[Federal Register Volume 59, Number 65 (Tuesday, April 5, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-8023]
[[Page Unknown]]
[Federal Register: April 5, 1994]
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Part III
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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21 CFR Parts 352, 700, and 740
Discussion of Ultraviolet A-Protection Claims and Testing Procedures
for Over-the-Counter Sunscreen Drug Products; Public Meeting and
Reopening of the Administrative Record; Proposed Rule
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 352, 700, and 740
[Docket No. 78N-0038]
RIN 0905-AA06
Discussion of Ultraviolet A-Protection Claims and Testing
Procedures for Over-the-Counter Sunscreen Drug Products; Public Meeting
and Reopening of the Administrative Record
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of public meeting and reopening of the administrative
record.
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SUMMARY: The Food and Drug Administration (FDA) is announcing that a
public meeting will be held to discuss testing procedures to
demonstrate that an over-the-counter (OTC) sunscreen drug product
protects users from ultraviolet A (UVA) radiation. FDA is holding this
meeting after considering public comments regarding UVA claims and
testing procedures received in response to the agency's notice of
proposed rulemaking and letters sent by the agency. In addition, FDA is
reopening the administrative record for the proposed rulemaking for OTC
sunscreen drug products to allow comment on matters considered at the
meeting. FDA intends to invite guests and consultants to address
technical matters related to the questions listed in this document.
This meeting is part of the ongoing review of OTC drug products
conducted by FDA.
DATES: The meeting will be held on May 12, 1994, 8:30 a.m. The agency
anticipates that the meeting will last 1 day. However, if there is
sufficient interest in participation, the meeting will be extended an
additional day at the discretion of the chairperson. Submit relevant
data and notice of participation by April 29, 1994. Submit comments
regarding matters raised at the meeting by July 31, 1994. The
administrative record will remain open until July 31, 1994.
ADDRESSES: Submit relevant data, notice of participation, and written
comments to the Dockets Management Branch (HFA-305), rm. 1-23, 12420
Parklawn Dr., Rockville, MD 20857. The meeting will be held in
conference rm. D, Parklawn Bldg., 5600 Fishers Lane, Rockville, MD
20857.
FOR FURTHER INFORMATION CONTACT: Jeanne Rippere, Center for Drug
Evaluation and Research (HFD-813), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-1003.
SUPPLEMENTARY INFORMATION: In the Federal Register of May 12, 1993 (58
FR 28194), FDA published a notice of proposed rulemaking for OTC
sunscreen drug products. In the proposed rule, the agency discussed OTC
sunscreen drug products that claim to provide protection from UVA
radiation and the public health significance of UVA radiation (58 FR
28194 at 28232 and 28233). The agency also discussed testing procedures
for sunscreens that absorb UVA radiation (58 FR 28194 at 28248 to
28250). The comment period for comments related to UVA ingredients,
claims, and testing closed on November 8, 1993.
To ensure that sunscreen drug products having UVA protection claims
offer significant UVA protection, the agency proposed that an OTC
sunscreen ingredient must have an absorption spectrum extending to 360
nanometers (nm) or above in order to display UVA protection claims in
its labeling (58 FR 28194 at 28233). The product would also have to
demonstrate meaningful UVA protection by satisfying UVA testing
procedures that would be included in the monograph. However, these
procedures have yet to be established. The agency requested specific
comments on appropriate procedures to be used. Previously, the agency
had requested specific information on UVA protection factors (Ref. 1).
In the proposed rule (58 FR 28194 at 28248 to 28250), the agency
tentatively suggested that a testing method similar to the one
described by Lowe et al. (Ref. 2) could be used to demonstrate that a
sunscreen drug product provides protection against UVA radiation. This
method uses 48- and 72-hour erythema reactions and 12- to 14-day
melanogenesis in skin sensitized with 8-methoxsalen (8-MOP). However,
because the agency did not have enough information or data to propose a
method for determining UVA protection in the proposed rule, the agency
stated that a method should be developed and validated in the same
manner as was the sunscreen testing procedure for protection against
ultraviolet B (UVB) radiation (i.e., sunscreen protection factor (SPF)
testing). Furthermore, the agency requested comments and data regarding
an appropriate testing methodology for OTC sunscreen drug products that
afford UVA protection.
The agency received a substantial amount of comments, data, and
information regarding UVA ingredients, claims, and testing procedures.
After evaluating the submitted material, the agency finds that there
are two basic interrelated questions regarding testing procedures for
determining UVA protection that must be addressed before the agency can
complete its assessment of appropriate UVA ingredients and claims.
These questions are:
(1) What action spectrum best describes the biological risk of UVA
radiation (i.e., which ultraviolet radiation wavelengths are most
likely to cause biological damage), and
(2) Which testing procedure best defines the UVA protection
provided by a sunscreen drug product?
I. Action Spectra for UVA-Related Skin Damage
Several comments discussed the appropriate action spectrum for
biological risk associated with UVA radiation. One comment stated that,
in developing a consensus regarding an acceptable assay for determining
the UVA protection provided by a sunscreen drug product, the specific
UVA effect that is to be blocked must be considered. These effects
include UVA erythema, UVA-induced drug photosensitivity, immediate
pigment darkening, delayed tanning, or other effects of photodamage.
One comment stated that several action spectra describing different
aspects of solar-induced skin damage have been determined in a number
of different species and cell types. The comment described these
aspects as photocarcinogenesis, DNA damage, photoaging, mutagenicity,
and immunosuppression. The comment maintained that each action spectrum
for UV-induced damage closely tracks the human erythemal action
spectrum. The comment stated that the best summary of the biological
risk of UV light has been published by the Commission Internationale de
l'Eclairage (CIE) (Ref. 3). The CIE Hazard Spectrum embodies the
comprehensive, yet normal, risks to human skin due to full-spectrum UV
exposure and reflects the findings of the action spectra biological
responses to UV described above. The CIE Hazard Spectrum shows that the
damage risk for UVB at 290 nm is 100 times higher than that at 320 nm.
The damage risk at 320 nm is 100 times higher than that at 400 nm. The
damage risk at 320 nm is at least 10 times greater than the damage risk
at 340 nm. This spectrum shows that the most damage potential is in the
UVB wavelengths (290 to 320 nm), followed by the shorter UVA
wavelengths (320 to 340 nm). The comment cited numerous scientific
articles and submitted action spectra to support its statements (Ref.
4).
Another comment stated that although protection against UVA is
important, it is not as important as protection against UVB. The
comment argued that, based on the CIE Hazard Spectrum, the UVB
wavelengths contribute 80 to 85 percent of the damage risk in sunlight,
while UVA contributes 15 to 20 percent of the damage risk.
One comment stated that some known effects on humans caused by UVA
radiation include:
(1) Photoaging of the skin,
(2) UVA-induced hypersensitivities,
(3) Augmentation of skin cancers, and
(4) Erythema. However, the comment noted that there is no single
known action spectrum to describe which parts of the UVA spectrum are
most active in causing these effects. Therefore, the comment maintained
that it is not appropriate to use the UVA-erythema action spectrum for
testing purposes. The comment stated that UVA protection should be
assessed in relation to UVB protection and that the assumption should
be made that all wavelengths are equally important.
One comment stated that the ``current test for erythema'' is
inadequate to test for the full spectrum of UVA radiation because
erythema is not a valid measurement of UVA exposure. The comment argued
that using the erythema action spectrum to test for UVA protection will
give consumers a false sense of the extent of UVA protection afforded
by a product. The comment added that the immediate pigment darkening
(IPD) action spectrum is preferable because it is broad enough to take
into account almost all UVA wavelengths. Another comment stated that
the IPD action spectrum is indicative of a true broad spectrum UVA
response.
One comment noted that the IPD action spectrum was first described
to extend from 300 to 420 nm, with a broad peak between 340 and 370 nm
(Ref. 5). The action spectrum was later described to extend from 300 to
620 nm, with a peak effectiveness between 400 and 500 nm (visible
light) (Ref. 6). Because of the difference between these two reported
spectra, the comment reevaluated the action spectrum for IPD between
310 and 400 nm and reported that the IPD action spectrum extends from
320 to 400 nm with a low peak around 340 nm (Ref. 7).
Concurrent with determining which testing procedure is appropriate
for use in validating the UVA protection provided by a sunscreen drug
product, the agency must determine what portion of the UVA spectrum
should be blocked by the product before consumers are effectively
protected against the hazards of UVA radiation. The agency would like
to consider the following specific questions at the meeting:
1. Which action spectra are the most important with respect to skin
damage caused by UVA radiation?
2. Is the erythema action spectrum an adequate surrogate for UVA
biological risk, or is some other action spectrum (such as the IPD
action spectrum) more appropriate?
3. Can a sunscreen drug product that protects consumers against the
shorter UVA wavelengths (320 to 340 nm) but not against longer UVA
wavelengths (340 to 400 nm) prevent significant UVA damage?
4. What should consumers expect from a sunscreen drug product that
is labeled to provide protection against UVA radiation or as a ``broad
spectrum'' sunscreen?
II. UVA Testing Procedures
The agency did not propose a method for determining UVA protection
in the tentative final monograph for OTC sunscreen drug products. The
agency stated that a method should be developed and validated in the
same manner as the sunscreen testing procedure for protection against
UVB radiation (58 FR 28194 at 28250). The agency noted that any such
method should clearly demonstrate that a particular product provides
significant protection against UVA radiation. The method should include
the use of a control sunscreen preparation that absorbs UVA radiation
and that can be used to assure the reliability of the testing procedure
and equipment. The method should demonstrate that a sunscreen
ingredient either does or does not protect against UVA radiation. The
agency requested comments and data regarding an appropriate testing
method for OTC sunscreen drug products that protect against UVA
radiation. In response, the agency received information and data
pertaining to several UVA testing procedures, including both in vivo
and in vitro test methods.
One comment recommended adoption of an in vitro test method that
does not rely upon either photosensitization or nonsolar light sources
for determining UVA protection for normal skin (Ref. 8). According to
the comment, this method involves:
(1) Determining the UV absorbance spectrum of the sunscreen
product,
(2) Calculating a convolution spectrum by multiplying the solar
spectrum with the current CIE Hazard Spectrum, and
(3) Incorporating the sunscreen transmission spectrum into the
convolution spectrum to obtain a UVA effectiveness ratio which is
conveniently expressed as a UVA protection percentage (APP). The
comment maintained that, unlike other methods, the APP represents the
fraction of full spectrum UVA (320 to 400 nm) removed by a product.
The comment stated that because the original ``full spectrum''
method produces an SPF value analogous to the clinically determined SPF
number, the APP has direct relevance to the SPF determined on human
subjects and is a subset of the full-spectrum SPF determination. The
comment added that once an SPF has been determined clinically, it is
simple to take the full-spectrum absorbance spectrum and calculate the
APP based on the clinical test results. Therefore, although the
determination of the APP does involve in vitro measurements, it also
relies on direct clinical measurements.
The comment contended that there are a number of advantages to
using the APP system:
(1) It is a subset of the existing SPF for sunscreen drug products
and, therefore, relates to an erythemal endpoint in normal skin;
(2) It does not unnecessarily duplicate clinical testing;
(3) It clearly demonstrates whether a sunscreen drug product
provides meaningful protection against UVA radiation, and it is useful
in determining comparative UVA protection;
(4) It avoids the deficiencies of nonsolar light sources,
photosensitizing chemicals, the failure of dose reciprocity for human
UVA exposures, and endpoints which do not relate to known UVA damage to
human skin;
(5) It is independent of exposure dose or duration;
(6) It includes all the UVA wavelengths in their direct proportion
and intensity as found in natural sunlight; and
(7) It is directly relevant to overall product effectiveness. The
comment added that in the absence of a light source specific to the UVA
range, APP determination is the best measurement of a product's UVA
protection level.
One comment stated that the in vitro APP test is difficult to
extend to a human in vivo situation and that the test cannot be used to
study substantivity or stability. The comment added that because the
APP test uses the erythema action spectrum and a mathematical
extraction of the UVA segment of the solar spectrum, it overestimates
the actual amount of UVA radiation blocked by most products. A reply
comment argued that the APP technique is derived from well-studied and
extensively published in vitro SPF methodology (Refs. 9, 10, and 11),
that it is simple to evaluate water resistance using this model, and
that data on water resistance have been published. The reply comment
added that APP values are derived from the same spectral data (320 to
400 nm) that provide in vitro SPF values. The final SPF value from
clinical studies is compared to the in vitro SPF and the absorbance
spectrum can be matched to the exact clinical SPF for UVA calculations.
The UVA portion of the sunscreen's efficacy can then be calculated from
the in vitro SPF data. Therefore, the comment argued that the APP has
direct relevance to the clinical effectiveness of the sunscreen
product, but does not require the exposure of human subjects to
unnecessary UV radiation.
One comment stated that an in vitro method developed by Diffey and
Robson (Ref. 12) avoids many of the limitations of in vivo methods
(e.g., lack of reciprocity and light sources that produce 5 to 20 times
the intensity of the sun) and allows the correct estimation of the
attenuating power of a sunscreen drug product. The comment described
this method as recording photocurrent in 5 nm steps from 290 to 400 nm
and measuring the spectral transmission of UV radiation through a
sample of TransporeTM tape with and without sunscreen applied.
TransporeTM tape is UV radiation transparent and has a rough
surface that distributes sunscreen products in a way similar to the
uneven surface of the skin. Any radiation source may be used, providing
there is a continuous power distribution between 290 and 400 nm. This
method assesses the SPF of a product and the UVA/UVB ratio. The UVA/UVB
ratio compares the reduction of UV radiation in the UVA region with
that in the UVB region of the spectrum. According to the comment, this
ratio can be used as an indicator of the UVA protection properties of a
sunscreen drug product.
One comment claimed that the method developed by Diffey and Robson
(Ref. 12) has many advantages, as well as being simple, inexpensive,
and well correlated with clinical testing. The comment noted that the
method does not require a biological endpoint such as erythema,
tanning, or immediate pigment darkening. The comment stated that the
method provides a basis for the classification of the UVA protection
provided by a product and added that a manufacturer planned to utilize
the Diffey and Robson method to standardize the UVA claims of its
products. Sunscreen products would be labeled with one to four stars
depending upon the amount of UVA protection provided by the products as
determined by the Diffey and Robson method. The comment concluded that
using the ``star'' rating system for UVA claims and the SPF designation
for UVB claims provides a simple method for consumers to determine the
protective nature of a sunscreen product. The comment submitted a
description of the manufacturer's methodology and ``star'' rating
system (Ref. 13).
Another comment submitted data describing the application of this
ratio method to the determination of the SPF and UVA/UVB ratio of
titanium dioxide and zinc oxide dispersions (Ref. 14). The comment
noted that the accuracy of this method is enhanced by good product
application and that the in vitro results obtained by this method show
good agreement with in vivo values.
However, another comment contended that the Diffey and Robson
method (Ref. 12) has been shown to have poor correlation with clinical
results (Ref. 15). The comment stated that the Diffey and Robson method
has been used as the basis for ``quantifying'' UVA protection expressed
as ``stars'' on the package labeling of some sunscreen products sold in
Europe (Ref. 16). Without using an action spectrum such as the CIE UV
Hazard Spectrum or the erythemal efficacy spectrum for weighting, the
``star'' method considers all UVA wavelengths as having the same
erythemal effectiveness. The ``star'' value results from an unweighted
ratio of the UVA absorbance to the UVB absorbance of the product.
Therefore, the comment maintained that a low SPF product with a flat
absorbance spectrum could get four ``stars'' (i.e., the highest
rating), while a higher SPF product would get fewer ``stars'' because
the higher SPF product would absorb disproportionately higher levels of
UVB, similar to the action spectrum for erythema. The comment stated
that the ``star'' concept is in direct contrast to the accepted concept
of formulating sunscreen drug products to provide the most protection
in the most damaging portion of the UV spectrum. The comment contended
that the ``star'' method is misleading to consumers and added that the
use of the ``star'' method in England has been criticized by
dermatologists, who have asked that the system be withdrawn.
One comment recommended that the agency adopt the current Standards
Association of Australia (SAS) UVA (broad spectrum) test method AS-2406
as an objective measure of UVA blocking (Ref. 17). This method measures
the percent transmission of the test sunscreen drug product between 320
and 360 nm. If an 8-micrometer layer of appropriately dissolved
sunscreen product does not transmit more than 10 percent of UV
radiation at any wavelength from 320 to 360 nm inclusive, the product
may be considered as providing broad spectrum protection. The comment
contended that this method has a number of advantages. UV protection
claims are most appropriately substantiated by measuring the blocking
of UV directly rather than measuring some consequence of UVA exposure.
Thin film spectrophotometric evaluation of sunscreen drug products has
reached a level of technical proficiency to permit instrumental
evaluation of UVA blocking potential. Adopting an already accepted
standard protocol will enhance the ability of the United States
sunscreen industry to compete equally in foreign markets. This test
will substantially reduce testing costs. No human subjects are used.
The comment added that this method provides a strict criterion that
serves to identify only the most effective UVA blockers. The comment
submitted several UVA scans to demonstrate that the SAS method
differentiates between the ``poorly effective'' oxybenzone-containing
sunscreens and an assortment of products containing ``excellent'' UVA
blockers, e.g., titanium dioxide and avobenzone (Parsol 1789) (Ref.
17).
Two comments contended that there are several deficiencies in the
SAS method. The results are not correlated to a clinical SPF test.
Numerous studies have shown that solution and thin-film spectra are not
relevant to actual product performance on skin. The performance of the
sunscreen is evaluated only in the limited range of 320 to 360 nm,
rather than throughout the entire UVA spectrum (320 to 400 nm).
Two comments recommended that the agency not adopt in vitro methods
that rely on measuring the transmission of UVA radiation through either
epidermis or a UV-transparent skin cast (Refs. 18 and 19). The comments
contended that these methods are inappropriate because they use
nonsolar UVA radiation sources and limited range UVA detectors or
detectors without an appropriately weighted response. The comments
stated that these limitations would cause the results to be nonrelevant
to the actual responses of normal skin to full-spectrum natural
sunlight. The comments mentioned that one method (Ref. 19) contains a
small but significant contamination by UVB energy below 320 nm that
would adversely affect the resulting efficacy values and lead to
erroneous measures of UVA efficacy. The comments stated that the other
method (Ref. 18) skews results toward the longer UVA wavelengths
because of the lamp's deficiencies in the shorter, energy-rich UVA. The
comments added that this skewing causes an overestimation of the
protection of some products, making those with ingredients that are
long wavelength absorbers (such as avobenzone) look unrealistically
effective.
One comment concluded that a rigorous and foolproof in vitro test
method has not been established or validated. The comment submitted two
scientific publications that discuss some of the difficulties
associated with in vitro sunscreen testing techniques (Refs. 15 and
20). The comment argued that none of the current in vitro methods
adequately evaluate the photostability of sunscreens. It further stated
that a validated in vivo human UVA test method must first be
established. Then, future in vitro test methods can be tested and
validated against this standard.
Several comments urged the agency not to adopt a testing method
that utilizes photosensitizing chemicals. The comments presented a
number of arguments against this type of testing. It is considered
unethical because of the carcinogenic potential of the photosensitizing
chemical (such as 8-MOP). The action spectrum (i.e., for 8-MOP induced
erythema) is artificial and inappropriate. The values obtained vary
with the sensitizing chemical used and the spectrum of the irradiating
source used. The values obtained have no relevance to real-life
situations. The testing may result in a persistence of pigmentation or
blistering reactions. 8-MOP sensitization exaggerates the biological
response and presents a risk of causing severe ulcerative acute
reactions. 8-MOP puts subjects at risk for phototoxic reactions for up
to 6 hours after exposure.
One comment contended that photosensitizing testing methods have a
number of benefits, such as short irradiance times, clearly defined
endpoints, and reproducible results. The comment added that the results
from these test methods are relevant to patients taking 8-MOP or other
photosensitizing drugs with similar action spectra. The comment
concluded that photosensitizing test methods could be useful to
determine photoprotection factors for claims against phototoxic
reactions.
Several comments urged the agency to accept the IPD testing method
for determining UVA protection. One comment stated that the IPD method
is generally recognized by a substantial body of scientists as the
preferred UVA testing method. Several comments provided a number of
benefits for using the IPD method. They claimed that this test method
is the one that is most representative of true conditions because it is
an in vivo determination that accounts for biological reactions that
can occur on living skin. Unlike the testing procedure using skin
photosensitized with 8-MOP, the IPD test is indicative of a true broad
spectrum response of normal healthy skin. Unlike erythema that is a
response only to the shorter wavelength UVA radiation, IPD is a
response to broad spectrum UVA radiation. The IPD method requires the
use of considerably lower doses of radiation energy, thus exposing
subjects to less risk. The IPD method uniquely compliments the current
SPF system by accurately reflecting the actual amount of long wave UVA
radiation attenuated by a sunscreen product. The IPD method is
reliable, accurate, and reproducible. The IPD test can be performed in
a standard sunscreen evaluation laboratory with minimal adaptation of
existing equipment. The comments concluded that until well-established
action spectra for specific UVA damage are established, IPD is the best
method currently available because it reflects broad spectrum UVA
protection equally across the entire UVA spectrum.
One comment submitted a testing protocol using IPD as the endpoint
(Ref. 21). The comment stated that the suggested testing procedure
fulfilled a number of criteria. The resulting protection factor gives
the consumer additional information about the sunscreen number,
complementing the SPF value. The response variable has a relatively
flat action spectrum (i.e., 320 to 400 nm, with a low peak at around
340 nm) throughout the region of interest. Using this spectrum results
in UVA protection values that closely reflect the actual amount of
radiation reduced. The testing response obeys dose reciprocity over the
anticipated irradiance range. The test is practical with minimal risk
to subjects. The comment added that an eight-center clinical test has
validated this method as acceptable for determining UVA protection over
the entire UVA spectrum, including long wavelength UVA (i.e., 340 to
400 nm).
The comment submitted clinical test results from the eight test
sites (Ref. 21). Each testing facility completed between 10 and 20
subjects. Subjects with skin types III and IV were used. Four sunscreen
formulations and a vehicle control were tested. The sunscreen products
contained:
(1) 7-percent padimate O,
(2) 2-percent oxybenzone,
(3) 5-percent oxybenzone, and
(4) 4 percent titanium dioxide.
The protocol used a randomized, complete block design with all
subjects at each testing center receiving all five test materials. The
comment stated that the studies were conducted similar to an SPF test,
but a detailed protocol was not submitted. For example, UVA dosages and
application density of the test sunscreens were not noted. Six sites
used a 150-Watt (W) Xenon lamp with 3-millimeter (mm) WG335 and 1-mm
UG11 filters. One site used a 1,000-W Xenon lamp with 3-mm WG335 and 2-
mm UG11 filters. One site used a Krypton lamp (i.e., Dermlite) of
unspecified wattage. The comment noted that neither of the last two UVA
sources are recommended, and the results obtained using these lamps
were included for information purposes only.
The IPD threshold dose of UVA radiation was first measured on
unprotected skin, then on protected skin. The ratio of these two doses
was then calculated to derive the UVA Protection Factor (UVA-PF). The
IPD was graded immediately after UV exposure, allowing complete testing
in a single visit.
The comment stated that comparison of test products indicated that
the mean UVA-PF of the vehicle (1.7), the 7-percent padimate O product
(1.8), and the 2-percent oxybenzone product (1.8) were similar. The 5-
percent oxybenzone product (2.1) and the 4-percent titanium dioxide
product (3.0) were both significantly greater than the other three
products. The titanium dioxide product was significantly greater than
the 5-percent oxybenzone product. Although overall statistical analysis
detected significant site-by-product interaction, the individual
results indicate that this was primarily a quantitative interaction
effect. The comment maintained that the consistency of the results was
encouraging, considering that this was the first experience in reading
the IPD response for most of the participating sites. The comment
stated that these data indicate that the IPD procedure can reliably
discriminate among products that provide meaningful long wavelength UVA
protection. The comment proposed using a base size of 20 subjects per
test and a 4-percent titanium dioxide product as a control to be run
concurrently with each subject. The comment proposed that the UVA-PF be
the lower 95 percent confidence interval subtracted from the mean.
Three comments recommended using an IPD test based upon two recent
publications (Refs. 22 and 23). One study (Ref. 22) used a Xenon lamp
equipped with a dichroic mirror filtered with 1-mm WG345, 1-mm WG320,
and 1-mm UG11 filters. The exposure increments were programmed in
arithmetic increments of 2 Joules per square centimeter (J/cm\2\). On
protected skin, the increments were 3 or 4 J/cm\2\. Application density
of the test sunscreen products was 2 milligrams per cm\2\. Visual
assessment of pigmentation was done immediately after exposure and was
performed on the basis of a homogenous pigmentation with well-defined
borders as endpoints. The UVA-PF is determined as the ratio of minimal
IPD dose with protection to the minimal IPD dose without protection.
The other study (Ref. 23) recommends the use of xenon or metal
halide sources, or a xenon/metal halide combination, with continuous
spectra restricted to the UVA spectrum (320 to 390 nm) with filters,
such as 3-mm WG335 and 1-mm UG5. Six UVA doses ranging from 4 to about
30 J/cm\2\ are applied in 50 percent increments to subjects with skin
types II, III, and IV. The study states that with potential free
interpolation, this is actually a 25-percent progression. The doses
applied on the protected skin are multiplied by the expected UVA-PF of
the product under test. Observation of the responses are delayed for at
least 1 hour, and typically 2 hours, after exposure. The study states
that results are less variable if read at 2 hours. A simultaneous
determination of the minimal IPD doses on protected and unprotected
skin is done at the same time in standard room and illumination
conditions. Other parameters concerning the test area, size of test
sites, product application density, selection of volunteers, etc.
follow the same current standards as for the SPF determination.
Several comments objected to the use of the IPD testing method. One
comment stated that the action spectrum for the IPD response is flat
and quite dissimilar from the action spectrum for damage to the skin
from ultraviolet light for erythema, skin cancer, or photoaging of the
skin. The comment contended that the IPD response has not been
demonstrated to be a direct or surrogate endpoint for biological damage
and, therefore, there is no relationship between a product's ability to
prevent IPD and to prevent damage to the skin. The comment added that
IPD has been shown to be unstable, variable, and nonlinear. Another
comment stated that the IPD reaction shows nonreciprocal behavior,
i.e., the severity of the reaction depends upon the time taken to
deliver a certain dose.
One comment noted that there are two methods of assessing UVA
protection that are referred to as IPD. The comment stated that these
two methods differ in the amount of energy needed to produce a response
and the time after irradiation at which the endpoint is read. In one
method, the response is read at 45 seconds after exposure. This
response is transient and has been shown to be highly variable and
nonreproducible. The response is oxygen-dependent and can only be
elicited in darker skin types. In the second method, the response is
read at 2 to 4 hours after exposure and uses a much higher dose of UVA.
The test causes a persistent pigment response in the skin that may last
up to several hours. The comment maintained that the action spectrum
for the persistent pigment endpoint has been neither determined nor
published.
The comment argued that the threshold problem of not having a truly
solar UVA-only light source further complicates the results obtained
using either IPD method. The comment contended that even filtered Xenon
lamps contain significant amounts of visible radiation which, while not
harmful to the skin, may cause the IPD reaction to occur. The comment
pointed out that a sunscreen's ability to block visible light should
not be confused or combined with its ability to provide UVA protection.
In addition, the comment argued that the light sources used for both
IPD methods lack significant energy in the shorter UVA wavelengths,
which are present in sunlight and which are responsible for the
preponderance of UVA damage to the skin.
Stating that there is great demand among the ``sunbather''
population for a ``great looking'' tan and for an indicator to predict
how good a tan can be obtained with a product, one comment argued that
tanning tests like the IPD are not appropriate for measurement of the
damage caused by UVA radiation. The comment contended that measures of
melanogenesis would be misinterpreted by consumers as indicators of
efficacy of tanning and that consumers would soon be choosing products
with the lowest IPD rating to help get the deepest tan.
One comment recommended that the agency adopt the Protection Factor
in UVA (PFA) test method (Refs. 24, 25, and 26). This method is similar
to the SPF testing procedures with a modification to the light source
to virtually eliminate UVB radiation and thus expose subjects to UVA
radiation (greater than 99 percent). The PFA test uses subjects with
skin types I, II, and III. The UVA source is a continuous UVA spectrum
(preferably xenon arc) filtered with a 3-mm Schott WG335 filter that
eliminates 99 percent of the UVB radiation, with less than 1,500 W per
square meter (W/m\2\) irradiance. UVA exposures are delivered at 25-
percent increments to skin above and below the expected UVA protection
level of the sunscreen product times the minimal response dose. The
endpoints measured in this testing method are delayed erythema or
tanning, whichever is present, observed 16 to 24 hours after UV
exposure. The comment stated that these acute responses have similar
action spectra to the chronic action spectra for nonmelanoma skin
cancer (as determined in animals), solar elastosis, and skin wrinkling.
The comment added that the data indicate equivalent results with either
response parameter. Minimal response doses are elicited with UVA
exposure ranging from approximately 80 to 250 J/cm\2\. The PFA is the
ratio of the minimal response dose on protected skin to the minimal
response dose on unprotected skin.
The comment submitted the results of a multicenter evaluation of
sunscreens using PFA methodology (Ref. 25). Sunscreens containing 2 or
5 percent oxybenzone, 7 percent padimate O, and a placebo were tested
in five laboratories using a PFA protocol. All the solar simulators had
intrinsic UV reflecting/IR absorbing dichroic mirrors and were fitted
with Schott 3-mm WG335 and 1-mm UG11 filters. The comment stated that
the PFA test method yielded reproducible results between test centers
and was capable of distinguishing between the three levels of UVA
protection provided by the placebo sunscreen and the sunscreens
containing 2- or 5-percent oxybenzone. The test was incapable of
distinguishing between the UVA protection provided by the placebo and
the 7-percent padimate O (a strong UVB absorber with little UVA
absorbency). The comment stated that these results indicate that the
PFA test method is not influenced by the presence of a strong UVB
blocker in the formulation and is specific in identifying UVA
protection. The comment added that the data show that the level of
irradiance of the light sources (i.e., 300 to 1,200 W/m\2\) did not
influence the protection factors of the sunscreens.
Two comments stated that testing procedures using modified lamps
that produce mostly UVA wavelengths are unsatisfactory for evaluating
the UVA protection afforded by a sunscreen drug product because the
filters required for such testing can remove 40 percent or more of the
critical, damaging wavelengths between 320 and 340 nm. In addition, the
comments pointed out that some of these modified lamps contain UVB
wavelengths below 320 nm that can overwhelm UVA effects. However,
another comment stated that PFA values obtained using modified lamps
and delayed tanning or erythema as endpoints weigh the UVA II (320 to
340 nm) heavily and, for the most part, ignore the contribution of the
longer UVA wavelengths (360 to 400 nm). One comment stated that failure
of reciprocity may occur with very long exposures and that making each
test exactly the same for each differently configured UV source used
and its particular energy distribution would be impossible. Another
comment stated that dose reciprocity for the endpoints of delayed
tanning or erythema has been reported to fail at irradiances between 10
and 50 milliwatts per cm2 and below. One comment noted that the
interval after exposure at which the responses are evaluated can bias
the results. The comment added that the infrared energy or heat
delivered to the skin during these exposures can affect and alter the
results.
The comment stated that no currently existing lamps accurately and
fully reproduce the UVA spectrum of sunlight. Pure UVA I lamps, e.g.,
the UVASUN series, are used primarily for photochemotherapy where only
longer wave UVA (above 340 nm) is wanted. Xenon arc lamps modified with
a WG345 filter are deficient in UVA energy below 335 nm and do not
accurately reflect the energies or damage risk of natural sunlight UVA.
According to the comment, such lamps remove too much of the energy at
the short end of the spectrum and result in overestimating the UVA
effectiveness of sunscreens. Xenon arc lamps filtered with 1- or 2-mm
WG335 filters contain UVB wavelengths below 320 nm and thus can greatly
affect test results. Thicker WG335 filters cut off too much lower UVA
energy to accurately represent UVA risk.
One comment submitted a method that assesses the attenuation of the
incident solar radiation on human skin by a sunscreen (Ref. 27). This
method utilizes the principles of diffuse reflectance and fluorescence
excitation spectroscopy. The method directly measures the optical
properties of the skin decoupled from its biological responses. Both
procedures are based on the same principle, any modification of the
surface of the skin will produce changes in its absorption properties.
Application of a sunscreen modifies the surface of the skin by
providing an additional barrier through which solar radiation must
penetrate before reaching the skin. Measurement of the absorption
properties of the skin before and after sunscreen application yields
the transmission spectrum of the product and permits calculation of it
solar protection value for the wavelength range investigated. The
comment stated that, because this method allows repetitive testing,
evaluations of substantivity and water resistance are possible. The
comment contended that, because the testing is done on human skin,
questions of binding, distribution, and photodegradation can be
answered. In addition, the comment maintained that this testing
procedure, like the Diffey and Robson method (Ref. 12), does not suffer
from a lack of dose reciprocity, as observed with UVA-induced acute
skin reactions. The comment concluded that this procedure allows for
the correct estimation of the attenuating power of a sunscreen; thus,
the protection potential of products in sunlight will be correctly
estimated.
The agency would like to discuss the advantages and disadvantages
of the various recommended testing procedures and the following
specific questions regarding these test methods at the meeting:
1. Which of the in vitro test methods described above would be
adequate to evaluate the UVA protection provided by a sunscreen drug
product? Why would the others not be appropriate?
2. Are the results of in vitro UVA testing methods relevant to the
UVA protection provided to consumers by a sunscreen drug product during
normal use?
3. Does the APP test method demonstrate whether a sunscreen drug
product provides meaningful protection against harmful UVA radiation?
4. Do the data show that the APP test does not overestimate the
actual amount of UVA radiation blocked by most sunscreen drug products?
Identify the data.
5. Describe the specifications for an appropriate light source for
the IPD testing method, e.g., spectral distribution, intensity, etc.
6. What UVA radiation doses are appropriate for use in the IPD
test?
7. When should the IPD response be read--immediately, or 1 or 2
hours after UVA exposure?
8. Is the IPD reaction relevant to protection of the skin from UVA
damage?
9. Do the available data demonstrate that the IPD test is stable,
nonvariable, and reproducible? Identify the data.
10. Do the available data demonstrate that the IPD testing response
obeys dose reciprocity over the anticipated irradiance range?
11. Are results of the PFA testing procedure relevant to protection
of the skin from UVA damage? Identify the results.
12. Do the data show that the PFA test obeys dose reciprocity?
Identify the data.
13. Can the interval after exposure at which PFA responses are read
affect the results?
14. Does the heat or infrared energy delivered to the skin during
PFA testing exposure affect the results?
15. Describe the specifications for an appropriate light source for
the PFA testing method, e.g., spectral distribution, intensity, etc.
The agency has concluded, under 21 CFR 10.65, that it would be in
the public interest to hold a public meeting to discuss the many
questions and topics associated with UVA testing for OTC sunscreen drug
products. The proposed rulemaking involves 21 CFR parts 352, 700, and
740; however, the discussion at the public meeting will be limited to
part 352.
The agency requests information regarding UVA protection claims and
UVA testing procedures from any interested person. However, the agency
requests that only new or additional information not previously
included in the rulemaking be submitted. Data should be specifically
limited and relevant to the questions asked. Any individual or group
may, on or before April 29, 1994, submit to the Dockets Management
Branch (address above), comments and data relevant to the questions and
topics on UVA protection and testing procedures contained in this
document. Two copies of any comments are to be submitted, except that
individuals may submit one copy. All comments are to be identified with
the docket number found in brackets in the heading of this document. It
is not necessary to resubmit data and information submitted previously
to this docket.
Any individual or group interested in making a presentation at the
meeting should contact Jeanne Rippere (address above). Presentations
should only address the questions and topics listed previously. Persons
interested in participating in the meeting must also send a notice of
participation on or before April 29, 1994, to the Dockets Management
Branch (address above). All notices of participation submitted should
be identified with the docket number found in brackets in the heading
of this document and should contain the following information: Name,
address, telephone number, business affiliation, if any, of the person
desiring to make a presentation, summary of the presentation, and the
approximate amount of time requested for the presentation.
Groups having similar interests are requested to consolidate their
comments and present them through a single representative. Depending on
the time available and the number of participants, FDA may require
joint presentations by persons with common interests. After reviewing
the notices of participation, FDA will notify each participant of the
schedule and time allotted to each person.
The administrative record for the OTC sunscreen drug products
rulemaking is being reopened to specifically include only the
proceedings of this public meeting. The administrative record will
remain open until July 31, 1994, to allow comments on matters raised at
the meeting.
References
(1) Letters from W. E. Gilbertson, FDA, to T. P. Koestler,
Westwood Pharmaceuticals, Inc., K. M. O'Brien, Schering-Plough
Corp., N. J. Lowe, UCLA School of Medicine, and M. A. Pathak,
Harvard Medical School, coded LET45, LET47, LET50, and LET52,
respectively, in Docket No. 78N-0038, Dockets Management Branch.
(2) Lowe, N. J. et al., ``Indoor and Outdoor Efficacy Testing of
a Broad Spectrum Sunscreen Against Ultraviolet A Radiation in
Psoralen-sensitized Subjects,'' Journal of the American Academy of
Dermatology, 17:224-230, 1987.
(3) McKinlay, A. F., and B. L. Diffey, ``A Reference Action
Spectrum for Ultraviolet Induced Erythema in Human Skin,'' CIE
Journal, 6:17-22, 1987.
(4) Comment No. C104, Docket No. 78N-0038, Dockets Management
Branch.
(5) Reference 29, Comment No. C128, Docket No. 78N-0038, Dockets
Management Branch.
(6) Reference 30, Comment No. C128, Docket No. 78N-0038, Dockets
Management Branch.
(7) Figure 2, Comment No. C128, Docket No. 78N-0038, Dockets
Management Branch.
(8) Comment No. 135, Docket No. 78N-0038, Dockets Management
Branch.
(9) Sayre, R. M. et al., ``A Comparison of In Vivo and In Vitro
Testing of Sunscreening Formulas,'' Photochemistry and Photobiology,
29:559-566, 1979.
(10) Sayre, R. M. et al., ``Sunscreen Testing Methods: In Vitro
Predictions of Effectiveness,'' Journal of the Society of Cosmetic
Chemists, 31:133-143, 1980.
(11) Cole, C. A., and R. L. VanFossen, ``In Vitro Models for UVB
and UVA Photoprotection,'' Comment No. RC1, Docket No. 78N-0038,
Dockets Management Branch.
(12) Diffey, B. L., and J. Robson, ``A New Substrate to Measure
Sunscreen Protection Factors Throughout the Ultraviolet Spectrum,''
Journal of the Society of Cosmetic Chemists, 40:127-188, 1989.
(13) Reference 13, Comment No. C257, Docket No. 78N-0038,
Dockets Management Branch.
(14) Comment No. C140, Docket No. 78N-0038, Dockets Management
Branch.
(15) Kelley, K. A. et al., ``In Vitro Sun Protection Factor
Evaluation of Sunscreen Products,'' Journal of the Society of
Cosmetic Chemists, 44:139-151, 1993.
(16) Reference 33, Comment No. C135, Docket No. 78N-0038,
Dockets Management Branch.
(17) Comment No. C171, Docket No. 78N-0038, Dockets Management
Branch.
(18) Lowe, N. J., M. M. Mobayen, and T. Bourget, ``UVA
Protection in Human Epidermis: Comparison of Three Sunscreen
Formulations,'' The Journal of Investigative Dermatology, 94:551,
1990.
(19) Stockdale, M., ``A Novel Proposal for the Assessment of
Sunscreen Product Efficacy Against UVA,'' International Journal of
Cosmetic Science, 9:85-98, 1987.
(20) Diffey, B. L., ``Pitfalls in the In Vitro Determination of
Sunscreen Protection Factors Using Broad Band Ultraviolet Radiation
Detectors and Solar Simulating Radiation,'' International Journal of
Cosmetic Science, 11:245-249, 1989.
(21) Comment No. C128, Docket No. 78N-0038, Dockets Management
Branch.
(22) Gonzenbach, H. U., and R. E. Romano, ``UVA Sunscreen In
Vivo Effectiveness Measurements,'' Cosmetics & Toiletries, 106:79-
84, 1991.
(23) Chardon, A. et al., ``Method for the UVA Protection
Assessment of Sunscreens Based on Residual Immediate Pigment
Darkening,'' Comment No. C104, Docket No. 78N-0038, Dockets
Management Branch.
(24) Cole, C. A., and R. VanFossen, ``Testing UVA Protective
Agents in Man,'' Comment No. C137, Docket No. 78N-0038, Dockets
Management Branch.
(25) Cole, C. A., ``Multi-Center Evaluation of Sunscreen UVA
Protectiveness using the PFA Test Method,'' Comment No. C137, Docket
No. 78N-0038, Dockets Management Branch.
(26) Cole, C., and R. VanFossen, ``Measurement of Sunscreen UVA
Protection: An Unsensitized Human Model,'' Journal of the American
Academy of Dermatology, 26:178-184, 1992.
(27) Kollias, N. K., and R. R. Anderson, ``The Non-Invasive
Determination of UV-A Sunscreen Effectiveness In Vivo,'' in
``Biological Responses to Ultraviolet-A Radiation,'' edited by
Urbach, F., Valdenmar Publishing, Overland Park, KS, pp. 371-376,
1992.
Dated: March 25, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-8023 Filed 4-4-94; 8:45 am]
BILLING CODE 4160-01-P
