[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]


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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.

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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.
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    \1\ See Sec. 201.66(b)(4) of this chapter.
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    (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