
forms to be generally recognized as safe and effective and to develop 
any additional labeling that may be needed for such dosage forms, it is 
necessary to obtain more information, specifically:
    1. The safe and effective concentration of the drug ingredient(s), 
especially under the occlusion of a plaster.
    2. Data on percutaneous absorption under occlusion.
    3. The length of contact time that it is safe to leave the poultice 
or plaster on the skin; how often the plaster or poultice needs to be 
changed for effective use.
    4. The frequency of application that is considered safe and 
effective.
    5. Whether or not directions and a warning are necessary regarding 
checking the area at specified intervals for erythema to prevent 
blistering, and what time intervals are recommended.
    6. The age groups for whom poultices and plasters are recommended 
for safe use.
    7. Labeling of currently marketed products.
    FDA's detailed comments are on file in the Division of Dockets 
Management (Ref. 5).
    Since that time, FDA has received a number of submissions on 
external analgesic counterirritant active ingredients in a plaster 
dosage form (Refs. 6 through 31). The submissions have included 
protocols and data to establish safety and effectiveness of the 
plaster/patch dosage forms. FDA has commented on the protocols and 
data, but has not found the information sufficient to support the 
safety and effectiveness of these dosage forms (Refs. 32 through 44). 
Further, FDA is not aware of sufficient data to classify any OTC 
external analgesic active ingredient in a patch, plaster, or poultice 
dosage form as Category I. Accordingly, FDA is classifying all OTC

[[Page 42326]]

external analgesic ingredients in a patch, plaster, or poultice dosage 
form in Category III (more data needed). FDA is proposing to amend the 
introductory language in Sec. Sec.  348.10 and 348.12 to include the 
following language at the end of the currently proposed language, to 
read as follows: ``The active ingredients of the product consist of any 
of the following, within the established concentration for each 
ingredient, but not for use in a patch, plaster, or poultice dosage 
form.'' FDA will revise this language if any of these active 
ingredients are found acceptable for use in one of these dosage forms.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). 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). Under the Regulatory 
Flexibility Act, if a rule has a significant economic impact on a 
substantial number of small entities, an agency must analyze regulatory 
options that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995 
requires that agencies prepare a written statement of anticipated costs 
and benefits before proposing any rule that may result in an 
expenditure in any one year by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million (adjusted 
annually for inflation).
    FDA believes that this proposed rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
FDA has determined that the proposed rule is not a significant 
regulatory action as defined by the Executive order and so is not 
subject to review under the Executive order. As explained later in this 
section, FDA believes that the proposed rule, if finalized, will not 
have a significant economic impact on a substantial number of small 
entities. The Unfunded Mandates Reform Act does not require FDA to 
prepare a statement of costs and benefits for this proposed rule, 
because the proposed rule is not expected to result in any 1-year 
expenditure that would exceed $100 million adjusted for inflation. The 
current inflation adjusted statutory threshold is about $110 million.
    The purpose of this proposed rule is to determine the monograph 
status of patch, plaster, and poultice dosage forms for external 
analgesic drug products for OTC human use. This proposed rule indicates 
that these dosage forms have not been determined to be generally 
recognized as safe and effective for any OTC external analgesic drug 
products at this time.
    Manufacturers who wish to market these types of products for 
external analgesic active ingredients need to provide additional safety 
and effectiveness data to FDA before the FM for these products is 
established. If adequate safety and effectiveness data are not 
provided, FDA will not include these types of dosage forms for external 
analgesic active ingredients in the FM, to be published in a future 
issue of the Federal Register, and any currently marketed products will 
no longer be able to be marketed when the FM becomes effective, unless 
they are the subject of an approved new drug application.
    FDA estimates that there is a limited number of OTC patch, plaster, 
and poultice external analgesic drug products currently in the 
marketplace. Reformulation will not be possible if these dosage forms 
are not included in the FM. Thus, manufacturers of these products may 
incur a loss of revenue. However, these manufacturers may be able to 
replace these products with other products that contain monograph 
ingredients in the dosage forms currently proposed for inclusion in the 
FM, e.g., creams, lotions, ointments. Manufacturers will not incur any 
costs related to proving safety and effectiveness of the active 
ingredients in these proposed monograph dosage forms. Based on the lack 
of adequate scientific information on external analgesic active 
ingredients in patch, plaster, and poultice dosage forms, FDA does not 
believe that there are any significant alternatives to the proposed 
rule that would adequately provide for the safe and effective use of 
these specific OTC drug products.
    Under the Regulatory Flexibility Act, if a rule has a significant 
impact on a substantial number of small entities, an agency must 
analyze regulatory options that would minimize any significant impact 
of a rule on small entities. This proposed rule would exclude patch, 
plaster, and poultice dosage forms from the final monograph for OTC 
external analgesic drug products. A few entities that currently market 
these products may incur significant impacts if these products are not 
included in the final monograph. However, as only a limited number of 
small firms market these products in the dosage forms that may not be 
included in the FM, FDA does not believe that this proposed rule will 
impose a significant economic burden on affected entities. Thus, this 
economic analysis, together with other relevant sections of this 
document, serves as FDA's initial regulatory flexibility analysis, as 
required under the Regulatory Flexibility Act.
    FDA invites public comment regarding any substantial or significant 
economic impact that this rulemaking would have on manufacturers who 
market these products. Comments regarding the impact of this rulemaking 
on such manufacturers should be accompanied by appropriate 
documentation. FDA is providing a period of 90 days from the date of 
publication of this proposed rulemaking in the Federal Register for 
comments to be developed and submitted. FDA will evaluate any comments 
and supporting data that are received and will reassess the economic 
impact of this rulemaking in the preamble to the final rule.

V. Paperwork Reduction Act of 1995

    This proposed rule contains no collections of information. 
Therefore, clearance by the Office of Management and Budget under the 
Paperwork Reduction Act of 1995 is not required.

VI. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) 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.

VII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
the agency tentatively concludes that the proposed rule does not 
contain policies that have federalism implications as defined in the 
Executive order and, consequently, a federalism summary impact 
statement is not required.

VIII. Request for Comments

    FDA is reopening the administrative record for a period of 90 days 
for

[[Page 42327]]

comments, new data, and information to be submitted. Interested persons 
have already had an opportunity to submit comments, objections, or 
requests for an oral hearing on the TFM. Therefore, any comments at 
this time should only address the data and information submitted to the 
administrative record after April 9, 1984, and should specifically 
identify the data and information on which the comments are being 
provided. In addition, only new information related to the submissions 
being included in the administrative record at this time should be 
submitted. Any data and information previously submitted to this 
rulemaking need not be resubmitted. In establishing an FM, FDA will 
consider only comments, data, and information submitted prior to the 
closing of the administrative record following this current reopening.
    Interested persons may submit to the Division of Dockets Management 
(see Addresses) written or electronic comments regarding this document. 
Submit a single copy of electronic comments to http://www.fda.gov/dockets/ecomments or three paper copies of any mailed comments, except 
that individuals may submit one paper copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

IX. Proposed Effective Date

    FDA is proposing that any final rule that may issue based on this 
proposal become effective 12 months after its date of publication in 
the Federal Register.

X. References

    The following references are on display in the Division of Dockets 
Management (see Addresses) under Docket No. 78N-0301 and may be see by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Comment No. CP6.
    2. OTC vol. 060051.
    3. OTC vol. 060033.
    4. OTC vol. 060052.
    5. Comment No. LET39.
    6. Comment No. C109.
    7. Comment No. CP8.
    8. Comment No. SUP8.
    9. Comment No. LET46.
    10. Comment No. RPT4.
    11. Comment No. LET51.
    12. Comment No. C111.
    13. Comment No. LET57.
    14. Comment No. LET66.
    15. Comment No. PR1.
    16. Comment No. PR2.
    17. Comment No. CR9.
    18. Comment No. CP13.
    19. Comment No. C116.
    20. Comment No. PR3.
    21. Comment No. LET71.
    22. Letter from M. Rapaport to D. Bowen, FDA, dated May 1, 1997.
    23. Letter from M. Rapaport to L. Katz and S. Aurecchia, FDA, dated 
May 28, 1997.
    24. Telefax from J. L. Boren, Argus Research, Inc., to M. Rapaport, 
dated June 17, 1997.
    25. Letter from M. Rapaport to S. Aurecchia, FDA, dated June 23, 
1997.
    26. Letter from M. Rapaport to L. Katz and S. Aurecchia, FDA, dated 
July 1, 1997.
    27. Comment No. LET84.
    28. Letter from M. Rapaport to E. Yuan, FDA, dated April 1, 2000.
    29. Comment No. SUP9.
    30. Comment No. SUP10.
    31. Comment No. SUP11.
    32. Comment No. LET49.
    33. Comment No. LET50.
    34. Comment No. LET55.
    35. Comment No. LET61.
    36. Comment No. MM9.
    37. Comment No. LET67.
    38. Comment No. LET68.
    39. Comment No. LET69.
    40. Comment No. LET70.
    41. Comment No. PDN2.
    42. Comment No. LET85.
    43. Comment No. MM10.
    44. Comment No. LET86.

List of Subjects in 21 CFR Part 348

    Labeling, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 348 (as proposed in the Federal Register of 
February 8, 1983 (48 FR 5852)) be amended as follows:

PART 348--EXTERNAL ANALGESIC DRUG PRODUCTS FOR OVER-THE-COUNTER 
HUMAN USE

    1. The authority citation for 21 CFR part 348 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
    2. Section 348.10 is amended by revising the introductory text to 
read as follows:


Sec.  348.10  Analgesic, anesthetic, and antipruritic active 
ingredients.

    The active ingredients of the product consist of any of the 
following, within the established concentration for each ingredient, 
but not for use in a patch, plaster, or poultice dosage form:
* * * * *
    3. Section 348.12 is amended by revising the introductory text to 
read as follows:


Sec.  348.12  Counterirritant active ingredients.

    The active ingredients of the product consist of any of the 
following, within the established concentration for each ingredient, 
but not for use in a patch, plaster, or poultice dosage form:
* * * * *

    Dated: July 7, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-17934 Filed 7-16-03; 8:45 am]
BILLING CODE 4160-01-S