Sunscreen Drug Products for Over-the-Counter Human Use; Marketing Status of Products Containing Avobenzone; Enforcement Policy

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 352

[Docket No. 78N-0038]

RIN 0910-AA01

Sunscreen Drug Products for Over-the-Counter Human Use; Marketing

Status of Products Containing Avobenzone; Enforcement Policy

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AGENCY: Food and Drug Administration, HHS.

ACTION: Announcement of Enforcement Policy.

SUMMARY: The Food and Drug Administration (FDA) is announcing an

enforcement policy allowing over-the-counter (OTC) marketing of

sunscreen drug products containing avobenzone (Parsol 1789)

at concentrations of up to 3 percent alone and 2 to 3 percent

avobenzone in combination with the OTC sunscreen ingredients cinoxate,

diethanolamine methoxycinnamate, dioxybenzone, homosalate, octocrylene,

octyl methoxycinnamate, octyl salicylate, oxybenzone, sulisobenzone,

and/or trolamine salicylate. OTC marketing of such drug products is

being permitted pending establishment under the OTC drug review of a

final monograph covering sunscreen drug products. FDA anticipates that

sunscreen drug products containing up to 3 percent avobenzone alone and

2 to 3 percent avobenzone in combination with the proposed Category I

cinnamate, benzophenone, salicylate, and/or diphenylacrylate sunscreen

ingredients will be determined to be generally recognized as safe and

effective and not misbranded.

EFFECTIVE DATE: The enforcement policy is effective April 30, 1997.

ADDRESSES: Written comments to the Dockets Management Branch (HFA-305),

Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville,

MD 20857.

FOR FURTHER INFORMATION CONTACT: John D. Lipnicki, 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 an amendment to the tentative final monograph for OTC sunscreen

drug products, published in the Federal Register of September 16, 1996

(61 FR 48645), FDA proposed conditions under which products containing

avobenzone are generally recognized as safe and effective and not

misbranded at concentrations of up to 3 percent alone and 2 to 3

percent avobenzone in combination with the proposed Category I

cinnamate, benzophenone, salicylate, and/or diphenylacrylate sunscreen

ingredients. This proposal was based on an evaluation of available

safety and effectiveness data, which have been placed on display in the

Dockets Management Branch (address above).

Because no OTC drug advisory review panel had considered avobenzone

or avobenzone-containing combination drug products, the agency stated

that these products could not be marketed until the agency stated by

notice in the Federal Register that the products have been tentatively

determined to be generally recognized as safe and effective and that

OTC marketing will be permitted under specified conditions (61 FR 48645

at 48653). Before marketing could begin, the comment period for the

proposal must have ended

[[Page 23351]]

and another Federal Register notice must have been published setting

forth the agency's determination concerning interim marketing before

publication of the final rule for OTC sunscreen drug products. The

agency requested written comments by October 16, 1996.

In response to the proposed rule, seven commercial organizations,

one international organization, one professional organization, and one

individual consumer submitted comments. Copies of the comments received

are on public display in the Dockets Management Branch (address above).

II. The Agency's Conclusions on the Comments

1. Several comments discussed issues that impact all OTC sunscreen

drug products or all such products that provide ultraviolet A (UVA)

radiation protection, e.g., the definition of a sunscreen active

ingredient, a maximum sun protection factor (SPF) of 30, and UVA

testing methodology.

Following publication of the proposed rule for OTC sunscreen drug

products on May 12, 1993 (58 FR 28194), the agency received numerous,

similar comments. Because these issues impact other OTC sunscreen drug

products, the agency intends to address all of the comments in future

issues of the Federal Register. The agency does not find it necessary

to resolve these issues now to allow interim marketing of OTC sunscreen

drug products containing avobenzone under the proposed monograph.

2. One comment suggested that FDA should clarify the implication

that its failure to rely explicitly on available foreign marketing data

in determining that avobenzone is generally recognized as safe and

effective for use in certain OTC sunscreen formulations does not mean

that such data are unreliable, irrelevant, or inadequate compared to

analogous U.S. marketing data or that foreign data would not have

supported the agency's ultimate determination. The comment maintained

that FDA can use foreign marketing data alone to establish that an OTC

sunscreen active ingredient is generally recognized as safe and

effective. The comment recommended that FDA should promptly review

citizen petitions for all proposed OTC sunscreen ingredients and not

only those that provide protection against UVA radiation. The comment

referred to the agency's advance notice of proposed rulemaking on

eligibility criteria for considering additional conditions in the OTC

drug monograph system (61 FR 51625, October 3, 1996) and hoped that it

would be expedited with issuance of a final rule within 12 months.

Another comment urged the agency to grant two other citizen

petitions to include methylbenzylidene camphor (Ref. 1) and isoamyl-p-

methoxycinnamate (Ref. 2) as Category I sunscreen active ingredients.

In addition to foreign marketing data contained in the petitions, the

comment stated that the agency already has supportive data for the

combination of avobenzone with methylbenzylidene camphor (61 FR 48645

at 48647). The comment contended that FDA had grandfathered other

cinnamates based on supportive data concerning octyl methoxycinnamate

in combination with avobenzone and that this should be extended to

isoamyl-p-methoxycinnamate.

The agency's reliance on information other than the available

foreign marketing data in the amendment to the proposed rule for OTC

sunscreen drug products is not intended to reflect an ultimate agency

conclusion about the potential usefulness of foreign marketing data. As

discussed in the advance notice of proposed rulemaking on eligibility

criteria for considering additional conditions in the OTC drug

monograph system, marketing of an OTC drug in a foreign country (but

never in the United States) has in the past not been considered

sufficient to satisfy the requirements of marketing to a material

extent and for a material time which is necessary to make the drug

eligible for consideration in the OTC drug monograph system (61 FR

51625 at 51627). Any possible changes to that approach will be

considered under that rulemaking. The agency notes that avobenzone has

been marketed for a material time and extent in the United States, and

thus differs from other ingredients that do not have this marketing

history.

The petitions mentioned by the comments are referred to in that

advance notice of proposed rulemaking (61 FR 51625 at 51627). Final

resolution of those petitions will depend upon the outcome of that

rulemaking. In the meantime, manufacturers may seek marketing approval

for their products having only foreign marketing experience via a new

drug application (NDA).

References

(1) Comment No. CP1, Docket No. 78N-0038, Dockets Management

Branch.

(2) Comment No. CP3, Docket No. 78N-0038, Dockets Management

Branch.

3. Eight comments agreed with the agency's proposal to include

avobenzone in Secs. 352.10 and 352.20 of the proposed monograph for OTC

sunscreen drug products. Although agreeing with the agency's proposal,

one comment stated that avobenzone has not been adequately tested for

safety in children. The comment contended that children may be at

greater risk than adults for contact irritation and photoallergenic

reactions, and that the proposed warning statement in

Sec. 352.52(c)(1)(iii) (``Discontinue use if signs of irritation or

rash appear * * *'') may not be adequate for children. The comment

provided an abstract (Ref. 1) that reported the results of photopatch

testing using UV absorbers on 387 patients with dermatitis of the sun-

exposed areas of the body. Isopropyl dibenzoylmethane was reported to

induce 26 allergic and 35 photoallergic reactions and butyl

methoxydibenzoylmethane (avobenzone) was reported to induce 10 allergic

and 17 photoallergic reactions in these photopatch tests. The abstract

stated that the production of isopropyl dibenzoylmethane was stopped in

1993 because of ``frequent (photo)sensitization'' to this ingredient.

The comment requested that the agency do the following for an initial

period of at least 2 years: (1) Restrict the general use of avobenzone-

containing OTC sunscreen drug products to use by adults with labeling

warnings to physicians and parents concerning its use on children, and

(2) request companies to monitor all adverse reactions from avobenzone-

containing products, especially those in children.

The agency is aware of several European studies and case reports

(Refs. 2 and 4 through 8) involving patch/photopatch testing of

isopropyl dibenzoylmethane and avobenzone on people suspected of having

photodermatoses. With regard to this population, Buckley, O'Sullivan,

and Murphy (Ref. 6) noted that ``Many cases of sensitization have

occurred in subjects with pre-existing photodermatoses, where sunscreen

use is frequent; contact and photocontact dermatitis are more likely to

develop in injured or inflamed skin.'' Parry, Bilsland, and Morley

(Ref. 7) observed that suggested cross-sensitivity to isopropyl

dibenzoylmethane and avobenzone has previously been reported. Motley

and Reynolds (Ref. 8) stated that primary sensitization to avobenzone

is thought to be unusual compared to sensitization to isopropyl

dibenzoylmethane. Trevisi et al. (Ref. 2) reported that their study

seems to confirm that avobenzone could be a weaker sensitizer than the

isopropyl derivative. Urbach (Ref. 9) and

[[Page 23352]]

Dromgoole and Maibach (Ref. 10) noted that some allergic reactions to

avobenzone may have been cross-reactions as a result of prior exposure

to the isopropyl derivative. However, Buckley, O'Sullivan, and Murphy

(Ref. 6) pointed out that although combined sensitivity to isopropyl

dibenzoylmethane and avobenzone has been documented previously, it is

generally impossible to attribute it to cross-sensitivity between

dibenzoylmethanes, as people may unknowingly have previously been

exposed through cosmetic or sunscreen use. According to White (Ref. 3),

isopropyl dibenzoylmethane was voluntarily removed from the European

market due to frequent reports of contact and photocontact allergy,

whereas avobenzone was classified by the European Commission as

Category A, i.e., ``no further evidence needs to be submitted to

support its safety.''

The agency believes that, overall, medical literature reports of

allergic reactions to avobenzone appear to be few in comparison to the

scope of its usage and to the number of allergic reactions associated

with isopropyl dibenzoylmethane, a sunscreen ingredient that has never

been approved for use in the United States and that has been removed

from the European market. Neither a 10-year (1982 to 1992) French study

of 283 people (5 to 85 years of age) with suspected photodermatosis

(Ref. 5) nor a 3-year (1990 to 1993) Italian study of 108 people (10 to

79 years of age) with suspected photodermatosis (Ref. 2) reported any

positive photopatch reactions to avobenzone. The two studies reported a

total of seven positive photopatch reactions to isopropyl

dibenzoylmethane. Several reports (Refs. 6 through 10) suggest that

some allergic reactions to avobenzone may be related to prior

sensitization to isopropyl dibenzoylmethane. None of the studies or

reports (including the abstract provided by the comment) described any

special relationships between sensitivity to dibenzoylmethanes and age.

One comment reported that an avobenzone-containing OTC sunscreen

drug product has been marketed in the United States since 1993 (under

an approved NDA) with a total adverse event rate of 0.0067 percent. The

product is marketed for the general population (with the exception of

children under 6 months of age) and contains 3 percent avobenzone, 3

percent oxybenzone, and 7.5 percent octyl methoxycinnamate. The agency

previously discussed the adverse event information submitted by this

comment and adverse event reports contained in the agency's Spontaneous

Reporting System (SRS) in the amendment to the proposed rule for OTC

sunscreen drug products (61 FR 48645 at 48650 and 48651). These data

reveal that 6 of the 59 adverse drug experience (ADE) reports in the

SRS concerned reactions in children 12 years of age and under. Three of

these reports mention ``no drug effect'' and/or ``rash'' (one report

noted multiple preexisting allergies), two mention ``itching,'' and one

mentions ``burning.'' Thus, although ADE incidence rates or drug safety

comparisons cannot be made using SRS data alone, the agency believes

that the data support the safe use of avobenzone on children.

The agency notes that the Advisory Review Panel on OTC Topical

Analgesic, Antirheumatic, Otic, Burn, and Sunburn Prevention and

Treatment Products (the Panel) discussed ``adult skin'' and ``infant

skin'' in its reports on OTC external analgesic drug products (44 FR

69768 at 69773, December 4, 1979) and OTC sunscreen drug products (43

FR 38206 at 38217, August 25, 1978). The Panel thoroughly discussed the

absorptive characteristics of infant and adult skin and defined adult

human skin to be that of individuals older than 6 months of age. The

agency continues to concur with the Panel's recommended age limitations

concerning the use of sunscreens because biological systems that

metabolize and excrete drugs absorbed through the skin may not be fully

developed in children under the age of 6 months.

Thus, the agency believes that at this time the data do not support

the contention that children 1 to 12 years of age ``may be at a greater

risk than adults with respect to contact irritation reaction and

photoallergenic potential'' of avobenzone. Moreover, the comment did

not submit any data to support such a contention.

FDA considers protection against UVA radiation an important public

health benefit. As the agency stated in the amendment to the proposed

rule for OTC sunscreen drug products (61 FR 48645 at 48653), the

addition of avobenzone to the proposed monograph would provide for wide

availability of new combination sunscreen products that will provide

consumers with broad spectrum protection. The agency is also aware that

some individuals can have moderate or acute adverse reactions to active

ingredients that cause no reactions in most people. FDA currently

considers the warnings proposed in Sec. 352.52(c)(1)(iii)

(``Discontinue use if signs of irritation or rash appear. If irritation

or rash persists, consult a doctor.'') sufficient to alert consumers to

the possibility of an allergic reaction to avobenzone or any other

sunscreen active ingredient. At this time, the agency does not believe

there is a sufficient basis for a warning to restrict use of

avobenzone-containing sunscreen drug products to adults only, as one

comment suggested. Avobenzone-containing sunscreen drug products will

need to bear the directions in proposed Sec. 352.52(d)(1) or (d)(2),

which include the statements: ``Children under 2 years of age should

use sunscreen products with a minimum SPF of 4'' and ``Children under 6

months of age: consult a doctor.''

Regarding the comment's request that FDA ask companies to monitor

all adverse reactions from avobenzone-containing products, especially

those in children, the agency's current good manufacturing practice

regulations for finished pharmaceuticals (21 CFR 211.198) include

requirements for handling all written and oral complaints regarding a

drug product. However, while FDA encourages OTC drug manufacturers to

report adverse events under the agency's Medwatch program,

manufacturers are not required to do so. At this time, the agency's

adverse experience reporting requirements only apply to those OTC drugs

subject to approved NDA's or abbreviated NDA's (ANDA's). The agency is

considering a proposed regulation that would, among other things,

require manufacturers, packers, and distributors of marketed OTC drug

products that are not the subject of approved applications to report

ADE information to FDA. In the meantime, the agency will continue to

monitor ADE's for sunscreen drug products reported to its Medwatch

program and in the medical literature.

References

(1) Schauder, S., ``UV Absorber Allergy and Photoallergy: A 14-

Year Experience,'' abstract in Comment No. C518, Docket No. 78N-

0038, Dockets Management Branch.

(2) Trevisi, P. et al., ``Sunscreen Sensitization: A Three-Year

Study,'' Dermatology, 189:55-57, 1994.

(3) White, I. R., ``Risk of Contact Dermatitis from UV-A

Sunscreens'' (reply letter), Contact Dermatitis, 29:221, 1993.

(4) Comment No. CP5, Docket No. 78N-0038, Dockets Management

Branch.

(5) Szczurko, C. et al., ``Photocontact Allergy to Oxybenzone:

Ten Years of Experience,'' Photodermatology, Photoimmunology, and

Photomedicine, 10:144-147, 1994.

(6) Buckley, D. A., D. O'Sullivan, and G. M. Murphy, ``Contact

and Photocontact Allergy to Dibenzoylmethanes and Contact Allergy to

Methylbenzylidene Camphor,'' Contact Dermatitis, 28:47, 1993.

[[Page 23353]]

(7) Parry, E. J., D. Bilsland, and W. N. Morley, ``Photocontact

Allergy to 4-tert.butyl-4'-methoxy-dibenzoylmethane (Parsol 1789),''

Contact Dermatitis, 32:251, 1995.

(8) Motley, R. J., and A. J. Reynolds, ``Photocontact Dermatitis

Due to Isopropyl and Butyl Methoxy Dibenzoylmethanes (Eusolex 8020

and Parsol 1789),'' Contact Dermatitis, 21:109, 1989.

(9) Urbach, F., ``Risk of Contact Dermatitis from UV-A

Sunscreens'' (letter), Contact Dermatitis, 29:220, 1993.

(10) Dromgoole, S. H., and H. I. Maibach, ``Sunscreening Agent

Intolerance: Contact and Photocontact Sensitization and Contact

Urticaria,'' Journal of the American Academy of Dermatology,

22:1068-1078, 1990.

4. Three comments expressed concern about the photostability of

avobenzone-containing sunscreen drug products, especially when used in

a formulation without any other sunscreen active ingredients. Two

comments stated that OTC sunscreen drug products with avobenzone as

their only sunscreen active ingredient may not provide effective

protection against ultraviolet B (UVB) radiation and that, even when

combined with other sunscreen active ingredients, the UVA radiation

tests (61 FR 48645 at 48652) do not stress the formulation enough to

determine if the product will remain effective after receiving higher

doses of UV radiation. One comment stated that because no official

method has yet been established to test for protection from UVA

radiation, broad marketing of avobenzone-containing sunscreen drug

products should not be allowed because of photostability concerns

related to avobenzone. One of the comments also questioned whether

avobenzone photoproducts are photoallergenic. None of the comments

supplied any data to support their contentions.

The agency is aware that avobenzone's maximum absorbance is in the

UVA radiation spectrum (i.e., 340 to 350 nanometers (nm)) and that most

of the data discussed in the amendment to the proposed rule for OTC

sunscreen drug products concerns combinations of avobenzone with other

Category I sunscreen active ingredients. However, data submitted to the

agency (Ref. 1) reported a mean SPF of 2.4 for avobenzone alone in an

appropriate vehicle. In its conclusions about the safety and

effectiveness of OTC avobenzone-containing sunscreen drug products (61

FR 48645 at 48652), the agency stated that it considered the submitted

data as supportive of the safety and effectiveness of up to 3 percent

avobenzone alone ``if the finished product provides at least an SPF

2.'' An SPF of 2 indicates that the ingredient provides some UVB

protection.

The agency agrees with the comment concerning the need for a

monograph method for determining UVA radiation protection and believes

that such a method should also address the photostability of sunscreen

active ingredients. However, FDA has determined that adequate and well-

controlled studies using currently accepted methods provide sufficient

evidence of the effectiveness of 2 to 3 percent avobenzone in

protecting against UVA radiation (61 FR 48651 and 48652). The agency

continues to evaluate data and information and plans to propose a

monograph method for determining UVA radiation protection in a future

issue of the Federal Register.

One of the comments also questioned whether avobenzone

photoproducts are photoallergenic. Agency review of adverse drug

experience data for an OTC 3 percent avobenzone combination product

marketed under an NDA since 1993 revealed no serious outcomes or

alarming trends in numbers or types of reactions. The agency previously

stated that, although more information will ultimately be required

before the nature and safety profiles of avobenzone photodegradation

products can be thoroughly assessed, it is presently not aware of any

safety or effectiveness problems associated with the photostability of

avobenzone (61 FR 48645 at 48651 and 48652). The agency also continues

to evaluate photostability information recently submitted following the

September 19 and 20, 1996, public meeting (61 FR 42398, August 15,

1996) on the photochemistry and photobiology of sunscreens. The agency

plans to address the photostability of all OTC sunscreen active

ingredients in a future issue of the Federal Register.

Reference

(1) Comment No. LET138, Docket No. 78N-0038, Dockets Management

Branch.

5. Three comments disagreed with the proposed requirement for a

minimum concentration of avobenzone when it is used in combination OTC

sunscreen drug products (i.e., a minimum of 2 percent when used in a

combination OTC sunscreen drug product with one or more of the proposed

Category I cinnamate, benzophenone, diphenylacrylate, and/or salicylate

sunscreen active ingredients). One comment stated that the minimum

concentration requirement is inappropriate and unnecessarily

restrictive. The comment stated that: (1) Meaningful and appropriate

UVA radiation protection can be provided by using avobenzone at

concentrations below 2 percent; (2) if a lower concentration of

avobenzone still provides effective UVA radiation protection, it will

be more cost effective for the consumer; (3) lower avobenzone

concentrations may provide for products with better aesthetics and thus

better usage compliance; and (4) Canada, the European Union, and

Australia have no minimum concentration requirement for avobenzone in

combination sunscreen products. The comment recommended that the

proposed minimum concentration be revised to permit use of alternative

efficacy-based minimums provided that supporting data are generated

showing that each ingredient in a combination drug product provides a

significant contribution to overall product effectiveness.

Two comments stated that the same rationale the agency used in

determining that OTC sunscreen drug products with only one active

sunscreen ingredient do not require minimum concentrations (i.e.,

finished product testing) should also apply to combination products.

Another comment contended that by using the synergies of various

sunscreen active ingredients in combination with avobenzone,

manufacturers will be able to fine tune active levels based on total

product efficacy. According to the comment, the combination of 1

percent avobenzone and 6 percent oxybenzone provides at least as much

protection as 3 percent avobenzone alone, while the combination of 1

percent avobenzone and 10 percent octocrylene provides more UVA

radiation protection than 2 percent avobenzone. The comment concluded

that minimum concentration requirements encourage overmedicating the

consumer without the benefit of increased UVA radiation protection.

In the notice of proposed rulemaking for OTC sunscreen drug

products, the agency discussed minimum concentration requirements for

OTC sunscreen ingredients (58 FR 28194 at 28214). The agency

tentatively concluded that minimum concentration requirements are

necessary for combination sunscreen products (i.e., until a method is

developed that can demonstrate the contribution of each OTC sunscreen

ingredient in a combination product) because of its concern that each

ingredient in a combination drug product contributes to the overall

effectiveness of the product. The agency further stated:

To require no minimum contribution at all could allow the use of

amounts so small as to be misleading and deceptive to the consumer

and could permit the inclusion of ingredients solely for promotional

purposes. In addition, this could result in the

[[Page 23354]]

consumer's exposure to an additional ingredient or ingredients with

minimal additional benefit being provided.

Following publication of the proposed rule for OTC sunscreen drug

products on May 12, 1993, the agency received several comments

concerning minimum concentrations for OTC sunscreen active ingredients.

Because this issue impacts other OTC sunscreen active ingredients, the

agency intends to address all of the comments in a future issue of the

Federal Register.

The minimum and maximum concentrations for avobenzone proposed in

Sec. 352.20 were based upon the agency's review of safety and

effectiveness data and other information. Adequate and well-controlled

studies using currently accepted methods have demonstrated the

effectiveness of 2 to 3 percent avobenzone (alone and in combination

with some proposed monograph sunscreen ingredients) in providing

protection against UVA radiation. None of the comments submitted any

data to support the effectiveness of avobenzone at concentrations lower

than 2 percent. In the absence of any data, the agency is unable to

address the overmedication/benefits issue raised by one comment.

6. Two comments asserted that all of the ``claims'' that can be

made for avobenzone-containing OTC sunscreen drug products can also

apply and should be allowed for such products containing titanium

dioxide and/or zinc oxide. One comment stated that titanium dioxide or

zinc oxide can enhance the UVA radiation protection effectiveness of

avobenzone, allow for formula flexibility and cost competition for

avobenzone, and promote usage compliance by consumers because titanium

dioxide and zinc oxide are nonirritating and nongreasy. The comment

added that consumers should not be misled into believing that only

avobenzone can provide broad spectrum protection.

In the proposed rule for OTC sunscreen drug products (58 FR 28194

at 28232 to 28233), the agency discussed UVA radiation protection

claims and proposed labeling that would apply to proposed Category I

sunscreen active ingredients (e.g., titanium dioxide) that met certain

criteria. Until the agency proposes a method for the determination of

UVA radiation protection, sunscreen drug products may bear UVA claims

provided that they: (1) Contain sunscreen active ingredients that

absorb UVA radiation, and (2) meet the agency's enforcement policy

which allows claims that were available in labeling prior to the

beginning of the OTC drug review to appear in labeling of currently

marketed products until the rulemaking for OTC sunscreen drug products

is completed, and the regulation for this class of products becomes

effective (Ref. 1). The agency is aware that some currently marketed

OTC sunscreen drug products that contain titanium dioxide are promoted

with claims pertaining to UVA radiation and/or broad spectrum

protection (Ref. 2). The agency has recently (Refs. 3 through 6)

discussed conditions under which OTC sunscreen drug products containing

2 to 25 percent zinc oxide would be generally recognized as safe and

effective with labeling claims for UVA radiation protection. Sunscreen

drug products containing zinc oxide that meet such conditions may be

marketed before the establishment of a final monograph in accordance

with the agency's longstanding policy regarding ingredients or

combinations of ingredients and uses being evaluated in the OTC drug

review (Ref. 1). Thus, the agency does not believe that consumers have

been misled into believing that only avobenzone-containing sunscreen

products can provide broad spectrum protection. The agency also plans

to address UVA radiation claims and testing procedures further in a

future issue of the Federal Register.

References

(1) ``Food and Drug Administration Compliance Policy Guides

7132b.15 and 7132b.16,'' in OTC Vol. 06ATFM, Docket No. 78N-0038,

Dockets Management Branch.

(2) ``Physicians' Desk Reference for Nonprescription Drugs,''

17th ed., Medical Economics Co., Montvale, NJ, 1996, pp. 629 and

760.

(3) Comment No. LET150, Docket No. 78N-0038, Dockets Management

Branch.

(4) Comment No. LET151, Docket No. 78N-0038, Dockets Management

Branch.

(5) Comment No. LET152, Docket No. 78N-0038, Dockets Management

Branch.

(6) Comment No. LET153, Docket No. 78N-0038, Dockets Management

Branch.

7. One comment recommended that FDA issue a ``call-for-data'' to

allow equal and ample opportunity for all interested parties to develop

and submit additional data that may be needed to support combinations

of avobenzone with other sunscreen active ingredients. Alternatively,

the comment suggested that the agency should allow other avobenzone

combinations provided that supporting safety data (i.e., clinical

phototoxicity, photoallergenicity, repeat insult patch testing) are

generated for products prior to marketing.

Several comments recommended that the agency allow avobenzone to be

combined with titanium dioxide, zinc oxide, and/or phenylbenzimidazole

sulfonic acid to provide for maximum flexibility in formulating

effective OTC sunscreen drug products. Some of the comments referenced

data presented at the September 19 to 20, 1996, Public Meeting to

Discuss the Photochemistry and Photobiology of Sunscreens (Ref. 1)

concerning products that contained avobenzone with either titanium

dioxide or zinc oxide. Three comments added that studies evaluated in

the amendment to the tentative final monograph were determined to be

supportive of the safety of avobenzone and that these studies utilized

combination test products that contained titanium dioxide and/or

phenylbenzimidazole sulphonic acid.

The agency has previously stated (Refs. 2 and 3) that data from

clinical studies are necessary to establish the safety and

effectiveness of combinations of avobenzone with proposed Category I

sunscreen active ingredients. In the amendment to the tentative final

monograph (61 FR 48645 at 48650), the agency concluded that data

submitted to the agency provide sufficient evidence to demonstrate the

low irritation, allergenic sensitization, photoallergenic, and

phototoxic potential of 2 to 3 percent avobenzone in combination with

the proposed Category I cinnamate, benzophenone, diphenylacrylate, and/

or salicylate sunscreen active ingredients. The agency further stated,

however, that it does not consider the submitted data adequate to allow

avobenzone to be combined with any and all proposed monograph sunscreen

ingredients. The clinical studies referenced by the comment (Refs. 4,

5, and 6) that utilized combinations of avobenzone with titanium

dioxide and/or phenylbenzimidazole sulfonic acid only assessed the

irritation and/or contact allergy potential of the products. Two of the

studies (Refs. 4 and 6) assessed irritation potential in study

populations of only 25 and 15 individuals, respectively. One cumulative

irritancy study (Ref. 5) utilized test products containing only low

concentrations of avobenzone (0.2 to 1.5 percent). Another study (Ref.

5), noted by the agency as being supportive of the safety of 2 percent

avobenzone, only assessed the cumulative irritancy and allergic

potential of an avobenzone-containing combination sunscreen product

containing 7.5 percent octyl methoxycinnamate and 3 percent titanium

dioxide. Until complete and adequate data are submitted, the agency has

no basis to allow other avobenzone combinations.

The agency sees no need to issue a ``call-for-data'' for all

interested parties to develop and submit additional data to

[[Page 23355]]

support combinations of avobenzone with other sunscreen active

ingredients. The agency is currently reviewing all data and information

received as a result of the September 19 to 20, 1996, Public Meeting to

Discuss the Photochemistry and Photobiology of Sunscreens and will

address this information in a future issue of the Federal Register.

Interested parties may submit additional data to support combinations

of avobenzone with other sunscreen active ingredients in an appropriate

citizen petition to amend the proposed monograph for OTC sunscreen drug

products. (See 21 CFR 10.30.)

References

(1) Comment No. TR3, Docket No. 78N-0038, Dockets Management

Branch.

(2) Comment No. LET118, Docket No. 78N-0038, Dockets Management

Branch.

(3) Comment No. MM11, Docket No. 78N-0038, Dockets Management

Branch.

(4) Comment No. LET127, Docket No. 78N-0038, Dockets Management

Branch.

(5) Comment No. LET130, Docket No. 78N-0038, Dockets Management

Branch.

(6) Comment No. SUP18, Docket No. 78N-0038, Dockets Management

Branch.

8. One comment requested clarification of the Category I sunscreen

active ingredients proposed as permitted combinations with avobenzone.

The comment stated that the list of Category I sunscreen active

ingredients in the summary section of the amendment to the proposed

tentative final monograph (61 FR 48645) did not coincide with the

combinations listed by alphabetical letters in proposed

Sec. 352.20(a)(2) (61 FR 48645 at 48654).

The agency corrected this discrepancy in the Federal Register of

February 26, 1997 (62 FR 8663). Section 352.20(a)(2) now states:

Two or more sunscreen active ingredients identified in

Sec. 352.10(b), (c), (d), (f), (i), (l), (m), (n), (o), (s), and (u)

may be combined when used in the concentrations established for each

ingredient in paragraph (a)(3) of this section and the finished

product has a minimum sun protection factor value of not less than 2

as measured by the testing procedures established in subpart D of

this part.

9. One comment asked whether clinical testing of avobenzone-

containing OTC sunscreen drug products prior to marketing would be

permitted without an approved investigational new drug application

(IND). The comment urged the agency to allow clinical testing without

an approved IND of avobenzone concentrations and active ingredient

combinations not specified in the amendment.

Section 312.2(b)(1) (21 CFR 312.2(b)(1)) exempts the clinical

investigation of a drug product that is lawfully marketed in the United

States from the procedures and requirements contained in part 312 (21

CFR part 312) (which governs the use of IND's) if, among other things,

the investigation is not intended to be reported to FDA as a well-

controlled study in support of a new indication for use nor intended to

be used to support any other significant change in the labeling for the

drug. Because this notice allows the lawful OTC marketing of certain

avobenzone-containing sunscreen drug products without an approved NDA,

an exemption from the requirements of part 312 would be allowed for

those products specified in this notice if all of the conditions in

Sec. 312.2(b)(1) are met. However, OTC sunscreen active ingredient

concentrations and combinations not specified in this notice may not be

lawfully marketed at this time without an approved NDA. Such products,

therefore, would not be exempted from the procedures and requirements

of part 312 on the basis of this notice. An IND would be needed to

study the safety and effectiveness of such products.

III. Enforcement Status

After carefully reviewing all of the comments received, the agency

is issuing a notice of enforcement policy permitting OTC marketing of

drug products containing up to 3 percent avobenzone alone and 2 to 3

percent avobenzone in combination with the following proposed Category

I sunscreen active ingredients: Cinoxate, diethanolamine

methoxycinnamate, dioxybenzone, homosalate, octocrylene, octyl

methoxycinnamate, octyl salicylate, oxybenzone, sulisobenzone, and/or

trolamine salicylate. The agency addressed the safety and effectiveness

of such avobenzone-containing drug products in the proposed amendment

to the tentative final monograph for OTC sunscreen drug products (61 FR

48645 at 48646 through 48652). Based on a comment received in response

to the proposal, the agency has reevaluated the use of OTC avobenzone-

containing sunscreen drug products on children and believes that the

need for the warning suggested by the comment regarding use on children

between 6 months and 12 years of age has not been established. Most of

the other comments concerned requests for other avobenzone-containing

sunscreen product combinations and/or concentrations, or issues similar

to those submitted in response to the proposed rule that apply to all

OTC sunscreen drug products and that will be addressed in future issues

of the Federal Register. Accordingly, the agency has tentatively

determined that it is appropriate at this time to allow the interim

marketing of the OTC avobenzone-containing products identified in

proposed Secs. 352.10 and 352.20.

The agency's enforcement policy in Compliance Policy Guide

7132b.16, relating to OTC marketing of combination drug products that

are under consideration in FDA's OTC drug review, makes it clear that

FDA may by notice in the Federal Register permit interim marketing of

products such as the sunscreen drug products discussed in this notice.

The agency advises that sunscreen drug products containing up to 3

percent avobenzone alone and 2 to 3 percent avobenzone in combination

with the proposed Category I cinnamate, benzophenone, salicylate, and/

or diphenylacrylate sunscreen ingredients as proposed in Secs. 352.10

and 352.20 may be marketed pending issuance of the final monograph for

this drug class, subject to the risk that the agency may adopt a

different position in the final monograph that could require

reformulation and/or relabeling, recall, or other regulatory action.

Products containing avobenzone require both UVA radiation protection

testing and SPF testing of the finished product, as discussed in the

amendment to the proposed rule for OTC sunscreen drug products (61 FR

48645 at 48652). Until the agency proposes a monograph UVA radiation

testing method, the agency considers testing procedures similar to

those described by R. W. Gange et al. and N. J. Lowe et al. as adequate

for determining the UVA radiation protection potential of a finished

OTC sunscreen drug product. Products containing avobenzone require SPF

testing of the finished product in accordance with proposed

Secs. 352.10 and 352.20 (58 FR 28194 at 28295 and 28296) and as amended

in Secs. 352.10 and 352.20 (61 FR 48645 at 48654). The products must be

marketed with the labeling proposed in Secs. 352.50 through 352.60 (58

FR 28194 at 28296 to 28298) and as amended in Sec. 352.52 (61 FR 48645

at 48655). Marketing of such products with labeling not in accord with

the labeling in these sections may also result in regulatory action

against the product, the marketer, or both. The final monograph for OTC

sunscreen drug products will establish the final formulation, labeling,

and testing requirements for such products.

[[Page 23356]]

IV. Opportunity for Comments

Interested persons may submit written comments to the Dockets

Management Branch (address above). Such comments will be considered in

determining whether further amendments or revisions to this policy are

warranted. 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.

(Secs. 201, 501, 502, 503, 505, 510, and 701 of the Federal Food,

Drug, and Cosmetic Act and under authority of the Commissioner of

Food and Drugs)

Dated: April 22, 1997.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 97-11116 Filed 4-29-97; 8:45 am]

BILLING CODE 4160-01-F