[Federal Register Volume 64, Number 158 (Tuesday, August 17, 1999)]
[Proposed Rules]
[Pages 44671-44674]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-21252]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310 and 344
[Docket No. 77N-334S]
RIN 091O-AA01
Topical Otic Drug Products for Over-the-Counter Human Use;
Products for Drying Water-Clogged Ears; Proposed Amendment of Monograph
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of
proposed rulemaking that would amend the final monograph for over-the-
counter (OTC) topical otic drug products (the regulation that
establishes conditions under which these drug products are generally
recognized as safe and effective and not misbranded). The amendment
would add conditions for marketing topical otic drug products for
drying water-clogged ears. Concurrently, the agency is proposing to
remove water-clogged ears from one part of the regulation that lists
conditions that are not generally recognized as safe and effective and
that are misbranded. This proposal contains labeling in the new OTC
drug format and is part of the ongoing review of OTC drug products
conducted by FDA.
DATES: Submit written comments on the proposed regulation by November
15, 1999. Please see section VIII for the effective date of any final
rule that may publish based on this proposal.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Elizabeth A. Ryland, Center for Drug
Evaluation and Research (HFD-560), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2222.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of July 9, 1982 (47 FR 30012), the agency
published a tentative final monograph for OTC topical otic drug
products used as earwax removal aids. Subsequently, in the Federal
Register of July 30, 1986 (51 FR 27366), the agency proposed to amend
this tentative final monograph to consider OTC topical otic drug
products for the prevention of swimmer's ear and for the drying of
water-clogged ears. At that time, no topical otic drug products for
these conditions were proposed as generally recognized as safe and
effective and not misbranded. The agency, however, did propose Category
I (monograph) labeling for such products in case data were submitted
that resulted in upgrading any ingredient(s) to monograph status in the
final rule.
In the Federal Register of August 8, 1986 (51 FR 28656), the agency
issued a final rule establishing part 344 (21 CFR part 344) for topical
otic drug products for OTC human use. The monograph included one active
ingredient for use as an earwax removal aid.
In the Federal Register of November 7, 1990 (55 FR 46914), the
agency published a final rule 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 (hereinafter referred to as the 1990 final rule). The 1990
final rule was effective on May 7, 1991, and included in
Sec. 310.545(a)(15) (21 CFR 310.545(a)(15)) the active ingredient
acetic acid, which had been under consideration as part of this
rulemaking for OTC topical otic drug products for the prevention of
swimmer's ear and for the drying of water-clogged ears. After the 1990
final rule published, only two ingredients remained to be evaluated in
this rulemaking: Isopropyl alcohol and anhydrous glycerin.
In the Federal Register of February 15, 1995 (60 FR 8916), the
agency issued a final rule establishing that OTC topical otic drug
products for prevention of swimmer's ear or for drying water-clogged
ears were not generally recognized as safe and effective for OTC use
and were new drugs under section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act) (21 U.S.C. 321(p)). The agency listed the
ingredients considered in the rulemaking (i.e., glycerin, anhydrous
glycerin, and isopropyl alcohol) in Sec. 310.545(a)(15)(ii), with an
effective date of August 15, 1995, after which products containing
these ingredients for these uses could no longer be initially
introduced or initially delivered for introduction into interstate
commerce. Acetic acid, which had been listed solely in Sec. 310.545,
was now listed in Sec. 310.545(a)(15)(i), with the same effective date
of May 7, 1991. This final rule did not affect the conclusion reached
in the 1990 final rule that acetic acid was not generally recognized as
safe and effective for the prevention of swimmer's ear. The phrase
``approved
[[Page 44672]]
as of May 7, 1991'' in Sec. 310.545(a)(15)(i) indicates when this
conclusion became effective for acetic acid.
Subsequently, a drug manufacturer submitted new data (Ref. 1) to
support the use of a product containing 95 percent isopropyl alcohol in
a 5 percent anhydrous glycerin base for drying water-clogged ears. The
agency has determined that the data support the use of this product for
drying water-clogged ears (Ref. 2). Accordingly, in the Federal
Register of August 16, 1995 (60 FR 42435), the agency issued a partial
stay of the August 15, 1995, effective date for Sec. 310.545(a)(15)(ii)
for products containing 95 percent isopropyl alcohol in a 5 percent
anhydrous glycerin base used for the drying of water-clogged ears. This
partial stay applied only to products with these ingredients for drying
water-clogged ears. The new data and the stay did not involve other
ingredients, such as acetic acid, and did not pertain to the prevention
of swimmer's ear. The August 15, 1995, effective date for
Sec. 310.545(a)(15)(ii) remains in effect for the listed ingredients
when used in topical otic drug products for the prevention of swimmer's
ear.
II. The Agency's Proposal
A. Evaluation of the Data
The new data (Ref. 1) included the results of a double-blinded,
three-arm, parallel study to evaluate the effectiveness and
tolerability of isopropyl alcohol in drying water-clogged ears in 90
adult volunteers. Subjects were recruited if they were otherwise
healthy but had a history of water-clogged ears. A screening test was
performed by instilling five drops of water into the ear designated for
testing and then examining the ear using an operating microscope.
Subjects who had only mild residual fluid, or none, were disqualified
from the study. Subjects with moderate fluid retention (defined as
having an amount of liquid that placed the meniscus up to one-half of
the visible height of the eardrum to the umbo) or greater were then
randomized into one of the three treatment arms: Isopropyl alcohol 95
percent in anhydrous-glycerin 5 percent, isopropyl alcohol 100 percent,
and no treatment. While subjects in the no-treatment control arm
received no drug, the study nurse conveyed a sense of treatment by
adding five drops of air from an empty dropper to the subjects' ears.
The results of the study showed that isopropyl alcohol (with and
without glycerin) is effective in drying excess water in the subjects'
ear canal compared to no treatment, even though the size was
insufficient to detect a statistical difference in efficacy between the
two isopropyl alcohol treatment arms. Many subjects in both alcohol
arms complained of burning/warming after even a single treatment. The
intensity of this sensation (as determined by each subject) was up to
40 on a visual analog score (VAS) 50-point scale. No irritation
(excessive burning) was documented after a single use. Overall, the
results showed that subjects who received isopropyl alcohol with
glycerin had better numerical scores than those on isopropyl alcohol
alone relative to both effectiveness and tolerability. Subjects on
isopropyl alcohol with glycerin had lower burning scores than those on
isopropyl alcohol alone, even though the power of this study was
insufficient to show a statistically significant difference. Thus, the
agency has determined that it would be preferable for consumers to use
a product containing 95 percent isopropyl alcohol in 5 percent
anhydrous glycerin instead of a product containing 100 percent
isopropyl alcohol. The agency's detailed comments and evaluations of
the data (Ref. 2) are on file in the Dockets Management Branch (address
above).
Based on these new data, the agency is proposing to amend part 344
to include ``ear drying aid'' drug products. The monograph active
ingredient for these products is 95 percent isopropyl alcohol in 5
percent anhydrous glycerin base.
B. Labeling
In the July 30, 1986, proposal (51 FR 27366 at 27373), the agency
proposed Category I labeling in the event that data were submitted that
resulted in upgrading any ingredient(s) to monograph status in the
final rule. The agency stated that although the term ``water-clogged
ears'' is not a recognized clinical entity, it is a term consumers use
to refer to the temporary retention of water in the ears after
swimming, showering, washing the hair, bathing, etc. (51 FR 27366 at
27370). The agency also stated that claims such as ``helps relieve the
discomfort of water-clogged ears by drying excess water,'' and ``helps
dry water in the ear,'' would be acceptable because these claims relate
to the relief of the symptoms as described in the previous sentence. At
this time, the agency is proposing language that is consistent with the
earlier version but is more concise, that is, ``Dries water in the
ear,'' or that incorporates some of the common causes of water-clogged
ears, that is, ``Dries and relieves water-clogged ears after swimming,
showering, bathing, or washing the hair.'' The agency is also allowing
other truthful and nonmisleading statements to be used as provided in
Sec. 330.1(c)(2) (21 CFR 330.1(c)(2)). The proposed statement of
identity for these products is ``ear drying aid.''
The agency is proposing the same warnings previously proposed in
Sec. 344.52(c)(1), (c)(2), (c)(3), and (c)(5) of the July 30, 1986,
tentative final monograph (51 FR 27366 at 27373) but is proposing them
in the new OTC drug labeling format (see 64 FR 13254, March 17, 1999).
The agency is changing the warning previously proposed in
Sec. 344.52(c)(4), which stated: ``Discontinue use and consult a doctor
if undue irritation or sensitivity occurs.'' The agency is expanding
the term ``irritation'' to include ``too much burning'' and is deleting
the term ``sensitivity'' because the alcohol treatment products in the
clinical study (Ref. 1) produced some burning (intensity was moderate
to severe during a single use (up to 40 on a 50-point scale)). The
agency is concerned about repeated use and long-term use. Accordingly,
the agency is revising the language in the proposed warning in
Sec. 344.52(c)(4) to now read: ``Stop use and ask a doctor if [in bold
type] irritation (too much burning) or pain occurs''. One manufacturer
expressed disagreement (Ref. 3) with the inclusion of the phrase ``too
much [or excessive] burning,'' and the agency requested the
manufacturer to provide additional data on this subject (Ref. 2).
However, no data were ever provided. Based on the clinical study (Ref.
1), the agency is proposing the following directions: ``apply 4 to 5
drops in each affected ear''.
Existing part 344 currently includes only topical otic drug
products used as earwax removal aids. The current headings for
Secs. 344.10 and 344.50 refer to a topical otic active ingredient and
labeling of topical otic drug products, respectively. Accordingly,
Secs. 344.10 and 344.50 will become ``Earwax removal aid active
ingredient'' and ``Labeling of earwax removal aid drug products,''
respectively. The agency is proposing new Secs. 344.12 and 344.52 as
``Ear drying aid active ingredient,'' and ``Labeling of ear drying drug
products,'' respectively. The agency is proposing to delete
Sec. 344.50(e), which refers to substitution of the word ``physician''
for the word ``doctor'' because this is now covered in
Sec. 330.1(i)(23) (21 CFR 330.1(i)(23)). Likewise, the agency is not
proposing previously proposed Sec. 344.52(e) (concerning substitution
of ``physician'' for ``doctor'') (51 FR 27366 at 27373) because it is
also covered by Sec. 330.1(i)(23).
[[Page 44673]]
III. Summary of Agency Changes
1. Section 344.52(b), under the heading ``Use,'' follows the new
OTC drug labeling format in Sec. 201.66(d)(4) (21 CFR 201.66(d)(4)) and
provides several options to customize the uses.
2. Section 344.52(c), under the heading ``Warnings,'' follows the
new OTC drug labeling format in Sec. 201.66(c)(5) (21 CFR 201.66(c)(5))
and states all of the warnings after the new appropriate subheadings.
3. The agency has revised the format of the headings for
Sec. 310.545(a)(15), (a)(15)(i), and (a)(15)(ii).
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).
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.
Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et
seq.) requires that agencies prepare a written statement and economic
analysis 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).
The agency believes that this proposed rule is consistent with the
principles set out in the Executive Order and in these two statutes.
The purpose of this proposed rule is to establish conditions for drug
products used to dry water-clogged ears containing alcohol and
glycerin. This proposed rule amends the final monograph for OTC topical
otic drug products containing alcohol and glycerin for the drying of
water-clogged ears and will require some product relabeling. The
agency's Drug Listing System identifies only one manufacturer/marketer
of one stockkeeping unit (SKU) (individual product, package, and size)
of OTC topical otic drug products with these ingredients for drying
water-clogged ears. There may be other manufacturers/marketers not
identified in sources FDA reviewed, but the agency believes there are a
limited number.
The agency has been informed that relabeling costs of the type
required by this proposal generally average about $2,000 to $3,000 per
SKU. Assuming there could be as many as five affected OTC SKU's in the
marketplace, total one-time costs of relabeling would be $10,000 to
$15,000. The agency believes that actual costs would be lower for
several reasons.
First, the agency has proposed the revised labeling in the new OTC
drug labeling format (64 FR 13254). Therefore, manufacturers will not
incur expenses determining how to state the new information in product
labeling. Manufacturers, however, will incur some expense to redesign
product labeling. Manufacturers will be able to incorporate the revised
labeling changes with the new general OTC drug labeling final rule,
implementing all labeling changes at one time. Thus, the relabeling
costs resulting from two different but related final rules will be
individually reduced by implementing both required changes at the same
time.
The agency certifies that this proposed rule will not have a
significant economic impact on a substantial number of small entities.
The one identified manufacturer/marketer is a small entity using the
U.S. Small Business Administration designations for this industry (750
employees). The agency believes that any other unidentified
manufacturer of these products is probably also a small entity. Based
on the limited number of SKU's (usually only one) each manufacturer has
to relabel, the cost for each manufacturer should be minimal.
This analysis shows that this proposed rule is not economically
significant under Executive Order 12866. Finally, this analysis shows
that the Unfunded Mandates Reform Act does not apply to the proposed
rule because it would not 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.
V. Paperwork Reduction Act of 1995
FDA tentatively concludes that the labeling requirements proposed
in this document are not subject to review by the Office of Management
and Budget because they do not constitute a ``collection of
information'' under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501
et seq.). Rather, the proposed labeling requirements are a ``public
disclosure of information originally supplied by the Federal Government
to the recipient for the purpose of disclosure to the public'' (5 CFR
1320.3(c)(2)).
VI. Environmental Impact
The agency has determined under 21 CFR 25.31(c) 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. Request for Comments
Interested persons may, on or before November 15, 1999, submit
written comments to the Dockets Management Branch (address above).
Written comments on the agency's economic impact determination may be
submitted on or before November 15, 1999. Three copies of all comments
are to be submitted, except that individuals may submit one copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document and may be accompanied by a supporting
memorandum or brief. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
VIII. Proposed Effective Date
FDA is proposing that any final rule based on this proposal become
effective 12 months after its date of publication in the Federal
Regiser.
IX. References
The following references are on display in the Dockets Management
Branch (address above) and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday.
1. Comment No. CP1, Docket No. 77N-334S, Dockets Management
Branch.
2. Letter from W. E. Gilbertson, FDA, to N. Buc, Buc Levitt &
Beardsley, attorneys for Del Pharmaceuticals, Inc., coded LET13,
Docket No. 77N-334S, Dockets Management Branch.
3. Comment No. C7, Docket No. 77N-334S, Dockets Management
Branch.
List of Subjects
21 CFR Part 310
Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.
21 CFR Part 344
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 parts 310 and 344 be amended as follows:
PART 310--NEW DRUGS
1. The authority citation for 21 CFR part 310 continues to read as
follows:
[[Page 44674]]
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262,
263b-263n.
2. Section 310.545 is amended by revising the headings of
paragraphs (a)(15), (a)(15)(i), and (a)(15)(ii) to read as follows:
Sec. 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) * * *
(15) Topical otic drug products--(i) For the prevention of
swimmer's ear and for the drying of water-clogged ears, approved as of
May 7, 1991.
(ii) For the prevention of swimmer's ear, approved as of August 15,
1995.
* * * * *
PART 344--TOPICAL OTIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
3. The authority citation for 21 CFR part 344 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
4. Section 344.3 is amended by adding paragraphs (c) and (d) to
read as follows:
Sec. 344.3 Definitions.
* * * * *
(c) Water-clogged ears. The retention of water in the external ear
canal, thereby causing discomfort and a sensation of fullness or
hearing impairment.
(d) Ear drying aid. A drug used in the external ear canal to help
dry water-clogged ears.
5. Section 344.10 is amended by revising the section heading to
read as follows:
Sec. 344.10 Earwax removal aid active ingredient.
* * * * *
6. Section 344.12 is added to subpart B to read as follows:
Sec. 344.12 Ear drying aid active ingredient.
The active ingredient of the product consists of isopropyl alcohol
95 percent in an anhydrous glycerin 5 percent base.
7. Section 344.50 is amended by revising the section heading and by
removing paragraph (e) to read as follows:
Sec. 344.50 Labeling of earwax removal drug products.
* * * * *
8. Section 344.52 is added to subpart C to read as follows:
Sec. 344.52 Labeling of ear drying aid drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
``ear drying aid.''
(b) Indications. The labeling of the product states, under the
heading ``Use,'' the following: ``dries water in the ears'' (optional,
which may be followed by: ``and relieves water-clogged ears'') (which
may be followed by any or all of the following: ``after: [bullet]\1\
swimming [bullet] showering [bullet] bathing [bullet] washing the
hair''). Other truthful and nonmisleading statements, describing only
the indications for use that have been established and listed in
paragraph (b) of this section, may also be used, as provided in
Sec. 330.1(c)(2) of this chapter, subject to the provisions of section
502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to
misbranding and the prohibition in section 301(d) of the act against
the introduction or delivery for introduction into interstate commerce
of unapproved new drugs in violation of section 505(a) of the act.
---------------------------------------------------------------------------
\1\ See Sec. 201.66(b)(4) of this chapter.
---------------------------------------------------------------------------
(c) Warnings. The labeling of the product contains the following
warnings under the heading ``Warnings'':
(1) ``Flammable [in bold type]: Keep away from fire or flame.''
(2) ``Do not use [in bold type] in the eyes.''
(3) ``Ask a doctor before use if you have [in bold type] [bullet]
ear drainage or discharge [bullet] pain, irritation, or rash in the ear
[bullet] had ear surgery [bullet] dizziness.''
(4) ``Stop use and ask a doctor if [in bold type] irritation (too
much burning) or pain occurs.''
(d) Directions. The labeling of the product contains the following
statement under the heading ``Directions'': [optional, bullet] ``apply
4 to 5 drops in each affected ear.''
Dated: August 9, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-21252 Filed 8-16-99; 8:45 am]
BILLING CODE 4160-01-F