[Federal Register Volume 62, Number 83 (Wednesday, April 30, 1997)]
[Rules and Regulations]
[Pages 23350-23356]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-11116]


=======================================================================
-----------------------------------------------------------------------

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

-----------------------------------------------------------------------

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