sunscreen active ingredients, we propose not to permit the marketing
(without an approved NDA) of sunscreen products with determined SPF
values above SPF 80 (which reflects a formulation margin intended both
to give full effect to the SPF 60 limit and to enable formulation
flexibility).
    c. Proposal for =SPF 15 labeling. Finally, we are
proposing to require that sunscreen monograph products with determined
SPF values of 15 or above be labeled with an SPF number corresponding
to the lowest number in a range of tested SPF results, as shown in
table 5.\45\ For example, sunscreens testing at SPF 15 to 19 would be
labeled ``SPF 15''; those testing at 40 to 49 would be labeled ``SPF
40.'' \46\
---------------------------------------------------------------------------

    \45\ We note that the use of ranges to represent SPF values on
product labeling is already in use in Australia and the European
Union (Refs. 180 and 181).
    \46\ The proposed labeled values are expressed in increments of
5 for products with determined SPF results of 15 to 29.9 (i.e., SPF
15, SPF 20, SPF 25), but for determined SPF results of 30 or more,
the proposed labeled values are expressed in increments of 10 (i.e.,
SPF 30, SPF 40, SPF 50, with a proposed maximum of SPF 60+.).
---------------------------------------------------------------------------

    This proposal is designed to avoid misleading consumers about the
relative efficacy of sunscreen products, given the lack of clinical
data showing meaningful efficacy differences between closely grouped
SPF values. We note that in the 2011 L&E Final Rule, FDA declined a
request that SPF be labeled in multiples of five, stating that there
was no mathematical or statistical basis for this labeling approach
because SPF values could generally be determined with a precision that
allowed for SPF values to be labeled in intervals of less than five
units. New data showing variability both between tested SPF values for
individual study subjects and for determined SPF results achieved
across multiple labs testing the same sunscreen formulation (i.e.,
variability inherent in a clinical test that relies on visual
assessments) (FDA-1978-N-0018-0740, 2011; Ref. 182), however, has
caused us to reexamine this issue.
    As described above, the clinical SPF test is conducted using a
solar simulator to administer several specified doses of UV radiation
that increase by 15 to 25 percent with each successive dose to a human
subject's back in both sunscreen-treated and untreated areas (with the
specific UV doses being derived from the expected SPF of the product
and a determination of the individual subject's UV sensitivity). The
clinical investigator then visually evaluates both the sunscreen-
treated and untreated areas of the subject's back to identify the areas
with perceptible skin redness (erythema) that has clearly defined
borders. Determining which of several areas on a single subject's back
should be considered to meet this ``clearly defined borders'' criteria
is an exercise of clinical judgment. Once the investigator has made
this judgment, he or she then records the smallest dose of UV radiation
it took to create an area with the observed skin reaction of erythema
with clearly defined borders. After assessing multiple individual test
subjects this way, the resulting UV exposure information is used in
calculating the determined SPF value of the sunscreen being tested. The
data we reviewed suggest that the clinical evaluation undertaken during
this process creates variability that justifies the use of SPF ranges.
    For example, in a study using panels of five subjects, the mean SPF
values observed across multiple labs ranged from 54 to 82 for a target
SPF 80 (FDA-1978-N-0018-0740, 2011). This same study also evaluated a
scenario where a lab was not told the target SPF, but was rather given
a range of SPF 20 to 100 for a product with an expected SPF of 100. The
results showed that it was extremely difficult for labs to reproduce
the labeled SPF 100, with mean SPF values ranging from 37 to 75. In a
second study with multiple panels of 25 subjects that was controlled
and randomized, the determined SPF of two sunscreen formulations tested
across four labs ranged from 63 to 69 for a target SPF 70 and from 82
to 89 for a target SPF 90 (Ref. 182). Although the magnitude of the
differences observed in this second study were not statistically
significant, the fact that multiple labs determined different specific
numerical values for a single formulation suggests that the use of
labeled values representing ranges more accurately represents the sun
protection provided by a product, and therefore is appropriate to avoid
misleading consumers.
    We note that variability in SPF values is exacerbated at high SPFs.
For example, individual test results with 30 percent variability from a
determined SPF value of 20 would range from SPF 14 to SPF 26;
individual test results with 30 percent variability from a determined
SPF value of 50 would range from SPF 35 to SPF 65. Accordingly, as
shown in table 5, we propose that the range of tested values reflected
in the labeled SPF number should be wider at higher SPF values and
narrower at lower ones, and that the requirement that labeled SPF
values correspond to ranges rather than precise numerical values is not
necessary below SPF 15.

                  Table 5--Proposed SPF Labeling Ranges
------------------------------------------------------------------------
      Range of determined SPF values        Associated labeled SPF value
------------------------------------------------------------------------
60-80.....................................  60+.
50-59.....................................  50.
40-49.....................................  40.
30-39.....................................  30.
25-29.....................................  25.
20-24.....................................  20.
15-19.....................................  15.
2-14......................................  Determined SPF Value.
------------------------------------------------------------------------

C. Proposed PDP Labeling Requirements

    We are also proposing some revisions to the principal display panel
(PDP) for sunscreen products (the PDP is the portion of an OTC drug
product label that is most evident when the product is displayed for
retail sale (Sec.  201.60)). In addition to satisfying general OTC drug
labeling requirements found in part 201,

sunscreen product PDPs are currently required to satisfy specific
labeling requirements in Sec.  201.327. We are proposing to amend these
requirements for sunscreen PDP labeling (currently codified in Sec.
201.327(a) and (b), and (for the statement of identity of products that
also include skin protectants) in Sec.  201.327(h)) to help consumers
better understand, evaluate, and compare sunscreen products by
providing additional information on the PDP, and by ensuring the
prominence and readability of information required to appear on the
front of the container or package. We are also proposing to renumber
and consolidate provisions on PDP labeling and the statement of
identity (SOI) in Sec.  201.327(b) to incorporate new proposed
provisions in Sec.  201.327(a), as described in section IX.D.2.b of
this preamble. In addition, we are proposing that labeling a sunscreen
product in accordance with proposed Sec.  201.327(b) would be a
condition for marketing a sunscreen under the OTC sunscreen monograph
in part 352.
    We are proposing to revise the current SOI, which is required to
appear on the PDP by both current and proposed Sec.  201.327.
Currently, the SOI for sunscreens under this regulation contains ``the
established name of the drug, if any'' and identifies the product as a
``sunscreen.'' The revised SOI would consist of an alphabetical listing
of all sunscreen active ingredients in the product using the names
shown in Sec.  201.327, followed by ``Sunscreen'' and the product's
dosage form (such as lotion or spray). In light of these proposed
changes to the SOI for sunscreens, we are also proposing harmonizing
changes to the provisions that address the SOI for products that
combine sunscreen and skin protectant active ingredients (proposed
Sec.  201.327(h) and cross-referenced in the sunscreen monograph in
Sec.  352.60 (21 CFR 352.60) and in the skin protectant monograph in
Sec.  347.60 (21 CFR 347.60)).
    The proposal to list all active ingredients as part of the SOI is
generally consistent with SOI labeling of other OTC and prescription
drugs. Providing information about a product's active ingredients and
dosage form would supplement other important elements of the PDP (SPF,
broad spectrum, and water resistance information) to provide a succinct
summary of the product's key characteristics on the front of the
package or container. We expect that this approach would enable
consumers to more readily compare differing products and either select
or avoid a given product accordingly. As an indication that consumers
value information about a sunscreen's active ingredients, an analysis
of top-rated sunscreen product reviews on Amazon.com found that product
ingredients were listed as a positive factor in 17 percent of
responses, and a negative factor in 10 percent of responses (Ref. 183).
    Based on a review of marketed sunscreen product labels, FDA is
concerned that the SOI may currently be obscured by the inclusion and
prominence of other printed or graphic information on the PDP. For this
reason, we also propose to require the SOI to appear in direct
conjunction with the most prominent display of the proprietary name, in
a boldface font at least one-fourth the size of the most prominent
printed matter on the PDP, and displayed so that the text is generally
parallel to the base of the packaging. We propose that the entire SOI
appear in the same font style, size, and color with the same background
color, and as continuous text with no intervening text or graphic
material other than text provided in accordance with the requirements
for the SOI for a product that also includes a skin protectant, where
applicable. These requirements would supplement, and not replace, the
general requirements regarding the PDP and SOI for all nonprescription
products in Sec. Sec.  201.60 and 201.61.
    Proposed Sec.  201.327(b) would incorporate the ``Broad Spectrum
SPF,'' ``SPF,'' and ``Water Resistant'' statements that already must
appear on the PDP as described in current Sec.  201.327(a).
Additionally, for all products with SPF values below 15, we propose to
require that the SPF statement be followed by an asterisk (*) directing
the consumer to the statement ``*See Skin Cancer/Skin Aging Alert.'' We
propose that the quoted statement must appear in the bottom 30 percent
of the PDP. This statement is intended to draw the consumer's attention
to the Skin Cancer/Skin Aging Alert that would continue to be required
for these products as part of the ``Warnings'' in the Drug Facts
portion of the label (Sec.  301.327(d)), because there is evidence that
some sunscreen consumers are not reading this information in its
current location (Refs. 184 and 185).
    Under the current regulation, the entirety of the ``Broad Spectrum
SPF'' or ``SPF'' statement, as applicable, must appear on the sunscreen
PDP in the same font style, size, and color and with the same
background color, and, if used, the ``Broad Spectrum SPF'' statement
must also appear as continuous text with no intervening text or
graphic. To further ensure the prominence and readability of
information that is important for consumers to evaluate and compare
sunscreen products, we propose that these statements must also appear
in bold typeface at least one-fourth the size of the most prominent
printed matter on the PDP, and as text generally parallel to the base
of the packaging.
    The proposed new ``*See Skin Cancer/Skin Aging Alert'' statement
would also be required to appear in bold typeface at least one-fourth
the size of the most prominent printed matter on the PDP, and as text
generally parallel to the base of the packaging. In addition, the
entire statement would appear in the same font style, size, and color
with the same background color, and as continuous text with no
intervening text or graphic.
    Finally, because water resistance is also an important
characteristic for consumers when choosing a sunscreen, we also propose
to apply comparable format requirements to the current ``Water
Resistant'' statement. The statement would also be required to appear
in bold typeface at least one-fourth the size of the most prominent
printed matter on the PDP, and displayed so that the text is generally
parallel to the base of the packaging. In addition, the entire
statement would appear in the same font style, size, and color with the
same background color, and as continuous text with no intervening text
or graphic.

D. Proposed Requirements Related to Final Formulation Testing and
Recordkeeping

    We are also proposing a number of revisions in Sec.  201.327: (1)
To ensure that efficacy testing of the sunscreen formulation to be
marketed is conducted in a way that protects human subjects and
produces reliable results and (2) to enable FDA to assess compliance
with this section's provisions going forward. We also propose to make
compliance with these requirements a monograph condition in part 352.
1. General Approach to Final Formulation Testing
    Current Sec.  201.327 includes technical instructions for
conducting the final formulation testing required to support the SPF
values, water resistance statements, and broad spectrum statements
shown in sunscreen product labeling. However, the current regulation
does not explicitly address important broader considerations that are
essential to ensure that final formulation testing is conducted and

documented in a way that verifiably provides for protection of human
subjects in SPF and water resistance testing, as well as ensuring the
reliability of all the testing data that underlies sunscreen labeling.
We expect that persons responsible for conducting final formulation
testing should already be following best practices in their current
testing programs. However, we are concerned that many entities may not
uniformly observe such practices and/or may not maintain the records
needed to document compliance with the final formulation testing
procedures set forth in Sec.  201.327. FDA's experience in conducting
inspections and other actions to verify testing under the current
provisions of Sec.  201.327 have suggested latent problems in these
areas. Although limited, this experience reinforces FDA's belief that
further clarification of regulatory expectations is necessary given the
public health importance of ensuring that sunscreen products are
effective and accurately labeled, and the broad range of entities that
may be involved in bringing sunscreen products to market. Thus, we are
proposing to incorporate FDA's current expectations more explicitly in
the revised provisions. The proposed provisions are broadly consistent
with current best practices for efficacy testing conducted in human
subjects, and are not expected to require significant changes by
reputable and experienced testing establishments. Key areas of concern
that are addressed by the proposed revisions include the following.
    a. Protection of human subjects and oversight of clinical final
formulation testing. Ensuring that clinical final formulation testing
is both designed and conducted in a manner that will yield reliable
results is critical, as is ensuring the protection of the human
subjects on whom SPF and water resistance testing are conducted.
Existing provisions within the SPF test in Sec.  201.327(i)(3)(iv)
require that informed consent be obtained, but do not otherwise specify
what this should involve or how clinical final formulation testing
should be overseen. Across disciplines, testing involving human
subjects is ordinarily conducted under institutional review board (IRB)
oversight as a means of ensuring that informed consent and other human
subject protections are provided and ensuring the integrity of study
design and execution. FDA likewise expects that IRB review is already
routinely being obtained by many establishments for SPF and water
resistance testing.
    Nonetheless, our experience in conducting inspections and other
actions to verify the reliability of final formulation testing under
the current provisions of Sec.  201.327 have raised some questions
about current practices. For example, FDA's observations have raised
questions about whether and how entities conducting final formulation
testing have put in place protocols and IRB oversight to ensure that
test subjects do not repeat participation in testing with a frequency
that could both compromise the ability to distinguish erythemic
reactions to the test article and raise other questions about human
subject protection. We are concerned that the lack of explicit
requirements with regard to IRB oversight, as well as the cursory
nature of the informed consent requirement in the current sunscreen
labeling regulation, may result in inconsistent practices in the
conduct of SPF testing that would compromise the reliability of
results. Among other things, IRB review is critical to verify the
adequacy of informed consent and to ensure that study protocols
incorporate appropriate inclusion/exclusion criteria for subject
selection (both to protect test subjects and to ensure the accuracy of
results).
    b. Qualifications of study personnel. In some instances, it may not
be clear upon inspection whether all aspects of a study were conducted
by appropriately qualified personnel. For example, FDA would not
consider it adequate for a technician, rather than an appropriately
trained medical professional (such as, for example, a nurse or
dermatologist), to perform a physical examination for potential nevi,
moles, or other dermal lesions. As with all clinical and nonclinical
testing done to support labeling, the use of properly trained and
appropriately qualified personnel is essential to ensure the
reliability and accuracy of test results. Documentation of the
qualifications and training of personnel is also necessary to enable
FDA's efficient enforcement of the FD&C Act.
    c. Documentation of equipment maintenance, study methods, and
observations. Failure to maintain adequate records of testing
equipment, methods, and observations can raise broad questions about
the reliability of final formulation testing. In FDA's experience since
the promulgation of current Sec.  201.327, there has been a lack of
uniformity in testing entities' approaches to recordkeeping for final
formulation testing, raising concerns about the adequacy of
recordkeeping procedures. Failure of testing entities to keep adequate
records to support final formulation testing may leave FDA unable to
verify that the UV doses provided in SPF and water resistance test
reports are accurate and valid. This is also true with respect to
documentation of emission spectrum, the percentage of erythema-
effective radiation contribution, and changes to solar simulator
components and the UV meter/dose controller system. Failure to
accurately calibrate and maintain equipment at one testing entity may
affect data across multiple clinical SPF testing studies and/or broad
spectrum testing for multiple different final formulations that are
ultimately sold under different labels. Inadequate recordkeeping may
interfere with efficient enforcement. We propose to address these
concerns and align the regulation with our existing expectations
through revised regulatory provisions that are described further in the
following sections.
2. Specific Regulatory Proposals
    a. Consequences of failure to observe best practices. We propose to
clarify in the introductory paragraph of Sec.  201.327 that a product
is deemed misbranded if its labeling relies on the results of final
formulation testing that was not conducted in compliance with all of
the applicable provisions of Sec.  201.327. Unless testing is conducted
in compliance with all applicable provisions of Sec.  201.327, FDA does
not have adequate assurance that the labeling reliably reflects the
properties of the sunscreen product. Therefore, if final formulation
testing is not properly conducted in accordance with this section,
labeling a sunscreen with an SPF value or representation of water
resistance or broad spectrum properties based on that testing is a
misrepresentation to the consumer that the labeling reliably states the
product's properties, which should also be consistent with a system of
standardized sunscreen labeling that can be used to make cross-product
comparisons. We propose to incorporate the provisions of Sec.
201.327(a) through (l) into part 352 as conditions under which a
sunscreen is GRASE and not misbranded. If these provisions are
finalized, failure to comply with these conditions would make a drug
subject to regulatory action as misbranded and an unapproved new drug.
    b. General obligations of responsible persons. We are aware that
many different business relationships involving numerous entities are
commonly used in the manufacturing, testing, and labeling of
nonprescription sunscreen drug products. To clarify the locus of
responsibility for ensuring that adequate final formulation testing
procedures are in place, and to clearly delineate responsibility for

recordkeeping related to final formulation testing, FDA proposes a new
defined term, responsible person.
    We propose to define the term responsible person in a way that is
consistent with FDA's treatment of regulatory responsibilities for
other OTC drug products and that is in alignment with requirements for
adverse event reporting for over-the-counter drug products, in section
760(b)(1) of the FD&C Act. The proposed definition for responsible
person is ``the manufacturer, packer, or distributor whose name appears
on the labeling of a sunscreen product covered by this section.''
Defining responsible person in this way will enable FDA to better
assess compliance with Sec.  201.327 because it creates a chain of
responsibility that is immediately apparent from the product's
labeling. The responsible person, as identified on the labeling, is
ultimately responsible for ensuring that the product bearing its name
is labeled in accordance with the requirements of Sec.  201.327.
    The proposed revision of Sec.  201.327(a) would broadly set forth
the general obligations of responsible persons with respect to final
formulation testing under Sec.  201.327(i) and (j), and it would make
clear that the responsible person is charged with ensuring that
sunscreen products are appropriately tested. The obligations of
responsible persons as enumerated in Sec.  201.327 are modeled after
those of investigational new drug application (IND) sponsors under part
312 (21 CFR part 312), but are somewhat modified to accommodate unique
aspects of clinical and nonclinical sunscreen formulation testing.
Because final formulation testing under Sec.  201.327(i) and (j) is
intended to verify the claimed properties of a final formulation, and
because this purpose is narrower in scope and duration than most
clinical testing performed under FDA's IND regulations in part 312, a
responsible person under proposed Sec.  201.327 would have
responsibilities that incorporate some of the traditional
responsibilities of investigators as well as those of sponsors under
part 312. For example, FDA proposes to clarify that responsible persons
must select appropriately qualified personnel to conduct testing,
ensure compliance with the requirements for IRB review and obtaining
informed consent, and monitor the compliance of personnel with
investigators' statements.
    This proposed approach accounts for situations in which
investigators and other personnel conducting final formulation testing
are employees of the responsible person. We also propose to clarify
that the responsible person must ensure that investigators and other
personnel conducting investigations under Sec.  201.327(i) comply with
requirements related to human subject protection and the appropriate
conduct of clinical testing. We believe that this better reflects the
employer/employee relationships that are more common in connection with
final formulation testing rather than with clinical testing conducted
under an IND. These proposed provisions regarding selection of
personnel are also consistent with the existing obligations of
manufacturers under parts 210 and 211 (21 CFR parts 210 and 211), both
of which govern compliance with CGMPs.
    The proposed revision of Sec.  201.327(a)(1) permits a responsible
person to transfer some or all of its obligations to another entity,
consistent with current industry practice, except for obligations with
respect to recordkeeping. The recordkeeping proposal is discussed in
section IX.D. Failure of an entity to comply with provisions of this
part governing responsibilities it has assumed would subject that
entity to the same regulatory action as if it were a responsible person
who had failed to comply with those obligations. This provision is
analogous to the provision in FDA's regulations at part 312 allowing
for transfer of obligations of IND sponsors.
    c. Adequate clinical testing procedures and conditions. Although
current Sec.  201.327 requires ``legally effective written informed
consent from all test subjects'' (Sec.  201.327(i)(3)(iv)), it does not
address broader underlying requirements for conducting clinical
testing. In light of the concerns we identified regarding current
clinical testing procedures and conditions, we propose to amend Sec.
201.327 by adding paragraph (i)(1), ``Adequate Clinical Testing
Procedures and Conditions.'' We expect that final formulation testing
conducted in compliance with the proposals in this paragraph will be
more likely to ensure protection of human subjects while also more
reliably determining the SPF value and water resistance properties of
the final formulations being tested. Unless appropriate clinical
testing procedures and conditions are adhered to, FDA cannot have
confidence in the resulting labeled SPF and water resistance properties
of the product.
    Proposed Sec.  201.327(i)1(B) and (C) have been added to make clear
that FDA's regulations governing informed consent (part 50 (21 CFR part
50)) and IRB approval of research (part 56 (21 CFR part 56)) apply to
clinical final formulation testing that is conducted under Sec.
201.327(i). In our view, as a matter of good clinical practice, IRB
approval should already be routinely currently obtained for clinical
final formulation testing under current Sec.  201.327 because it is
essential to producing results that are scientifically sound and
ethically appropriate. Because clinical final formulation testing
required to support labeling under current Sec.  201.327 is not
conducted under an IND or in support of a GRASE determination in the
OTC sunscreen monograph, it was not previously included explicitly in
the scope of testing covered by parts 50 and 56. We propose to rectify
this omission by explicitly cross-referencing parts 50 and 56 in
revised Sec.  201.327(i). This will clarify that both of these parts
apply to clinical final formulation testing and will resolve any
inconsistency in current practice.
    The proposed reference to part 50 clarifies FDA's position that
legally effective written informed consent to participate in clinical
final formulation testing should share the same properties as informed
consent required for all other clinical testing covered by FDA's
regulations in part 50. Similarly, by referencing part 56, the proposal
ensures that final formulation testing is held to the same standards
for IRB review as other clinical testing covered by FDA's regulations.
In reviewing clinical protocols, IRBs have the ability to determine
whether the protocol is adequately designed to study the endpoints
sought, and to ensure that protocol elements, such as enrollment
criteria, adequately protect both human subjects and the scientific
rigor of the experiment.
    d. Control of personnel. We propose to place responsibility on the
responsible person to ensure that investigators and other personnel
conducting clinical final formulation testing adhere to the
investigational plan, the signed investigator statement, and all
applicable regulations. We also propose to place responsibility on the
responsible person for ensuring human subjects' protection, including
through appropriately reporting changes in the testing to IRBs, and by
appropriately seeking prior IRB approval for any changes to the
testing, except where necessary to eliminate apparent immediate hazards
to human subjects. Under the proposed rule, responsible persons are
also expected to obtain from each investigator, and retain for their
records, a signed investigator statement. This is similar to what is
required of sponsors of INDs, and it helps to ensure that the
investigator is qualified, understands his or her obligations, and will
comply with the requirements of

this paragraph and with the protocol. It also enables better oversight
of clinical investigations by FDA because it creates a record of the
investigator's relevant experience and qualifications.
    e. Research monitoring. A number of changes in Sec.  201.327(i)(1)
are being proposed to ensure adequate monitoring of clinical final
formulation testing. Revised Sec.  201.327(i)(1) would require that
responsible parties inform all investigators testing a formulation if
there are new observations about the drug, particularly with regard to
adverse events or safe use. This is necessary to ensure proper
communication between study personnel and protection of human subjects.
Responsible persons must also monitor the conduct of investigations to
ensure that clinical testing is being conducted in accordance with the
protocol and with applicable regulations. If a responsible person
discovers noncompliance by study personnel, then the responsible person
must either secure compliance or remove the noncompliant personnel from
conducting testing.
    Finally, we propose to require that investigators report adverse
events and/or safety concerns to the responsible person, and that
investigators also provide responsible persons with final reports at
the conclusion of testing. We believe that this will ensure there is
appropriate documentation and communication of adverse events and/or
safety concerns that arise during testing. It will also ensure there is
a record of SPF testing conducted under Sec.  201.327(i) that can be
relied upon should questions related to a particular formulation arise
when the sunscreen formulation is marketed. The proposed requirements
are consistent with reporting required in the IND context, although,
because of the short duration of the clinical final formulation testing
conducted under Sec.  201.327(i), we are not proposing to require
annual reporting.
    f. Test subject selection. We propose additional language regarding
the selection of test subjects in Sec.  201.327(i)(4). This is an area
in which FDA's inspections of testing entities have suggested a lack of
consistency. We are particularly concerned that inclusion/exclusion
criteria provide for adequate time between study and enrollment and
prior UV exposure, such as from participation in a previous SPF test,
sunbathing, or sunlamp use. Erythemal responses can remain for days
after sunbathing, and it is known that pigmentation development takes
up to a week after initial exposure and remains for weeks to months
(Ref. 186). SPF clinical studies should not include individuals who
have participated in sunbathing, tanning bed use, or another SPF
clinical study for at least the past 4 weeks or perhaps longer if UV-
induced responses remain. The proposed clarification regarding conduct
of physical examinations of test subjects reflects this consideration,
and our additional proposal for IRB review, addressed elsewhere, will
help ensure it is appropriately acted on.
    g. Applicability of registration and CGMP requirements. Proposed
Sec.  201.327(k) reflects FDA's existing view that final formulation
testing conducted under Sec.  201.327 constitutes the ``manufacture''
of a drug. As such, this testing must be conducted in an establishment
registered in accordance with part 207 (21 CFR part 207) and section
510 of the FD&C Act. This interpretation is consistent with the
definition of manufacture in part 207, which includes ``each step in
the manufacture, preparation, propagation, compounding, or processing
of a drug . . . .'' (Sec.  207.1). The definition of manufacture as
used in part 207 also ``includes manipulation, sampling, testing, or
control procedures applied to the final product or to any part of the
process, including, for example, analytical testing of drugs for
another registered establishment's drug'' (id). Accordingly, a
sunscreen product labeled in reliance on final formulation testing done
in an unregistered establishment is misbranded under section 502(o) of
the FD&C Act. This interpretation is also consistent with FDA's
regulations in Sec.  330.1, which require that OTC monograph drug
products be manufactured in a registered establishment in order to be
generally recognized as safe and effective and not misbranded. The
incorporation of this provision in Sec.  201.327, therefore, is
intended to clarify an existing requirement for facilities performing
this type of testing.
    We also propose to clarify that, as a manufacturing activity, final
formulation testing conducted under this paragraph is expected to be
done in accordance with CGMPs as set forth in parts 210 and 211 (see
Sec.  210.3(b)(12), indicating that for the purposes of parts 210 and
211, ``Manufacture, processing, packing or holding of a drug product
includes packaging and labeling operations, testing, and quality
control of drug products''). This is consistent with FDA's regulations
in Sec.  330.1, which require compliance with CGMPs as a condition for
OTC drug products to be GRASE and not misbranded when otherwise
marketed consistent with conditions in a final monograph. Adherence to
CGMP requirements in parts 210 and 211 includes compliance with the
requirements to keep certain records and to have appropriately trained
and qualified personnel. Failure to comply with CGMPs results in a
product being adulterated under section 501(a)(2)(B) of the FD&C Act.
    h. Recordkeeping. To enable FDA to better monitor compliance with
the requirements of Sec.  201.327, we propose to include specific
recordkeeping requirements for final formulation testing. Accordingly,
proposed Sec.  201.327(l) clarifies what records of testing performed
under this section must be kept, by whom, and for how long. This
provision also allocates responsibility for records maintenance and
specifies what records must be made available to FDA for inspection.
Recordkeeping is essential for FDA to evaluate whether required testing
of final formulations is being conducted in accordance with Sec.
201.327(i) and (j), and to enable the Agency to investigate
postmarketing product failures or adverse events. Appropriate
recordkeeping also enables FDA to conduct better and more efficient
inspections of entities conducting final formulation testing.
    These recordkeeping requirements are in alignment with what is
required for other types of manufacturing under CGMPs as set forth in
parts 210 and 211. The proposed provisions are intended to clarify how,
and for how long, records must be kept to substantiate required final
formulation testing. We are proposing that records of testing must be
kept by the responsible person (as newly defined in Sec.  201.327(a),
discussed previously), as well as by any other entity that actually
performs testing (under a transfer of obligations per Sec.
201.327(a)(1) or otherwise). Requiring that records be kept by both the
responsible person and the testing entity (if different) will enable
FDA to more easily identify records supporting the labeling of any
given final formulation even when the product is labeled with the
responsible person's information, but testing and manufacturing was
completed by a third party.
    The proposed recordkeeping requirements reflect FDA's experience in
interacting with regulated industry. By requiring that records be kept
by both the responsible person and any other entity that performs final
formulation testing, the proposed rule will enable more efficient
enforcement of the FD&C Act by, for example, allowing FDA to identify
the source of formulation failures or apparent inconsistencies between
the product labeling and consumer experience. The proposed
recordkeeping requirements

will also assist FDA when it is conducting inspections of entities that
perform final formulation testing for a number of different responsible
persons and products, as we believe is the norm in this industry.
Having ready access to records reflecting the overall conduct of final
formulation testing during an inspection of such an entity is important
because it will enable FDA to identify potential systemic problems in
final formulation testing that may have an impact on the reliability of
results supporting the labeling of multiple different sunscreen
products marketed by a variety of responsible persons. We note that
these recordkeeping requirements should not be understood to mandate
duplicative records within the files of a single testing entity or
single responsible party. For example, if one investigator is
responsible for testing multiple final formulations, one copy of the
signed investigator statement and Curriculum Vitae (CV) would be
sufficient to support all formulations tested by that investigator.
    Consistent with FDA's view that final formulation testing is
manufacturing, and thus is subject to CGMPs, equipment maintenance
records and other records documenting compliance with CGMPs are
expected to be maintained as required by parts 210 and 211.
Accordingly, we clarify in proposed Sec.  201.327(l) that records
documenting proper maintenance of equipment used in final formulation
testing must be kept, consistent with existing obligations in 21 CFR
211.68. In our view, this clarification will promote uniformity in
adherence to best practices and will help ensure more accurate and
reliable labeling of sunscreen products based on final formulation
testing. Additional specificity has been proposed here to clarify how
the more general recordkeeping provisions of part 211 apply to final
formulation testing. To provide assurance that the test results are not
compromised by faulty equipment maintenance or equipment failure, FDA
proposes that testing entities must keep documentation demonstrating
that equipment used for final formulation testing has been maintained
in accordance with established written specifications. This requirement
will enable FDA to more efficiently monitor compliance. Failure to keep
required records of final formulation testing will render a product
whose labeling relies on that testing adulterated under section
501(a)(2)(B) of the FD&C Act. Without recordkeeping, there is no
assurance that a sunscreen drug product has the identity and strength,
and meets the quality and purity characteristics, which it purports or
is represented to possess.
    This proposal also elaborates on recordkeeping necessary to
document compliance with the requirements of proposed Sec.  201.327
regarding conduct of final formulation testing.
    Proposed required records for SPF testing include records that: (1)
Identify the facility conducting the testing; (2) identify the
equipment used; (3) identify product samples and lots; (4) characterize
the SPF standard that is used; (5) document parameters for water
resistance testing; and (6) demonstrate compliance with the provisions
governing adequate clinical testing procedures and conditions. For
example, these would include documentation of IRB review, case
histories for each human subject (which must document protocol
deviations or injuries), administration of the sunscreen, and reading
of test results. These proposed recordkeeping obligations are
consistent with those required of parties engaged in human subjects
testing governed by other portions of FDA's regulations.
    Required records of broad spectrum testing conducted under proposed
Sec.  201.327(j) would include those records necessary for identifying
the facility conducting the testing, providing information associated
with the sample, identifying equipment used, and documenting sunscreen
product application. These proposed requirements provide greater
specificity than existing requirements in FDA's CGMP regulations, and
are expected to increase uniformity in current practice.
    We propose to clarify FDA's expectations regarding access to
records that responsible persons and other testing entities are
required to keep under this paragraph. These provisions are consistent
with FDA's inspection authorities in section 704 of the FD&C Act.
    i. Minor proposed revisions to test procedures. In addition to the
changes discussed in section IX.D, we are proposing several
modifications to the technical instructions for sunscreen final
formulation testing (Sec.  201.327(i) and (j)) to clarify how the
testing should be conducted.
    We are concerned that manufacturers conducting the SPF test
procedure may be relying on determinations of the initial minimal
erythema dose of unprotected skin (MEDu) generated too far in advance
of testing the sunscreen product. The current regulation in Sec.
201.327(i)(5) addresses four different determinations of MED for each
test subject: (1) An initial MED for unprotected skin (initial MEDu);
(2) a final MED for unprotected skin (final MEDu); (3) an MED for skin
to which the SPF standard has been applied (ssMEDp); and (4) an MED for
skin to which the sunscreen test product has been applied (tpMEDp). The
initial MEDu is used to set the UV exposures administered to determine
final MEDu, ssMEDp, and tpMEDp (see Sec.  201.327(i)(5)(iii)).
    Although the regulation already requires that each of the MED
values be determined 16 to 24 hours after UV exposure, it merely notes
that the final MEDu, ssMEDp, and tpMEDp are ``typically determined the
day following determination of the initial MEDu'' (see current Sec.
201.327(i)(5)(iv)). Because the skin reactivity of a test subject
changes over time, we propose to clarify that the initial MEDu of a
person's unprotected skin must be determined no more than 1 day before
the UV exposures for final MEDu, ssMEDp, and tpMEDp are administered.
We are also clarifying that to calculate the SPF value for each test
subject, under proposed paragraph Sec.  201.327(i)(6), it is the
subject's final MEDu that should be used.
    In our review of the testing requirements as part of this
rulemaking, we also revisited our position on the input slit bandwidth
specification in the in vitro broad spectrum test. In the 2011 L&E
Final Rule, we modified the in vitro broad spectrum test that was
proposed in the 2007 proposed rule to change the input slit
spectrometer bandwidth specification from <=5 nm to <=1 nm. After the
2011 final rule published, FDA received a comment from a spectrometer
manufacturer arguing that the 1 nm input slit bandwidth specification
was unreasonable. The manufacturer argued that common spectrometer
models that are currently used to test sunscreens cannot comply with
the <=1 nm input slit bandwidth specification, and those that can are
more expensive, more difficult to use, and take more time to use. The
manufacturer provided data that indicate that spectrometers with <=1 nm
input slit bandwidths do not produce more reliable results than
spectrometers with larger input slit bandwidths (see Comment, Docket
No. FDA-2010-D-0509-0004). In light of this submission, FDA reassessed
the input slit bandwidth parameters and concluded that <=5 nm will be
sufficient for the broad spectrum procedure. Although decreasing
bandwidth improves the ability to resolve closely spaced peaks (i.e.,
the spectral resolution), this is not a significant consideration for
in vitro broad spectrum testing of sunscreen products because
transmittance/absorbance curves for sunscreen

products are typically smooth with no individual sharp peaks.
Accordingly, we propose to revise Sec.  201.327(j)(1)(iv) to require
that spectrometer input slits be set to provide a bandwidth that is <=5
nm.
    Establishing standardized testing procedures for sunscreen products
and basing the products' labeling on this testing not only helps assure
the safety and effectiveness of each product, it also provides
consumers with consistent information about the sun protection
properties of sunscreen products across brands, which in turn
facilitates consumer comparisons when selecting products. Accordingly,
we propose to delete the provision in Sec.  352.77 (21 CFR 352.77)
addressing test modifications or alternative testing procedures.
Section 352.77 indicates that such test modifications or alternative
testing procedures require submission of a petition in accordance with
Sec.  10.30 (21 CFR 10.30). The proposed removal of Sec.  352.77 does
not alter the existing ability of a firm or individual to petition the
Agency to amend the monograph (see Sec. Sec.  330.10(a)(12) and 10.30)
to change the conditions that apply to products marketed under its
provisions, such as to modify testing procedures for all products
having some particular set of characteristics. Rather, the proposed
deletion will clarify that the sunscreen monograph does not permit
variation for individual products from the standardized testing
procedures that are monograph conditions, because such variation could
undermine important values supported by standardization.
    We are also proposing to correct a minor inaccuracy in the existing
regulatory language describing testing procedures. Specifically, Sec.
201.327(i)(1)(ii)(C) currently states that ``emission spectrum must be
determined using a handheld radiometer.'' As written, this statement is
inaccurate because a handheld radiometer cannot determine the emission
spectrum of a solar simulator. We propose to resolve this error by
clarifying that the handheld radiometer measures the solar simulator
radiation intensity rather than the emission spectrum. Finally, we have
proposed edits to certain provisions describing final formulation
testing procedures to clarify our long-standing intention that these
provisions of the test are requirements, not merely suggestions.

E. Proposed Status of Sunscreen-Insect Repellent Combination Products

1. Background
    Sunscreen-insect repellent combination drugs are products used on
human skin that contain both a sunscreen drug component and an insect
repellent component. A list of insect repellent products on the EPA
website identified a number of such products as of November 2017
(including multiple products within a single brand line).\47\ Among
those products, the majority contained either N,N-Diethyl-meta-
toluamide (also called DEET) or IR3535 as the insect repellant, and a
few contained oil of citronella as the insect repellent. Combination
insect repellent-sunscreen products have been marketed in a variety of
dosage forms (see section IX.A for a discussion of dosage forms), with
labeled SPF levels ranging from 15 to 30 (Ref. 187). Some products are
also labeled as water resistant or very water resistant (Ref. 187). The
products are generally labeled for use without regard to age (Ref.
187).
---------------------------------------------------------------------------

    \47\ EPA Product List (Ref. 187); a similar list of insecticide
products on the National Pesticide Information Center (NPIC) website
produced similar results (Ref. 188).
---------------------------------------------------------------------------

    FDA regulates sunscreens as drug products under the FD&C Act, and
EPA concurrently regulates insect repellents as pesticides under
FIFRA.\48\ FIFRA defines a ``pesticide'' in relevant part as ``any
substance . . . intended for repelling . . . any pest,'' including
insects (7 U.S.C. 136)(u)). Before they can be marketed, most skin-
applied insect repellents must be registered by EPA, although a few
plant-derived insect repellent active ingredients are exempt from
registration because EPA has determined they present minimum risk
potential to humans (Ref. 189).
---------------------------------------------------------------------------

    \48\ Some insect repellents are also regulated by FDA as human
drugs (e.g., pediculicides and scabicides intended to control
parasites on humans) or animal drugs (e.g., pesticide products for
oral administration to animals) (7 U.S.C. 136 et seq.); see also
``MOU 225-73-8010 Memorandum of Understanding Between the
Environmental Protection Agency and the United States Department of
Health, Education and Welfare Food and Drug Administration,''
(available at https://www.fda.gov/aboutfda/partnershipscollaborations/memorandaofunderstandingmous/domesticmous/ucm115873.htm (accessed April 17, 2018).
---------------------------------------------------------------------------

    Sunscreen-insect repellent combination products have been marketed
in the United States since before the OTC review began, but they have
not previously been addressed in the rulemaking for the OTC sunscreen
monograph (72 FR 7941 at 7943). Both FDA and EPA have historically
declined to object to the marketing of these products pending the
issuance of a final sunscreen monograph, provided that the sunscreen
active ingredient(s) is listed in the stayed final monograph and the
insect repellent component is registered with the EPA (79 FR 7941 at
7943). In 2011, FDA issued a draft enforcement guidance intended for
manufacturers who market OTC sunscreen products without an approved
application, which recommended that manufacturers of sunscreen-insect
repellent combination products should comply as closely as possible
with FDA's sunscreen testing and labeling requirements in Sec.
201.327. This guidance was finalized in May 2018 (Ref. 1).
    In the Federal Register of February 22, 2007 (72 FR 7941), FDA
issued a notice seeking public comments on sunscreen-insect repellent
combination products, and, in particular, whether FDA should amend the
OTC sunscreen monograph to add conditions for marketing insect
repellent-sunscreen drug products (FDA Call for Data or call for data).
The call for data summarized the regulatory status and history of both
sunscreens and insect repellents, and sought public input on a number
of issues (see table 6). On that same date (February 22, 2007, 79 FR
7979), EPA published a similar notice announcing that it was also
seeking information to determine how insect repellent-sunscreen
combination products should be regulated.

Table 6--Key Issues and Information Requests in FDA's 2007 Call for Data
------------------------------------------------------------------------
                                        Key concerns and information
           General issue                          requests
------------------------------------------------------------------------
Possible manufacturing conflicts..  Requested information about whether
                                     there are known conflicts between
                                     FDA and EPA manufacturing
                                     requirements and, if so, how to
                                     resolve them.
                                    Asked how FDA should address EPA-
                                     registered insect repellents in
                                     finalizing the OTC sunscreen
                                     monograph; which requirements
                                     should FDA retain, revise, or
                                     eliminate?
                                    Inquired about manufacturer testing
                                     of sunscreen-insect repellent
                                     combination products and whether
                                     any problems were encountered.
Possible formulation conflicts....  Requested comments on the
                                     significance of published research
                                     suggesting a potential formulation
                                     conflict.

Possible labeling conflicts         Labeling differences noted:
 between OTC sunscreen monograph     FDA uses ``warning''; EPA
 and EPA registration requirements.  uses ``caution'' (and only uses the
Note: Since publication of the       word ``warning'' to indicate
 call for data, FDA has              toxicity levels).
 established additional labeling     Many differences in
 regulations for certain OTC         required warning/caution section
 sunscreen products marketed         headings.
 without approved applications.      Directions for sunscreen
 However, the labeling concerns      use call for liberal application
 expressed in the call for data      and frequent reapplication; EPA
 remain relevant..                   directions may limit where and how
                                     to apply product and restrict
                                     frequency of application.
                                    Asked whether different directions
                                     for use can be integrated without
                                     leading to improper application,
                                     overexposure to insect repellent,
                                     and/or underexposure to sunscreen.
                                    FDA requires the outside container
                                     or wrapper of the retail package or
                                     the immediate container label to
                                     list all active and inactive
                                     ingredients (see section
                                     502(e)(1)(A)(iii) of the FD&C Act;
                                     Sec.   201.66(c)). EPA requires
                                     listing of the percentage of each
                                     active ingredient, and the total
                                     percentage of all ``inert'' or
                                     ``other'' ingredients, in the
                                     pesticide. Inert ingredients are
                                     not required to be identified
                                     individually on the product except
                                     in certain cases (in which case all
                                     inert ingredients are listed).
                                     Asked whether there is a way to
                                     label combination sunscreen-insect
                                     repellent drug products in a way
                                     that satisfies both the
                                     requirements of the FD&C Act and
                                     the FIFRA, and whether ``inert''
                                     ingredients under the FIFRA are
                                     equivalent to ``inactive''
                                     ingredients under the FD&C Act.
Safety issues.....................  More safety data needed given
                                     published animal studies indicating
                                     increased absorption of DEET and
                                     various sunscreens active
                                     ingredients when the components are
                                     combined. Asked for more safety
                                     data on combined products.
                                    Requested data on whether increased
                                     absorption of a sunscreen
                                     ingredient occurs when combined
                                     with an insect repellent.
                                    Information needed about incidence
                                     of skin irritation from combination
                                     products.
Effectiveness issues..............  Requested information on:
                                        Possible effects of
                                        insect repellent on sunscreen
                                        SPF; possible decreased
                                        sunscreen efficacy or increased
                                        exposure to insect repellent
                                        without greater efficacy
                                        resulting from inconsistent
                                        reapplication intervals.
                                     Potential chemical or
                                     physical incompatibilities between
                                     particular sunscreens and insect
                                     repellents.
                                        Potential need to
                                        specify minimum SPF for these
                                        combinations.
                                        Any potential
                                        performance benefits of these
                                        combination products other than
                                        convenience.
                                        Possible adjustments to
                                        formulations to minimize
                                        application time disparities.
------------------------------------------------------------------------

2. FDA's Evaluation of Sunscreen-Insect Repellent Combination Products
    FDA has reviewed the comments submitted in response to FDA's and
EPA's calls for data, as well as pertinent scientific literature and
publicly available EPA regulatory documents. Based on that review, we
have tentatively concluded that sunscreen-insect repellent combination
products, as a class, are not GRASE (i.e., are Category II) and are
misbranded because conflicting labeling requirements for their
sunscreen and insect repellent components cannot be reconciled to
create labeling that will sufficiently ensure safe and effective use of
the sunscreen component, as well as adequate directions for use as a
sunscreen, as required by section 502(f) of the FD&C Act. Also, if we
did not have this labeling concern, we would still tentatively
determine that available data regarding the safety and effectiveness of
these products for their use as sunscreens are insufficient to classify
these sunscreen products as GRASE for such use (i.e., Category III).
Specifically, evidence suggests that interactions between some
sunscreen active ingredients and insect repellents may decrease safety
by increasing systemic absorption of one or both components, and
potential synergistic effects on the efficacy of sunscreen active
ingredients apparently have not been studied. Although the available
data are limited and not conclusive, they give rise to questions about
the safety and effectiveness of these products. Our reasons for these
tentative conclusions are detailed in the discussion that follows.
    a. Public comments on the 2007 call for data. FDA received six
submissions in response to the 2007 call for data. None of the comments
included substantive data, although some cited published scientific and
medical literature, which is addressed in the following section of this
document. Five of the six comments were from manufacturers or a trade
association. Industry comments generally favored retaining joint
regulation between EPA and FDA (perhaps with enhanced coordination and
information-sharing) and amending the stayed OTC sunscreen monograph to
address sunscreen-insect repellent combinations. Several industry
comments claimed there was an absence of conflicting requirements
relating to manufacturing, formulation, and/or labeling. Others
suggested approaches for minimizing labeling conflicts, such as
permitting exemptions to FDA's Drug Facts labeling requirements to
accommodate EPA-required information, or placing FDA- and EPA-required
information in separate areas of the label. The remaining comment was
submitted by a medical association that opposed continued marketing of
sunscreen-insect repellent products, emphasizing concerns about
children's exposure to DEET. Industry comments favoring the continued
marketing of combination sunscreen-insect repellent drug products also
contended that combining sunscreen and insect repellent ingredients in
a single product is more convenient and cost-effective than using
separate products. Two comments stated that properly formulated,
tested, and labeled, combination products are better than the
unpredictable effects that could arise when consumers use two different
products. Regarding safety, one comment asserted various flaws in the
studies cited in the call for data that questioned the safety of these
combination products. (These studies are discussed in section
IX.E.2.d.)
    In general, the comments that we received in response to the 2007
call for data were not accompanied or corroborated by data. Although
the comments did not identify further concerns relating to product
manufacturing or formulation, they did not adequately address FDA's
concerns about safety, effectiveness, and labeling of these products.
FDA renews its request for data to support labeling and safety for
sunscreens with insect repellent added.
    b. Pesticide-related information. Pesticides that are or have been
used in combination products that also contain sunscreens include DEET,
IR3535, and oil of citronella. In evaluating combination insect
repellent-sunscreen products for the purposes of this rule, FDA defers
to EPA's expertise and authority regarding insect repellent
ingredients. We have not independently evaluated these pesticides, but
instead have focused on potential sunscreen-insect repellent ingredient
interactions and the feasibility of effectively labeling these
combination products for their use as sunscreens.

    As of June 2017, DEET was by far the most commonly used insect
repellent. According to the EPA Product list, the amount of DEET in
combination sunscreen-insect repellent products ranged from 10 to 20
percent. DEET product labels recommend that users avoid over-
application, use just enough repellent to cover exposed skin and/or
clothing, and not apply to hands or near the eyes or mouth of young
children (Ref. 190). DEET-containing products listed on the EPA website
in 2017 had concentrations ranging from 5 percent to 98 percent and
provided protection from mosquitos for 2 to 12 hours, with many
products having protection times of 4 hours or more (Ref. 187). The
American Academy of Pediatrics recommends that repellents should
contain no more than 30 percent DEET when used on children, and that
insect repellent should not be used on children younger than 2 months
(Ref. 191).
    EPA classifies the acute toxicity of insect repellents and other
pesticides into one of four toxicity categories (ranging from Category
I, highly toxic, to Category IV, practically nontoxic) (see 40 FR
156.62). DEET is classified in Category III based on EPA's review of
available animal studies, indicating slight acute toxicity for acute
oral, dermal, ocular, and inhalation tests in animals, and low acute
toxicity for the human health risk assessment (Ref. 192). Although DEET
is registered for use in humans of any age, adverse events related to
DEET toxicity have been documented and these events primarily relate to
the central nervous system. As summarized by Katz et al., DEET has been
associated with seizures and other central nervous system symptoms,
cardiovascular symptoms, and topical and allergic symptoms (Ref. 193).
Most reported cases of adverse or lethal events involved overuse or
otherwise incorrect use of the product (Ref. 193), and EPA concluded
that available data were insufficient to identify DEET as the cause of
the reported adverse events (Ref. 192). EPA is currently in the process
of updating its registration of a number of older pesticides, including
DEET, and is deferring decision on the regulatory status of combination
DEET/sunscreen products as described in the EPA Call for Data.\49\
However, EPA has stated that DEET does not pose a significant health
risk to the U.S. population.\50\
---------------------------------------------------------------------------

    \49\ DEET 2014 reregistration interim review final decision
(EPA-HQ-OPP-2012-0162) (available at https://www3.epa.gov/pesticides/chem_search/reg_actions/reregistration/red_PC-080301_1-Apr-98.pdf (accessed April 17, 2018).
    \50\ Id. In June 2014, EPA issued an interim review of DEET and
did not identify any specific new concerns. The proposed interim
registration review decision became final on September 24, 2014.
DEET 2014 reregistration interim review final decision (EPA-HQ-OPP-
2012-0162) (available at https://www.regulations.gov/document?D=EPA-HQ-OPP-2012-0162-0012 (accessed April 17, 2018).
---------------------------------------------------------------------------

    IR3535 is classified by EPA as a biopesticide because it is
biochemically, functionally identical to beta-alanine, a naturally
occurring substance that repels insects (Ref. 194). IR3535 is
classified in Toxicity Category IV (practically nontoxic) for acute
oral, dermal, and inhalation toxicity and Category III (slightly toxic)
for eye irritation (Ref. 195). Overall, EPA has assessed IR3535 as not
harmful when ingested, inhaled, or used on skin (Ref. 195). Eye
irritation could occur if the chemical enters a person's eyes (Ref.
195). IR3535 is used at concentrations of 7.5 percent to 20 percent in
a popular line of sunscreen-insect repellent combination products (EPA
Product List) (Ref. 187). Products containing IR3535 identified on
EPA's website in summer 2017 had concentrations ranging from 7.5
percent to approximately 20 percent and listed protection time against
mosquitoes of 2 to 8 hours (EPA Product List) (Ref. 187).
    Oil of citronella is a plant-derived biochemical insect repellent
(72 FR 7979 at 7981). Depending on its source, it may be categorized as
``Ceylon'' type or ``Java'' type. It is currently listed by EPA as a
minimum risk pesticide (registration generally not required if
formulated only with EPA-permitted inert ingredients and not labeled as
effective against disease-causing pests) (40 FR 152.25(f)). Oil of
citronella is also an approved food additive for use as a flavoring
agent in foods and beverages (Ref. 196). EPA has designated oil of
citronella as Toxicity Category III (slightly toxic) for acute oral
toxicity (Java type only), dermal toxicity, dermal irritation, and
acute eye irritation (both types), and Category IV (practically
nontoxic) for acute oral toxicity (Ceylon type) and acute inhalation
(Ref. 197). The National Pesticide Information Center (NPIC) fact sheet
on oil of citronella states that oil of citronella products should not
be used on children less than 6 months old (Ref. 198).
    c. Disparities in required labeling of sunscreens and insect
repellents. FDA and EPA regulate the format and content of the labeling
of nonprescription sunscreen products and pesticides, respectively. FDA
regulations on nonprescription sunscreen labeling include the general
drug labeling regulations in subpart A of part 201; the ``Drug Facts''
format and other OTC drug labeling requirements in subpart B of part
201; and the sunscreen-specific labeling requirements that apply to
sunscreens marketed without an approved NDA, including those based on
the current requirements for SPF and broad spectrum testing in Sec.
201.327. The labeling of registered insect repellents is subject to EPA
labeling requirements under FIFRA (40 CFR 156), as well as specific
language specified in individual product registration documents.
Although the FDA and EPA labeling requirements for nonprescription
sunscreens and registered pesticides cover some of the same information
(such as ingredient lists, net quantity statements, and warnings/
precautions), there is considerable variation in the language, format,
and placement of common label elements between the two Agencies, while
other elements do not overlap.
    Furthermore, both Agencies limit the degree to which a drug
manufacturer or pesticide registrant may depart from the prescribed
text, format, and/or location of required labeling elements. This is
particularly true for the wording and format of ``drug facts''
information for OTC drugs (see Sec.  201.66). Similarly, EPA
regulations state that although a registrant may choose to place non-
FIFRA-required information on a pesticide label, it may not replace,
obscure, conflict with, or supersede the FIFRA-required text (Ref.
199).
    The intended uses of sunscreens and insect repellents are quite
different, as are the associated labeling requirements; in particular,
the instructions for using the two types of products are different.
Required labeling for OTC sunscreens marketed without approved NDAs
calls for reapplication at least every 2 hours (see Sec.  201.327(e)(3)
through (e)(4)). The duration of protection for insect repellents
varies according to the active ingredient and strength. Based on
information from the EPA product list, many insect repellent-sunscreen
products provide protection against mosquitoes and/or ticks for more
than 2 hours, and some provide protection for as many as 6 to 10 hours.
EPA has stated that it is ``concerned about consumer use of products
that contain sunscreens and DEET, since directions to reapply generally
and frequently may promote greater use of DEET than needed for
pesticidal efficacy and thus pose unnecessary exposure to DEET.\51\ The
Centers for Disease Control and Prevention (CDC) advises consumers

that ``products that combine sunscreen and repellent are not
recommended, because sunscreen may need to be reapplied more often and
in larger amounts than needed for the repellent component to provide
protection from biting insects.'' (Ref. 200). Similarly, the American
Academy of Pediatrics advises consumers not to use products that
combine DEET with sunscreen, in part because ``[t]hese products can
overexpose your child to DEET because the sunscreen needs to be
reapplied often'' (Ref. 201). Additionally, DEET is approved for use on
children with no age restriction (Ref. 202), whereas FDA labeling
states ``[bullet] children under 6 months of age, ask a doctor'' (see
Sec.  201.327(e)(1)(iv)).
---------------------------------------------------------------------------

    \51\ DEET 2014 reregistration interim review final decision,
supra note 49, v.
---------------------------------------------------------------------------

    The recommended manner of application also differs for sunscreens
and insect repellents. For example, the directions on the label for all
insect repellent products containing DEET say to apply just enough to
cover exposed skin, and avoid over-application (Ref. 190), whereas the
labeling of nonprescription sunscreens marketed without approved NDAs
calls for liberal or generous application (see Sec.
201.327(e)(1)(ii)). The EPA-mandated directions on the labels of DEET
products also state, ``Do not apply near eyes and mouth; apply
sparingly around ears; do not use under clothing'' (Ref. 190). Such
statements are potentially troublesome from the standpoint of sun
protection in light of surveillance data from Australia, which suggest
that the incidence of certain skin cancers is more frequent on highly
exposed areas of the body such as ears and the backs of hands (Refs.
203 and 204). The CDC advises consumers who need protection from both
sun and insects to apply sunscreen product first, followed by an insect
repellent (Ref. 200).
    Additional disparities in the content and format of labeling
elements for sunscreens and registered insect repellents include the
following:
     EPA pesticide labeling includes required elements that
generally must appear on the front panel of the label, such as the
ingredient statement (40 CFR 156.10(g)(2)), specified signal word such
as ``CAUTION'' (40 CFR 156.64), and child hazard warning (40 CFR
156.66), which could crowd or detract from drug information required to
appear on the principal display panel for drugs (see Sec.  201.60
(``The principal display panel shall be large enough to accommodate all
the mandatory label information required to be placed thereon by this
part.'')). Other labeling elements that only EPA requires include
registration numbers and manufacturing establishment numbers (40 CFR
156.10(a)).
     FDA labeling for sunscreens uses the word ``warning'' (see
Sec. Sec.  201.66(c)(5) and 201.327(d)), while the EPA requirements
specify that pesticide products that, like DEET, IR3535, and oil of
citronella, meet the criteria of Toxicity Category III or IV as the
highest category by any route of exposure bear on the front panel
either no signal word or only the signal word ``CAUTION'' (40 CFR
156.64). In EPA labeling the word ``WARNING'' is used as a signal word
only for toxicity category II, which is a higher toxicity category than
that applicable to any insect repellent ingredients used in sunscreen-
insect repellent combination products (40 CFR 156.64(a)(2)).
     FDA labeling uses the term ``directions'' (see Sec. Sec.
201.66(c)(6) and 201.327(e)), while EPA regulations use the term
``directions for use'' (see 40 CFR 156.10(i)(2)).
     FDA calls for ingredients to be listed as ``active'' and
``inactive'' (see Sec.  201.66(b) through (c)), while EPA labeling uses
the term ``inert'' or ``other'' instead of ``inactive'' for all non-
pesticide ingredients (40 CFR 156.10(g)).
    Given the extent of the disparities discussed above, FDA
tentatively concludes that attempting to merge the required labeling
for monograph sunscreens and insect repellents in a way that would
comply with both Agencies' requirements and permit adequate consumer
understanding and proper use would be impracticable. In this regard, we
specifically disagree with comments made in response to the 2007 FDA
Call for Data suggesting that acceptable ``merged'' labeling could be
crafted by varying the OTC sunscreen drug facts to include insect-
repellent-related information, and/or by providing EPA-required
labeling outside the drug facts box. We are particularly concerned that
consumers would be confused by the juxtaposition of two sets of
different and, in some cases, contradictory information in the labeling
about these products' dual intended uses. We are also concerned that
the sheer amount of required information would result in crowded,
difficult-to-read labels lacking in the clarity and prominence of
important safety and use information that are both required by FDA
regulations and vital to consumer comprehension. We solicit comment and
data about how to reconcile the labeling of suncreens and insect
repellents such that a combined product could meet FD&C Act
requirements for OTC sunscreen drugs.
    d. FDA's review of published medical literature. The results of
FDA's literature review raise potential safety concerns about products
that combine sunscreen and insect repellent active ingredients. The
available data suggest that the dermal penetration and systemic
absorption of at least one combination of a sunscreen active ingredient
and an insect repellent is increased when both are present.
    There have been some studies assessing the penetration of DEET and
the effects of DEET combined with sunscreen (particularly the active
ingredient oxybenzone) on dermal penetration. Ross et al. tested for
synergistic effects between DEET and oxybenzone using an in vitro mouse
skin diffusion model and showed substantial penetration of a 20 percent
DEET standard in ethanol, while penetration of sunscreen active
ingredients was not found (Ref. 205). Despite a lower DEET content (10
percent), a commercially marketed sunscreen formulation had a 6-fold
more rapid detection and a 3- to 4-fold greater penetration of DEET
than the 20 percent standard. Other diffusion tests using pigskin or
artificial membranes and various combinations of DEET and oxybenzone in
different media suggested an enhancing effect on dermal penetration of
both DEET and oxybenzone (Refs. 206 and 207). The same investigators
obtained similar results in a later in vitro study using human skin
(Ref. 207).
    Kasichayanula et al. assessed the dermal absorption of DEET and
oxybenzone using an in vivo piglet model, in which samples were
collected from plasma, urine, and under the skin. Their results
indicated that the enhanced dermal penetration evidenced in the in
vitro studies translated to increased systemic exposure to both
oxybenzone and DEET (Refs. 208 and 209). Finally, a study by Yiin et
al. suggests that enhanced systemic absorption would also occur in
humans (Ref. 210). Yiin et al. used human urinary metabolites of DEET
and oxybenzone to evaluate the mutual enhancing effect on absorption of
these ingredients and concluded that their findings confirm that
concurrent use of DEET-containing insect repellent and oxybenzone-
containing sunscreen results in the enhancement of dermal absorption of
DEET when insect repellent (DEET) was applied first and then covered by
sunscreen (Ref. 210). The study authors suggested that placing
repellent spray on top of sunscreen lotion with no mixing seems to be
the best approach to diminish DEET penetration through the skin.
    Although insect repellents and sunscreens are designed to exert
their

protective effects on the surface of the skin, the studies described
above suggest that combining a sunscreen and insect repellent in a
single product may result in unintended systemic exposure to the
sunscreen ingredient oxybenzone and the insect repellent ingredient
DEET. We acknowledge the study limitations cited by comments to the FDA
Call for Data, and that in vitro diffusion studies have their
limitations in terms of reflecting clinical use. We also note that many
of the studies tested formulated commercial products with multiple
sunscreen ingredients and excipients for which details were not given,
and it is unclear how this may have influenced the results. Although
we, therefore, do not view these data as conclusory, we have determined
that they raise a valid safety concern that warrants a tentative
conclusion that, even if one could overcome the misbranding and
associated safety and effectiveness concerns created by the
inconsistent application directions for sunscreens and insect
repellants, there would not be sufficient evidence to conclude that
combination sunscreen and insect repellent products are GRASE for
sunscreen use without further investigation.
    Regarding future investigations that could assist FDA in
determining whether these products have sufficient evidence of safety
to be GRASE for use as sunscreen, we are not aware of any data that
define the extent of systemic exposure to either DEET or oxybenzone
that would occur with maximal exposure to a sunscreen-insect repellent
combination product. There also are few data from which to assess
whether there would be a similar enhancement of skin penetration for
other combinations of sunscreen and insect repellent active
ingredients. Moreover, without adequate human absorption studies under
maximal use conditions of particular sunscreen-insect repellent
combinations (i.e., a MUsT, as discussed in section VII.B.4), it is
difficult to evaluate potential risks associated with the use of such
combination products. Because of the potential synergistic interaction
between the sunscreen active ingredient and the insect repellent active
ingredient, human absorption data for the individual components would
not provide adequate data to estimate the level of systemic absorption.
Likewise, in vitro data would not be able to provide a reliable
estimate of the systemic exposure that would occur with such products'
use.
    In terms of sunscreen active ingredient effectiveness, we have
little data from which to determine whether the presence of an insect
repellent would affect the determined SPF value of combination
sunscreen-insect repellent products. Montemarano et al. reported a
reduction in sunscreen efficacy because of concomitant use with insect
repellent. However, in that study, the sunscreen and insect repellent
ingredients were applied separately and were not part of a combination
product (Ref. 211).
    With respect to efficacy, we recognize that the testing required by
Sec.  201.327 (both the current regulation and the regulation if
amended as proposed elsewhere in this proposed rule) to support labeled
SPF levels and other efficacy claims that may be made for certain OTC
sunscreen products could potentially mitigate concerns about the impact
of insect repellent active ingredients on sunscreen effectiveness.
However, we are not aware of any data evaluating the reliability of SPF
testing for sunscreen formulations that contain insect repellent
ingredients. There also is the possibility that increasing the amount
of the sunscreen active ingredient to compensate for any loss in
efficacy because of the presence of the insect repellent could result
in unnecessarily high exposure to the sunscreen active ingredient. For
these additional reasons, we tentatively conclude that even if other
concerns could be overcome, there is not currently sufficient evidence
to conclude that combination sunscreen-insect repellent products are
GRASE for use as sunscreens. We solicit comment on the data needs
identified above and tentative conclusions, including supporting data
and analysis. We also solicit data and information to address these
data needs.
3. Conclusion
    FDA tentatively concludes that the inherent disparity in labeling
requirements that apply to sunscreens marketed under the OTC monograph
and insect repellents prevent the creation of labeling that will
sufficiently ensure safe and effective use of the sunscreen component
of sunscreen-insect repellent combination products, particularly in
connection with duration of action. We also conclude that these
conflicting requirements prevent these products from having adequate
directions for use as a sunscreen, and thus these products would be
misbranded under section 502(f) of the FD&C Act. In addition, even if
these issues could be overcome, existing safety concerns about
potential enhanced systemic absorption resulting from combining
individual sunscreen active ingredients and insect repellent
ingredients would also need to be addressed by further studies on both
combinations of individual sunscreen and insect repellent ingredients
and final formulations.
    Existing data indicates there is a risk of systemic absorption of
insect repellent and/or a sunscreen active ingredient when both are
present. Additional data would be needed to identify any interactions
between specific sunscreen active ingredients and insect repellents, in
particular, to characterize any enhancement of skin penetration and/or
systemic absorption if the resulting data presents safety or
effectiveness concerns. As stated above, FDA would need adequate human
absorption studies, such as a MUsT, as part of the clinical safety
assessment (for more discussion on assessment of dermal absorption of
sunscreen active ingredients using MUsT, see section VII.B.4). The
effectiveness of sunscreen-insect repellent combination products is
also a continuing concern. For all of those reasons, we tentatively
determine that these products are not GRASE for nonprescription
sunscreen use. We solicit comment on this tentative determination.

X. Proposed Actions To Effectuate Lifting of Stay and Harmonize
Impacted Regulations

    In the 2011 L&E Final Rule, FDA explained that although we were not
yet lifting the stay on the 1999 final monograph, the provisions set
forth in the L&E Final Rule reflected the Agency's position on the
appropriate testing and labeling of sunscreen products that were
previously identified as falling within the Stayed 1999 Final Monograph
(76 FR 35620 at 35621). We explained that Sec.  201.327 would therefore
supersede the prior approach to labeling and effectiveness testing
described in the never-effective provisions of part 352, subparts C and
D.
    We are now proposing to lift the stay on the 1999 final monograph
(21 CFR part 352) while making certain changes in its provisions. To
fully effectuate this proposal, we are proposing several harmonizing
revisions to part 352 and Sec.  201.327. These changes remove certain
provisions from part 352 that were superseded by the 2011 L&E Final
Rule and, where applicable, replace them with appropriate cross
references to the applicable testing and labeling provisions in Sec.
201.327, as we propose to amend these regulations in this document. We
also have made minor revisions in parts 347, 352 and Sec.  201.327 to
improve readability and to correct certain typographical errors and
erroneous internal cross references.

    We are also proposing revisions to certain provisions describing
requirements for products containing both sunscreen active ingredients
and skin protectant active ingredients to avoid duplication between
Sec.  201.327 and part 352 and to harmonize the requirements set forth
in those provisions. As in the past, the proposed sunscreen monograph
would include conditions under which a single product could include
certain sunscreen active ingredients as well as certain ingredients
determined to be GRASE for use in skin protectants under part 347 (see
proposed Sec.  352.20(b), as well as current Sec.  347.20(e) (21 CFR
347.20(e)). Current Sec.  201.327(h) allows for such products to
combine certain labeling statements applicable to each ingredient in
the product to eliminate duplicative words or phrases. The stayed
provisions of part 352 contain similar allowances for products that
contain both sunscreen and skin protectant active ingredients, but also
outline more detailed requirements for presenting such a product's
statement of identity, indications, warnings, and directions. We
propose to relocate the labeling requirements for such products from
Sec.  352.60 to Sec.  201.327(h), thereby consolidating labeling
conditions for these products in one section of the regulations. We
also propose to retain compliance with these labeling provisions as a
monograph condition for sunscreen/skin protectant products under both
parts 352 (the sunscreen monograph) and 347 (the skin protectant
monograph) by incorporating cross references to Sec.  201.327(h) in
Sec.  352.20(b)(4), and Sec.  352.60, and incorporating cross
references to Sec. Sec.  352.20 and 352.60 in Sec. Sec.  347.20(e), and
347.60.
    Additionally, we propose to consolidate under new Sec.  310.549 (21
CFR 310.549) certain properties that render an OTC drug product offered
for use as sunscreen a new drug for which an approved NDA is required
prior to marketing. Section 310.545 (21 CFR 310.545) currently contains
several such provisions addressing specific ingredients and efficacy
claims. We propose to relocate these provisions from Sec.  310.545 to
Sec.  310.549. In addition, in the interest of completeness, we are
clarifying in Sec.  310.549 that labeling a product with claims that it
decreases the risk of skin cancer or early skin aging caused by the sun
if that product has an SPF of less than 15 when tested in accordance
with Sec.  201.327(i) and/or does not pass the broad spectrum test in
Sec.  201.327(j) renders the product a new drug.
    Finally, we propose to add to Sec.  310.549 new characteristics
that would render a product a new drug. These characteristics include:
(1) Containing the ingredients we propose to classify as categories II
and III (see sections VIII.B-C); (2) being labeled, represented, or
promoted for use as a combined sunscreen-insect repellant (see section
IX.E); (3) failing to comply with provisions relating to maximum SPF
values and broad spectrum requirements (see section IX.B); and (4)
failing to conform to certain other sunscreen formulation and dosage
form conditions (see sections IX.A and D).

XI. Comment Period

    We are providing a comment period of 90 days (see DATES). FDA will
also consider requests to defer further rulemaking with respect to a
specific sunscreen active ingredient to allow the submission of new
safety and/or effectiveness data to the record if such requests are
submitted to the docket within the initial 90-day comment period. FDA
will review all data and information submitted to the record in
conjunction with all timely and complete requests to extend. In
assessing whether to extend the comment period to allow for additional
time for studies to generate new data and information, FDA will
consider the data already in the docket along with any information that
is provided in any requests to extend. FDA will determine whether the
sum of the data, if timely submitted, is likely to be adequate to
provide all the data that are necessary to make a determination of
general recognition of safety and effectiveness.

XII. Proposed Effective/Compliance Dates

    The proposed effective date of final regulations resulting from the
proposals described in this rulemaking is November 26, 2019 (see FD&C
Act section 586E). We recognize that industry will need time after
publication of any final regulations to comply with their provisions.
To allow for orderly implementation of final regulations and help
assure continued product availability to consumers, we would not expect
full compliance with such final regulations for units of sunscreen
product initially introduced or initially delivered for introduction
into interstate commerce, until 1 year after the effective date of the
final rule. We also would not expect full compliance, even after that
date, for units of product that were initially introduced or initially
delivered for introduction into interstate commerce before that date,
such as those remaining in retail outlets. Our current thinking on
implementation is informed in part by our understanding there are no
currently marketed sunscreen products that contain the active
ingredients we propose here as Category II. We solicit comment on this
proposed approach.

XIII. Preliminary Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, Executive Order 13771, the
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and
13563 direct us to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Executive Order 13771
requires that the costs associated with significant new regulations
``shall, to the extent permitted by law, be offset by the elimination
of existing costs associated with at least two prior regulations.'' We
believe that this proposed rule is a significant regulatory action as
defined by Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because many sunscreen manufacturers are small entities and
the one-time costs of the proposed rule represent a significant
fraction of annual revenue to sunscreen manufacturers, we find that the
proposed rule will have a significant economic impact on a substantial
number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $150 million, using the most current (2017) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
result in an expenditure in any year that meets or exceeds this amount.

    We have developed a comprehensive preliminary regulatory impact
analysis that assesses the impacts of the proposed rule. We present a
summary of this analysis below.

B. Summary of Costs and Benefits

    If finalized, the proposed rule would update and make effective
regulations to ensure the safety and effectiveness of sunscreen
products marketed under the OTC drug monograph. The rule would update
sunscreen product labeling standards, address the safety of sunscreen
active ingredients, revise and clarify our expectations for testing and
recordkeeping by entities that conduct sunscreen testing, and address
other sunscreen safety or efficacy concerns, like combination
sunscreen-insect repellents and alternative dosage forms.
    Consumers would benefit from less exposure to sunscreen products
containing active ingredients about which safety questions remain, less
exposure to sunscreen products labeled with potentially misleading sun
protection information, increased consumption of products with better
UVA protection, less exposure to flammable spray sunscreens, and less
exposure to spray and powder sunscreen products posing inhalation
risks. Consumers would also experience transaction cost savings. The
costs of the rule to sunscreen manufacturers include administrative
costs, costs to fill data gaps for active ingredients and powder dosage
forms, product formulation testing costs, and costs to reformulate and
relabel sunscreen products. Finally, testing entities would incur
recordkeeping costs if they do not already maintain adequate records of
testing equipment, methods, and observations in final formulation
testing.
    Table 7 summarizes the costs and benefits of the proposed rule, if
finalized. The annualized benefits of the proposed rule, if finalized,
would range from $0.00 million to $3.72 million at a 7 percent discount
rate and from $0.00 million to $3.62 million at a 3 percent discount
rate. Our primary estimate of annualized benefits would equal $0.91
million at a 7 percent discount rate and $0.88 million at a 3 percent
discount rate. The annualized costs of the proposed rule, if finalized,
would range from $15.57 million to $75.84 million at a 7 percent
discount rate and from $12.40 million to $60.42 million at a 3 percent
discount rate. Our primary estimate of annualized costs would be $47.55
million at a 7 percent discount rate and $37.79 million at a 3 percent
discount rate.\52\
---------------------------------------------------------------------------

    \52\ The primary estimate of the costs is not the average of the
lower bound costs and the upper bound costs.

              Table 7--Summary of Benefits, Costs, and Distributional Effects of the Proposed Rule
----------------------------------------------------------------------------------------------------------------
                                                                             Units
                                                               ---------------------------------
           Category             Primary      Low        High                            Period        Notes
                                estimate   estimate   estimate     Year     Discount   covered
                                                                 dollars    rate (%)   (years)
----------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized ($m/      $0.91      $0.00      $3.72       2017          7         20
     year).                         0.88       0.00       3.62       2017          3         20
    Annualized Quantified         201.79      98.16     286.26                                   Increased use
     (mil oz/year) \1\.                                                                           of products
                                                                                with improved
                                                                                UVA
                                                                                protection.
    Annualized Quantified          51.42      19.43      83.41                                   Less exposure
     (mil oz/year) \2\.                                                                           to sunscreens
                                                                                containing
                                                                                active
                                                                                ingredients
                                                                                about which
                                                                                safety
                                                                                questions
                                                                                remain.
    Annualized Quantified         161.04     159.88     162.20                                   Less exposure
     (mil oz/year) \3\.                                                                           to sunscreens
                                                                                with
                                                                                potentially
                                                                                misleading sun
                                                                                protection
                                                                                information.
    Annualized Quantified         386.44     384.86     388.02                                   Less exposure
     (mil oz/year) \4\.                                                                           to spray and
                                                                                powder
                                                                                sunscreens
                                                                                posing
                                                                                inhalation
                                                                                risks.
                              ------------------------------------------------------------------
    Qualitative..............   Quicker responses to adverse events, improved inspections, and
                                better protection of human subjects. Potential transaction cost
                                 savings related to changes in the effort required to choose a
                                                          sunscreen.
----------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized ($m/      47.55      15.57      75.84       2017          7         20
     year).                        37.79      12.40      60.42       2017          3         20
    Annualized Quantified....
                              ------------------------------------------------------------------
    Qualitative..............     Recordkeeping costs to testing entities that do not already
                                                  maintain adequate records.
----------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized
     Monetized ($m/year).
                              ----------------------------------------------------------------------------------

                               From:
                               To:
                              ------------------------------------------------------------------
    Other Annualized
     Monetized ($m/year).
                              ----------------------------------------------------------------------------------
                               From:
                               To:
                              ------------------------------------------------------------------
Effects:                       State, Local, or Tribal Government: None.
                               Small Business: Some small businesses could exit the sunscreen
                               market by discontinuing their products or going out of business.
                               Wages: None.
                               Growth: None.
----------------------------------------------------------------------------------------------------------------
\1\ Values represent the 2016 consumption of sunscreens that would provide improved UVA protection under the
  proposed rule.
\2\ Value represent the 2016 consumption of sunscreens that contain active ingredients about which safety
  questions remain.
\3\ Values represent the 2016 consumption of sunscreens with potentially misleading sun protection information.
\4\ Values represent the 2016 consumption of potentially inhalable spray sunscreens and powder sunscreens.

    Table 8 shows the Executive Order 13771 summary over an infinite
time horizon. In this analysis we assume that the costs and cost
savings of the rule would end after 20 years. We estimate that this
rule generates $29.85 million in net annualized costs, discounted at 7
percent, over a perpetual time horizon. Based on these costs, this
proposed rule would be considered a regulatory action under E.O. 13771.

                                                            Table 8--E.O. 13771 Summary Table
                                              [In $ millions 2016 dollars, over an infinite time horizon) 1
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                              Primary       Lower bound     Upper bound       Primary       Lower bound     Upper bound
                                                           estimate (7%)       (7%)            (7%)        estimate (3%)       (3%)            (3%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Present Value of Costs..................................         $456.33         $149.22         $730.46         $618.16         $201.53       $1,002.22
Present Value of Cost Savings...........................            0.00            0.00            0.00            0.00            0.00            0.00
Present Value of Net Costs..............................          456.33          149.22          730.46          618.16          201.53        1,002.22
Annualized Costs........................................           29.85            9.76           47.79           40.44           13.18           65.57
Annualized Cost Savings.................................            0.00            0.00            0.00            0.00            0.00            0.00
Annualized Net Costs....................................           29.85            9.76           47.79           40.44           13.18           65.57
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ We assume that the benefits and costs of the proposed rule would diminish after 20 years. Negative values denoted in parentheses.

    We have developed a comprehensive Economic Analysis of Impacts that
assesses the impacts of the proposed rule. The full preliminary
analysis of economic impacts is available in the docket for this
proposed rule (Ref. 63) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

XIV. Analysis of Environmental Impact

    We have determined under 21 CFR 25.31(c) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

XV. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that
are subject to review by OMB under the Paperwork Reduction Act of 1995
(PRA) (44 U.S.C. 3501-3520). A description of these provisions is given
in the Description section of this document with an estimate of the
annual reporting, recordkeeping, and third-party disclosure burden.
Included in the estimate is the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data
needed, and completing and reviewing each collection of information.
    FDA invites comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
    Title: Sunscreen Drug Products for OTC Human Use.
    Description: The proposed rule would amend FDA's current sunscreen
labeling regulation (Sec.  201.327) and sunscreen products monograph
(part 352) regarding product labeling, testing, and recordkeeping
requirements. We note that existing regulations (e.g., current Sec.
201.327) already require SPF testing and labeling. The information
collections associated with current testing, labeling, and
recordkeeping requirements have previously been approved in accordance
with the PRA under OMB control numbers 0910-0139, 0910-0717, and 0910-
0755. For more information about current regulations and their history,
see the Background and Scope sections of the

proposed rule (sections III and IV, respectively). The proposed rule
would also amend parts 310 and 347.
    While the proposed provisions are broadly consistent with current
best practices for testing conducted in human subjects and are not
expected to require significant changes by reputable and experienced
testing establishments, the proposed rule clarifies and confirms the
application of existing requirements to sunscreens and adds certain new
requirements, particularly for labeling and recordkeeping. The purpose
of these changes is to help ensure that sunscreen testing is conducted
and documented in a way that verifiably provides for protection of
human subjects and increases the reliability of the testing data that
underlies sunscreen labeling, and to update the labeling requirements.
    Description of Respondents: Affected entities include: (1)
``responsible persons,'' as defined in proposed Sec.  201.327(a); (2)
entities to which the responsible person transfers its obligations as
permitted under proposed Sec.  201.327(a)(1) (e.g., contract
manufacturers, contract testing entities, contract research
organizations); and (3) clinical investigators conducting the testing
(the investigator(s) required to submit investigator statements and
other materials to the responsible person).
    FDA estimates that up to 772 entities could meet the proposed
definition of responsible person (equivalent to ``brands'' in the
economic analysis found in section XIII, Preliminary Analysis of
Economic Impacts). The estimate of 772 entities also includes nearly
all entities to which a responsible person might transfer its
obligations (``transferees''), such as contract manufacturers, contract
repackagers, contract distributors. For example, a manufacturer may be
a responsible person for one brand and a contract manufacturer for
another. However, in addition to the 772 entities and potential
transferees already described, we estimate that there are approximately
10 U.S.-based contract testing entities used by multiple responsible
persons to conduct sunscreen testing (e.g., contract laboratories and
contract research organizations). These 10 potential transferees are
not included in the 772 figure. Thus, for certain information
collections, the estimated respondent number may be 782. We note that
this estimate does not include non-U.S.-based contract testing
entities.
    In addition to the 10 contract testing entities, FDA estimates that
approximately 10 of the estimated 772 responsible persons conduct their
own SPF or broad spectrum testing. Thus, we estimate that there are
approximately 20 entities that conduct covered sunscreen testing; we
estimate these entities have approximately 20 lead clinical
investigators to whom certain information collection obligations (e.g.,
reporting) may apply.

A. Labeling for Sunscreen Products and Associated Clinical Testing

    The proposed rule includes third-party disclosure obligations for
responsible persons. The provisions may also apply to entities to which
the responsible persons transfer their responsibilities under section
201.327(a)(1) (``transferees''), depending on the scope of transferred
obligations. There are labeling-related information collections
(requirements include certain information on product labels) and a
related testing burden (requirements for certain clinical testing to
determine and support labeling information).
1. Labeling-Related Information Collection and Burden
    Proposed Sec.  201.327(b) and Sec.  201.327(h)(1) amend certain
labeling requirements applicable to the PDP. Among other things,
proposed Sec.  201.327(b) sets forth labeling requirements for the
statement of identity and SPF value claims discussed in this section.
Proposed Sec.  201.327(h)(1) applies to the statement of identity for
sunscreen products that also contain skin protectant active
ingredients. Proposed Sec.  352.50 requires that the PDP labeling
comply with the requirements of Sec.  201.327(b). The SPF value
statements set forth in proposed Sec.  201.327(b) and referenced in
proposed Sec.  352.50 are based on the results of the testing required
in proposed Sec.  201.327(i) and proposed part 352 (Sec.  352.70).
    a. Statement of identity. Proposed Sec.  201.327(b)(1) requires
that sunscreen drug products bear a statement of identity consisting of
the name of each sunscreen active ingredient listed in alphabetical
order, followed by ``Sunscreen'' and ``[Dosage form]'' (e.g.,
``Lotion'', ``Spray''). Proposed Sec.  352.52(a) requires the labeling
to contain a statement of identity in accordance with Sec.  201.327(b).
    Proposed Sec.  201.327(h)(1) applies to sunscreen drug products
that also contain skin protectant active ingredients; it requires that
the product bear a statement of identity consisting of the name of all
sunscreen and skin protectant active ingredients in alphabetical order,
followed by ``Sunscreen/Skin Protectant'' and ``[Dosage form],''
presented in accordance with Sec.  201.327(b)(1)(ii). Proposed Sec.
352.60(a) requires that the product bear a statement of identity as set
forth in Sec.  201.327(h)(1). Proposed Sec.  352.20(b)(4) requires that
the product must be labeled in accordance with Sec. Sec.  201.327(h)
and 352.60. Proposed Sec.  347.60(a)(3) requires that the labeling of
the product bear the statement of identity set forth in proposed Sec.
352.60(a).
    We note that current regulations already include a requirement that
OTC products bear a statement of identity (see Sec.  201.66). This
proposed rule would set forth the specific requirements just described
for sunscreen drug products and sunscreen drug products that also
contain skin protectant active ingredients. We believe this analysis
reflects the additional burden beyond current statement of identity
requirements.
    b. SPF value. Proposed Sec.  201.327(b)(2) requires, among other
things, that the labeling display certain statements regarding the
product's SPF value; the statements must be supported by the testing
required by proposed Sec.  201.327(i) and referenced in proposed Sec.
352.70. As previously noted, certain SPF testing and labeling is
already required under current regulations. This analysis reflects the
estimated additional burden of the proposed changes to SPF testing and
labeling requirements.
    c. Burden for proposed statement of identity and SPF value
information collections. The estimated burden for the statement of
identity and SPF value information collections just described is
provided in table 11 (Estimated Annual Third-Party Disclosure Burden).
For currently marketed OTC sunscreen products, FDA believes that
responsible persons need only complete the testing (or reanalyze
existing testing data) and relabel the product as required by the rule
one time, and may then continue to utilize the resultant labeling going
forward without additional burden. We estimate that 772 respondents
would need to complete this relabeling and related testing (if not
already done) or reanalysis of existing test results one time for up to
4,078 total products. In addition, there may be new products introduced
each year. We estimate that as many as 1,500 new OTC sunscreen product
stock keeping units (SKUs) may be introduced each year by up to 772
respondents. These new products must be tested and labeled with the SPF
value and broad spectrum results determined in the tests. We estimate
that the 1,500 new sunscreen SKUs represent 975 new formulations.

    Table 11, row 1 provides FDA's estimate that 772 respondents will
need to create PDP labeling for currently marketed sunscreen
formulations in accordance with the statement of identity and SPF value
requirements of proposed Sec.  201.327(b)(1), (b)(2), and (h)(1). This
would be a one-time burden, and FDA estimates 5.2824 responses per
respondent for a total of 4,078 responses. FDA estimates a burden of
0.5 hours per response. We estimate the total burden of this
recordkeeping to be 2,039 hours.
    Table 11, row 2 provides FDA's estimate that up to 772 respondents
will need to create PDP labeling for new formulations each year in
accordance with the statement of identity and SPF value requirements of
proposed Sec.  201.327(b)(1), (b)(2), and (h)(1). FDA estimates 1.943
responses per respondent for a total of 1,500 responses. FDA estimates
a burden of 0.5 hours per response. We estimate the total burden of
this recordkeeping to be 750 hours.
    Table 11, row 3 provides FDA's estimate that 20 respondents will
conduct SPF testing in accordance with Sec.  201.327(i) (to determine
the SPF value required by Sec.  201.327(b)(2)) for currently marketed
sunscreen formulations, if this has not already been done. This would
be a one-time burden. The estimated number of respondents reflects
FDA's assumption based on its knowledge of the existing market that, of
the 772 responsible persons, approximately 10 will conduct their own
final formulation testing under Sec.  201.327(i), while most will
delegate the responsibility for conducting final formulation testing to
the approximately 10 independent testing entities that FDA believes
conduct most final formulation testing. FDA estimates 111 responses per
respondent for a total of 2,220 responses. FDA estimates a burden of 24
hours per response. We estimate the total burden to be 53,280 hours.
    Table 11, row 4 provides FDA's estimate that 20 respondents will
conduct SPF testing in accordance with Sec.  201.327(i) (to determine
the SPF value required by Sec.  201.327(b)(2)) for new sunscreen
formulations. FDA estimates 48.75 responses per respondent for a total
of 975 responses. FDA estimates a burden of 24 hours per response. We
estimate the total burden to be 23,400 hours.
    Regarding proposed Sec.  352.70, because that section does not add
any additional labeling or testing-related information collections not
already addressed elsewhere (it incorporates the proposed SPF testing
requirements as a condition of the part 352 monograph), there is no
additional burden.
2. Clinical Testing-Related Information Collection and Burden
    Proposed Sec.  201.327(i) contains requirements for clinical
testing of SPF values for inclusion on sunscreen product labeling. As
previously noted, current regulations already require SPF testing.
While FDA expects that SPF testing and some of the proposed
recordkeeping is already being done, the proposed changes are intended
to clarify existing requirements applicable to sunscreen drug products
and set forth certain new requirements intended to improve the
reliability of SPF testing and ensure the protection of human subjects.
Proposed Sec.  352.70 references the Sec.  201.327(i) testing
requirements and makes the referenced testing requirements part of the
monograph conditions of use.
    Across disciplines, testing involving human subjects is ordinarily
conducted under IRB oversight as a means of ensuring that adequate
human subject protections are provided and to ensure the integrity of
study design and execution. Thus, in this proposed regulation, FDA is
proposing to apply certain human subject protection requirements to
sunscreens, with the aim of having a framework similar to that used in
the IND context, but tailored to sunscreen testing.
    Information collections related to proposed Sec.  201.327(i) are
addressed in detail in the sections that follow. Regarding proposed
Sec.  352.70, as in the previous section, because the proposed change
does not add any additional labeling or testing-related information
collections not already addressed elsewhere (it cross-references the
proposed Sec.  201.327(i) testing requirements as a condition of the
part 352 monograph), there is no additional burden.
    a. Investigator statements and notifications. Proposed Sec.
201.327(i), among other things, requires responsible persons to obtain
a signed investigator statement and an investigator CV, and to provide
certain notifications (e.g., notification of adverse drug experiences).
These may result in third-party disclosure or reporting requirements
for responsible persons (and entities to which they have transferred
relevant obligations) as well as for clinical investigators. As noted
above, our experience leads us to believe that most responsible persons
will transfer their obligations under Sec.  201.327(i) to the
approximately 20 entities that currently conduct clinical SPF testing.
This assumption is reflected in the estimates regarding the number of
respondents below.
    b. Investigator statements, CVs, and related burden. Proposed Sec.
201.327(i)(1)(i) requires responsible persons to, among other things,
obtain a signed investigator statement from each investigator. Proposed
Sec.  201.327(i)(1)(iv)(B) requires responsible persons to obtain a
signed investigator statement and CV. In FDA's experience,
investigators for SPF testing are most often employed by the testing
entities, and we therefore believe this is a recordkeeping requirement
rather than a third-party reporting requirement. We request comment on
this assumption. As noted above, we estimate that responsible persons
will typically delegate this obligation to the approximately 20
entities conducting final formulation testing. We estimate that each
testing entity employs one clinical investigator to run the SPF testing
they conduct. One investigator may run multiple SPF tests, and so long
as the responsible person (or testing entity) has the investigator
statement and CV on file for each investigator, there need not be a
separate copy for each investigation.
    Table 10, row 1 provides FDA's estimate that approximately 20
respondents will need to obtain and keep a signed investigator
statement and CV in accordance with Sec.  201.327(i)(1)(i) and
(i)(1)(iv)(B). FDA estimates 2 responses per respondent (1 CV and 1
investigator statement) for a total of 40 annual responses. FDA
estimates a burden of 0.6 hours per response. We estimate the total
burden of this recordkeeping to be 24 hours.
    c. Notifications and related burden. Proposed Sec.
201.327(i)(1)(i) requires responsible persons to, among other things,
ensure that FDA and all participating investigators are promptly
informed of significant new adverse effects or risks with respect to
the drug. Proposed Sec.  201.327(i)(1)(v) requires responsible persons
to keep each participating investigator informed of new observations
about the drug, particularly with respect to adverse effects and safe
use. As mentioned above, like other obligations associated with testing
under proposed Sec.  201.327(i), we anticipate that this obligation
will be delegated in most instances to the approximately 20 entities
that currently conduct SPF testing on behalf of responsible persons.
    Table 9, row 1 provides FDA's estimate that approximately 20
respondents will need to inform FDA and participating investigators of
significant new adverse effects or risks in accordance with Sec.
201.327(i)(1)(i) and

of new safety and other observations in accordance with Sec.
201.327(i)(1)(v). FDA estimates up to 40 responses per respondent for a
total of up to 800 annual responses. FDA estimates a burden of 0.5
hours per response. We estimate the total burden of this recordkeeping
to be 400 hours.
    d. Informed consent, IRB review, and related burden. Proposed Sec.
201.327(i)(1)(ii) requires responsible persons to obtain informed
consent, as defined in part 50, before clinical final formulation
testing and proposed Sec.  201.327(i)(1)(iii) requires that clinical
testing under Sec.  201.327(i) be reviewed and approved by an IRB
meeting the requirements of part 56. These two proposed provisions make
clear that FDA's regulations governing informed consent (part 50) and
IRB approval of research (part 56) apply to clinical final formulation
testing conducted pursuant to Sec.  201.327(i).
    Regarding proposed Sec.  201.327(i)(1)(ii) and (iii), the
information collections associated with FDA's regulations governing
informed consent (part 50) and IRB approval of research (part 56) have
previously been approved in accordance with the PRA under OMB control
number 0910-0755. FDA does not expect that proposed Sec.
201.327(i)(1)(ii) or (iii) would affect the number of recordkeepers,
records, reports, or associated burdens included in the existing
approval (0910-0755), but we invite stakeholders to comment if they
have a different view.
    Proposed Sec.  201.327(i)(1)(vii) requires investigators to provide
safety reports and a final study report to the responsible person.
Although investigators are often employees of testing entities, we are
basing our estimate on our assumption the respondents in this case are
the investigators themselves because of the framing of the duty
proposed by the regulation.
    Table 9, row 2 provides FDA's estimate that up to 20 respondents
will need to provide safety reports in accordance with Sec.
201.327(i)(1)(vii)(A). FDA estimates 24.4 responses per respondent for
a total of 488 annual responses. FDA estimates a burden of 0.5 hours
per response. We estimate the total burden of this recordkeeping to be
244 hours.
    Table 9, row 3 provides FDA's estimate that up to 20 respondents
will need to provide a final report in accordance with Sec.
201.327(i)(1)(vii)(B). This will occur one time per study, with each of
the 20 investigators conducting multiple studies per year. FDA
estimates 48.75 responses per respondent for a total of 975 annual
responses. FDA estimates a burden of 3 hours per response. We estimate
the total burden of this recordkeeping to be 2,925 hours.
    Proposed Sec.  352.40(i)(1) references limitations on particle size
for sunscreens in a spray dosage form. Proposed Sec.  352.40(i)(2) and
(3) proposes limitations on flammability and drying time for spray
sunscreen formulations. These proposed sections (Sec.  352.40(i)(1)
through (3)) make the referenced limitations on flammability and
particle size requirements part of the monograph conditions of use.
Proposed Sec.  352.40(i)(5) states that applicable requirements for
particle size, flammability, and drying time for spray sunscreens must
be verified through batch and lot testing as part of CGMP compliance
under part 211. Entities conducting testing required by these sections
must also comply with associated recordkeeping requirements, including
those set forth in parts 210 and 211.
    The recordkeeping associated with ensuring compliance with Sec.
352.40(i)(5) (batch and lot testing to ensure compliance with particle
size, flammability, and drying time limitations) is considered to be
part of the manufacturers' CGMP requirements under parts 210 and 211
(OMB control number 0910-0139). While FDA believes that sunscreen