Topical Otic Drug Products for Over-the-Counter Human Use; Products for Drying Water-Clogged Ears; Proposed Amendment of Monograph

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