[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]
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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
