Federal Register, Volume 80 Issue 37 (Wednesday, February 25, 2015)

[Federal Register Volume 80, Number 37 (Wednesday, February 25, 2015)]
[Proposed Rules]
[Pages 10035-10043]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-03883]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. FDA-2008-N-0474]

Over-the-Counter Sunscreen Drug Products--Regulatory Status of
Ecamsule

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
issuing a proposed sunscreen order (proposed order) under the Federal
Food, Drug, and Cosmetic Act (the FD&C Act), as amended by the
Sunscreen Innovation Act (SIA). The proposed order announces FDA's
tentative determination that ecamsule (also known as terephthalylidene
dicamphor sulfonic acid) at concentrations up to 10 percent is not
generally recognized as safe and effective (GRASE) and is misbranded
when used in over-the-counter (OTC) sunscreen products because the
currently available data are insufficient to classify it as GRASE and
not misbranded, and additional information is needed to allow us to
determine otherwise.

DATES: Submit either electronic or written comments on this proposed
order by April 13, 2015. Sponsors may submit written requests for a
meeting with FDA to discuss this proposed order by March 27, 2015. See
section VI for the proposed effective date of a final order based on
this proposed order.

ADDRESSES: You may submit comments by any of the following methods:

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

Submit written submissions in the following ways:
Mail/Hand delivery/Courier (for paper submissions):
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must clearly identify the
specific active ingredient (ecamsule) and the Docket No. FDA-2008-N-
1474 for this

[[Page 10036]]

rulemaking. All comments received may be posted without change to
http://www.regulations.gov, including any personal information
provided. For additional information on submitting comments, see the
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket numbers, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Submit requests for a meeting with FDA to discuss this proposed
order to Kristen Hardin (see FOR FURTHER INFORMATION CONTACT).

FOR FURTHER INFORMATION CONTACT: Kristen Hardin, Division of
Nonprescription Drug Products, Center for Drug Evaluation and Research,
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm.
5491, Silver Spring, MD 20993-0002, 240-402-4246.

SUPPLEMENTARY INFORMATION:

I. Regulatory Background

A. Regulatory and Statutory Framework

The data and information addressed in this proposed order were
originally submitted for review under FDA's Time and Extent Application
(TEA) regulation, Sec. 330.14 (21 CFR 330.14), a process that has
since been supplemented with new statutory procedures established in
the SIA (Pub. L. 113-195), enacted November 26, 2014. The discussion
that follows briefly describes and compares the TEA and SIA processes
as they apply to the regulatory status of ecamsule.
The TEA regulation established a process through which a sponsor
could request that an active ingredient or other OTC condition,\1\
particularly one not previously marketed in the United States, be added
to an OTC drug monograph to enable compliant OTC drug products
containing the condition to be marketed in the United States without an
approved new drug application (NDA) or abbreviated new drug application
(ANDA). Because this proposed order specifically addresses an OTC
sunscreen active ingredient (ecamsule), the remainder of this
discussion will refer only to ``active ingredients.''
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\1\ For purposes of OTC drug regulation, a ``condition'' is
defined as an active ingredient or botanical drug substance (or a
combination of active ingredients or botanical drug substances),
dosage form, dosage strength, or route of administration marketed
for a specific OTC use, with specific exclusions (see Sec.
330.14(a)(2)). This document will refer simply to new ``active
ingredients,'' since that is the condition under consideration.
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Critical steps in a proceeding under the TEA regulation include the
following: (1) FDA's determination that an active ingredient had been
marketed for the proposed OTC use for a material time and to a material
extent (eligibility determination), and public call for submission of
safety and efficacy data, followed by; (2) review of safety and
efficacy data submitted by the sponsor or other interested parties; and
(3) FDA's initial determination that the data show the active
ingredient to be either GRASE or not GRASE for OTC use under the
applicable monograph conditions (including any new conditions rising
from FDA's review) (GRASE determination). Under the TEA regulation,
FDA's GRASE determinations are effectuated through notice and comment
rulemaking to amend or establish the appropriate monograph.
The TEA process in FDA regulations was supplemented by Congress's
enactment of the SIA. Among other amendments it makes to the FD&C Act,
the SIA creates new procedures specifically for reviewing the safety
and effectiveness of nonprescription sunscreen active ingredients,
including those, such as ecamsule, that were the subject of pending TEA
proceedings at the time the SIA was enacted. Like the TEA regulation,
the SIA calls for an initial eligibility determination phase for
nonprescription sunscreen active ingredients, followed by submissions
of safety and efficacy data and a GRASE determination phase. However,
the SIA requires FDA to make proposed and final GRASE determinations
for nonprescription sunscreen active ingredients in the form of
administrative orders rather than the multistep public rulemaking
required by the TEA regulation, and establishes strict timelines for
the necessary administrative actions.
Among other requirements, no later than 90 days after the SIA was
enacted (i.e., no later than February 24, 2015), FDA must publish a
proposed sunscreen order in the Federal Register for any
nonprescription sunscreen active ingredient, including ecamsule, for
which, on the date of enactment, an eligibility determination had been
issued under the TEA regulation and submissions of safety and efficacy
data received, and for which a TEA feedback letter had not yet been
issued (section 586C(b)(4) of the FD&C Act (21 U.S.C. 360fff-3(b)(4)),
as amended by the SIA). Other provisions of the SIA that are not
discussed in this proposed order address procedures applicable to other
pending and future sunscreen active ingredient GRASE determinations,
pending and future GRASE determinations for OTC products other than
sunscreens, issuance of specified guidances and reports, and completion
of pending sunscreen rulemakings, among others.
A proposed sunscreen order under the SIA is an order containing
FDA's tentative determination proposing that a nonprescription
sunscreen active ingredient or combination of ingredients: (1) Is GRASE
and is not misbranded when marketed in accordance with the proposed
order; (2) is not GRASE and is misbranded; or (3) is not GRASE and is
misbranded because the data are insufficient to classify the active
ingredient or combination of ingredients as GRASE and not misbranded,
and additional information is necessary to allow FDA to determine
otherwise (section 586(7) of the FD&C Act, as amended by the SIA).
Publication of a proposed sunscreen order triggers several timelines
under the SIA, including a 45-day public comment period, and a 30-day
period in which a sponsor may request a meeting with FDA to discuss the
proposed order.

B. FDA's Review of Ecamsule

L'Oreal asked FDA to include ecamsule in concentrations up to 10
percent as an active ingredient in the OTC sunscreen monograph in a TEA
submitted September 19, 2007. FDA announced on September 12, 2008, that
ecamsule had been found eligible in concentrations up to 10 percent to
be considered for inclusion in the OTC sunscreen monograph (21 CFR part
352, currently stayed), and requested submissions of safety and
effectiveness data to support a GRASE determination for the requested
OTC use (73 FR 53029). L'Oreal submitted safety and efficacy data on
ecamsule to the designated docket (FDA-2008-N-0474) on November 14,
2008 (ecamsule data submission). At the time the SIA was enacted, FDA
had not issued a TEA feedback letter or otherwise responded to that
submission.
In accordance with new section 586C(b)(4) of the FD&C Act as
amended by the SIA, we are issuing this notice as a proposed order for
ecamsule. Based on our review of the ecamsule data submission, we have
made a tentative determination that ecamsule is not GRASE for OTC
sunscreen use and is misbranded because the data are insufficient to
classify it as GRASE and not misbranded, and additional

[[Page 10037]]

information is necessary to allow us to determine otherwise. The
remainder of this proposed sunscreen order describes our review of
safety and efficacy data, identifies additional data needed to
demonstrate that ecamsule is GRASE for the requested use, and explains
our rationale for specific conclusions and data requirements.
This proposed order will be open for public comment (see DATES).
The sponsor may request a meeting with FDA to discuss this proposed
order (see DATES). We also invite the sponsor to submit additional
safety and/or efficacy data to inform our further consideration, as
publication of a final sunscreen order for ecamsule under the SIA will
be contingent on receipt of such information. (See section
586C(b)(9)(ii) of the FD&C Act.) We specifically encourage the sponsor
to discuss any proposed study protocols with us before performing the
studies.

II. Safety Data Considerations for OTC Sunscreen Products Containing
Ecamsule

In evaluating the safety of a proposed monograph active ingredient,
FDA applies the following regulatory standard: Safety means a low
incidence of adverse reactions or significant side effects under
adequate directions for use and warnings against unsafe use as well as
low potential for harm which may result from abuse under conditions of
widespread availability. Proof of safety shall consist of adequate
tests by methods reasonably applicable to show the drug is safe under
the prescribed, recommended, or suggested conditions of use. This proof
shall include results of significant human experience during marketing.
General recognition of safety shall ordinarily be based upon published
studies which may be corroborated by unpublished studies and other data
(Sec. 330.10(a)(4)(i) (21 CFR 330.10(a)(4)(i))).
FDA's OTC drug regulations generally identify the types of
information that may be submitted as evidence that an active ingredient
or other OTC drug condition is safe, as part of the consideration of
whether an active ingredient or other condition is GRASE (Sec.
330.10(a)(2)). For convenience, this order uses the term ``generally
recognized as safe (GRAS)'' to refer to that aspect of the GRASE
determination. To apply the general OTC safety standard to each
potential new condition, FDA uses its scientific expertise to determine
what constitutes ``adequate tests by methods reasonably applicable to
show the drug is safe under the prescribed, recommended, or suggested
conditions of use.'' In assessing what specific testing or other data
are needed to adequately demonstrate the safety of ecamsule for use in
sunscreen, FDA considers the circumstances under which OTC sunscreen
products that could contain ecamsule would be used by consumers.
When used as directed with other sun protection measures, broad
spectrum OTC sunscreen products with a sun protection factor (SPF)
value of 15 or higher strongly benefit the public health by decreasing
the risk of skin cancer and premature skin aging associated with solar
ultraviolet (UV) radiation, as well as by helping to prevent sunburn.
(Sunscreens with lower SPF values, or without broad spectrum
protection, also help prevent sunburn.) When used as directed by the
required labeling, all OTC sunscreen products are applied liberally to
the skin and reapplied frequently throughout the day (Sec. 201.327(e)
(21 CFR 201.327(e))). Because the effects of UV exposure are
cumulative, to obtain the maximum benefit, users of broad spectrum
sunscreens with an SPF value of 15 or higher are directed to use such
products regularly--on a routine basis (id.). Given these conditions of
use, our safety evaluation of an OTC sunscreen active ingredient such
as ecamsule must consider both short-term safety concerns (such as skin
sensitization/irritation and photosafety) and potential concerns
related to long-term sunscreen use, including potential systemic
exposure via dermal absorption.
The purpose of the safety testing described in this section II is
to establish whether an OTC sunscreen product containing ecamsule and
otherwise marketed under the conditions described in a final sunscreen
order and in accordance with all requirements applicable to
nonprescription drugs would be GRAS for use as labeled. To demonstrate
that these requirements are met for ecamsule, initial safety testing
should be performed using ecamsule as the sole active ingredient up to
the highest concentration for which marketing status is sought and
eligibility has been established: 10 percent. If initial testing
suggests a particular safety concern associated with ecamsule (e.g., a
hormonal activity), FDA may request additional studies to address that
concern.

A. Human Safety Data

1. Human Irritation, Sensitization, and Photosafety Studies
Studies of skin irritation, sensitization, and photosafety are
standard elements in the safety evaluation of topical drug products
that, like ecamsule-containing sunscreens, are applied to the skin
repeatedly over long periods of time. FDA recommends separate studies
for skin irritation and sensitization. Skin irritation studies should
generally include at least 30 evaluable subjects and should evaluate
the test formulation (i.e., ecamsule in an appropriate test vehicle),
the vehicle alone, and both negative and positive controls. Skin
sensitization studies generally should include at least 200 subjects
and should evaluate the test formulation containing ecamsule, the
vehicle, and a negative control. For both irritation and sensitization
studies, test site applications should be randomized and the test
observer blinded to the identities of the test formulations.
FDA recommends that photosafety evaluation generally involve
studies of skin photoirritation (phototoxicity) and skin
photosensitization (photoallergenicity). General principles for
designing and conducting photosafety studies are described in FDA
guidance (Ref. 1). Photosafety studies, like sensitization and
irritation studies, should be conducted using ecamsule 10 percent in an
appropriate test vehicle, the vehicle alone, and a negative control. In
addition, phototoxicity studies should include at least 30 evaluable
subjects and photoallerginicity studies should include at least 45
evaluable subjects.
Data Available for Ecamsule: Human Irritation, Sensitization, and
Photosafety Studies
We received information regarding 26 non-U.S. human dermal safety
studies evaluating formulations containing up to approximately 4
percent ecamsule with one or more other additional active ingredients
(Note 1). These studies exposed a total of approximately 1,500 adults
to formulations containing ecamsule. Reports of 21 of these studies
were complete: 2 of these studies assessed primary cutaneous
irritation, 7 assessed cumulative irritation and sensitization
potential, 9 assessed phototoxicity potential, and 3 assessed
photosensitizing potential. However, the information provided in the 21
complete study reports does not meet FDA's current standards to support
the human dermal safety of ecamsule at any concentration. All of these
studies assessed formulations containing more than one active
ingredient and therefore provide only limited insight into the safety
of ecamsule. Furthermore, the formulations used in these studies
included ecamsule only in concentrations of between 0.33 percent and
3.96 percent, and therefore would

[[Page 10038]]

not support a determination that ecamsule is GRAS at concentrations
between 3.96 percent and 10.0 percent as found eligible for review and
requested for GRASE evaluation by L'Oreal. Other deficiencies noted
included:
Failure to provide individual skin reaction scores to
negative controls in all studies.
Failure to enroll a sufficient number of subjects in the
sensitization, phototoxicity, and photoallergenicity studies.
Although the cumulative irritation studies enrolled an
adequate number of evaluable subjects, there was a failure to indicate
whether positive controls were used, and only three study reports
indicated a negative control was used.
Failure to indicate whether or not investigators in the
primary cutaneous irritation, phototoxicity, and photoallergenicity
studies were blinded to patch applications.
Failure to indicate whether the phototoxicity and
photoallergenicity studies included vehicle controls.
The ecamsule data submission also included reports for 14 studies
exposing a total of over 500 children primarily between 3 and 12 years
of age to sunscreen formulations containing ecamsule in concentrations
of 1.5 percent to 9 percent, with 1 or more other additional active
ingredients (Note 2). Numerous dermatologic reactions were reported;
however, none were considered serious.
Three human safety-related literature citations listed in the
submission were limited to studies describing photoallergic reactions
to combination sunscreen products formulated both with and without
ecamsule (Note 3). One publication described a single case of
photoallergy to an ecamsule-containing sunscreen product (Ref. 2). A
second publication was a review that summarized published and
unpublished data from a single center's experience with patch and
photopatch testing in a consecutive series of 402 patients who
presented to a photobiology unit from 1981 to 1996 with suspected
clinical photosensitivity (Ref. 3). The authors did not observe allergy
or photoallergy to 1 percent ecamsule, but experience with ecamsule was
limited in this study because it was included in the sunscreen series
beginning in 1995, towards the end of the 15-year study period. The
third publication was a case report describing no photoallergy to an
ecamsule-containing combination sunscreen drug product in a 71-year-old
male patient with persistent photocontact allergy to other UV filters
(Ref. 4). A literature search conducted by FDA did not identify
additional publications regarding the human dermal safety of ecamsule
in concentrations up to 10 percent for use as an OTC sunscreen.
FDA concludes that the data submitted are not sufficient to assess
the dermal safety of ecamsule in concentrations up to 10 percent and
specifically its potential to cause irritation, sensitization,
photoirritation, or photoallergenicity. Submission of data from human
irritation, sensitization, and photosafety studies that meet FDA
standards (see section II.A.1) is recommended to demonstrate that an
OTC sunscreen product containing up to 10 percent ecamsule is not an
irritant, sensitizer, photosensitizer, or photoirritant.
2. Human Dermal Pharmacokinetic (Bioavailability) Studies
Because sunscreens are topically applied, another important safety
consideration for ecamsule for use in sunscreens is whether dermal
application may result in skin penetration and systemic exposure to
ecamsule, and if so, to what extent. A well-designed and -conducted
human dermal pharmacokinetic study can be expected to detect and
quantify the presence of ecamsule and/or any metabolites in blood or
other bodily fluids that may have a bearing on safety, using recognized
parameters such as bioavailability percentage, maximum plasma
concentration (Cmax), time to maximum plasma concentration (Tmax),
total area under the plasma concentration versus time curve (AUC),
half-life, clearance, and volume of distribution. This information can
help identify potential safety concerns and help determine whether an
adequate safety margin for sunscreens containing ecamsule exists. FDA
recommends that the pharmacokinetic studies performed on ecamsule also
collect additional safety-related data from regularly scheduled
physical examinations, collection of vital signs, and other measures,
which may help capture adverse skin events or other potential safety
signals. To ensure that maximum penetration of ecamsule has taken place
and chances of it being detected are optimal, studies should continue
until steady state is reached.
General information and recommendations on the design and conduct
of human pharmacokinetic studies can be found in FDA guidance (Ref. 5).
To support a GRAS determination for ecamsule (up to 10 percent), such a
study should be conducted under maximal use conditions using ecamsule
up to 10 percent in various vehicles, including vehicles that would be
expected to enhance absorption. We encourage study sponsors to consult
with us before conducting pharmacokinetic studies, because the
properties of ecamsule bear on the optimal design.
Data Available for Ecamsule: Human Dermal Pharmacokinetic
(Bioavailability) Studies
Human dermal pharmacokinetic studies for ecamsule were submitted in
response to our call for data. We reviewed one in vitro study that
evaluated the potential for dermal penetration of topically applied
ecamsule from human skin samples (Note 4). Because this study was not
designed to detect or quantify ecamsule in the blood or other body
fluids, it provides no useful information about systemic exposure. One
urinary excretion study conducted with a 4.95 percent ecamsule test
formulation suggested minimal systemic absorption in seven male
volunteers dosed over an extensive body surface area for a total of 5
days (Note 5). A study in which radiolabeled 2 percent ecamsule was
topically applied to the forearms of five male volunteers and retained
for 4 hours detected a minimal level of radiation above background in
urine after dosing but radiation levels above background were not
detected in blood (Note 6). Although this study suggests that ecamsule
is minimally absorbed following dermal application, the study
formulation contained ecamsule at a concentration much lower than the
requested 10 percent maximum and only a small number of subjects were
dosed over a limited surface area. The last human dermal
pharmacokinetic study assessed the absorption of 3 percent ecamsule
from a formulation containing a total of four active ingredients (Note
7). The formulation was applied to an extensive body surface area of
six male subjects twice daily for 8 days. Results showed that there
were quantifiable plasma concentrations of ecamsule at several time
points, suggesting that ecamsule is absorbed via dermal application.
None of the submitted human dermal pharmacokinetic studies assessed an
adequate number of subjects, or tested ecamsule at the maximum
requested concentration of 10 percent.
Our literature search found no additional publications regarding
human pharmacokinetics of ecamsule. Accordingly, we request data from
human pharmacokinetic studies to assess the potential for and the
extent of systemic absorption. These studies should be performed under
expected

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maximal use conditions with the proposed maximum concentration, as
discussed previously in this section, in a sufficiently large study
population to control for both gender and age.
3. Human Safety Data To Establish Adverse Event Profile
An evaluation of safety information from adverse event reports and
other safety-related information derived from commercial marketing
experience of sunscreen products containing ecamsule, as well as from
other sources, is a critical aspect of FDA's safety review for
ecamsule. The TEA regulation under which the original request for
ecamsule was submitted specifically calls for submission of information
on all serious adverse drug experiences, as defined in 21 CFR
310.305(a) and 314.80(a), from each country where the active ingredient
or other condition has been or is currently marketed as either a
prescription or an OTC drug; in addition, it calls for submission of
all data generally specified in Sec. 330.10(a)(2), which includes
documented case reports and identification of expected or frequently
reported side effects (Sec. 330.14(f)(1) and (f)(2)). To evaluate
ecamsule, FDA continues to seek individual adverse drug experience
reports, a summary of all serious adverse drug experiences, and
expected or frequently reported side effects of the condition (id.). To
assist in the Agency's safety evaluation of ecamsule, FDA emphasizes
its need for the following data:
A summary of all available reported adverse events
potentially associated with ecamsule;
All available documented case reports of serious side
effects;
Any available safety information from studies of the
safety and effectiveness of ecamsule in humans; and
Relevant medical literature describing adverse events
associated with ecamsule. Submissions of adverse event data should also
include a description of how each country's system identifies and
collects adverse events, unless this information has been previously
submitted as part of ecamsule's TEA package.
Although we recognize that adverse event data from foreign
marketing experience may reflect patterns of use and regulatory
reporting requirements that differ from those in the United States, we
nonetheless consider such information to be strongly relevant both to
our overall GRASE assessment of ecamsule for use in sunscreens and to
our consideration of potential product labeling. FDA recognizes that
such information may not be available from all countries; where that is
the case, please provide a written explanation for the lack of data.
Overall, we seek sufficient data to characterize ecamsule's adverse
event profile.\2\
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\2\ See 67 FR 3060 at 3069 (January 23, 2002) (agreeing that the
absence of an adverse experience reporting system in a foreign
country for drugs or cosmetics does not necessarily mean that a
condition cannot be GRAS/E. The GRAS/E determination will be based
on the overall quality of the data and information presented to
substantiate safety and effectiveness).
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Ecamsule: Human Safety Data To Establish Adverse Event Profile
The submission describes the marketing history of ecamsule and
provides eight case report forms (Form FDA 3500A) that have been
submitted to FDA's MedWatch program in association with marketed
sunscreen products containing ecamsule in combination with other active
ingredients (Note 8). Our review of the FDA Adverse Event Reporting
System (FAERS) identified one additional case report associated with
such a sunscreen product. These case reports describe serious allergic
reactions such as redness, swelling and urticaria, breathing
difficulties, and anaphylaxis. The role, if any, of ecamsule in these
cases cannot be fully assessed due in part to the presence of multiple
active ingredients in the associated sunscreen products. To support the
evaluation of the safety of ecamsule for use in OTC sunscreens, we
request that the sponsor either supplement the information already
submitted with adverse event or other safety-related data derived from
commercial marketing experience, or explain why such information cannot
be provided.

B. Nonclinical (Animal) Studies

Another important element of FDA's GRAS review of ecamsule for use
in sunscreens is an assessment of data from nonclinical (animal)
studies that characterize the potential long-term dermal and systemic
effects of exposure to ecamsule. Even if the bioavailability data
discussed in section II.A.2 suggest that dermal application is unlikely
to result in skin penetration and systemic exposure to ecamsule, FDA
still considers data on the effects of systemic exposure to be an
important aspect of our safety evaluation of ecamsule. A determination
that ecamsule up to 10 percent is GRASE for use in sunscreens would
permit its use in as-yet-unknown product formulations, which might in
turn alter the skin penetration of the active ingredient. Therefore, an
understanding of the effects of ecamsule, were systemic exposure to
occur, is critical to determine whether and how regulatory parameters
can be defined to assure that all conforming ecamsule-containing
sunscreens would be GRASE as labeled.
FDA recommends animal testing of the potential long-term dermal and
systemic effects of exposure to ecamsule because these effects cannot
be easily assessed from previous human use. Taken together, the
carcinogenicity studies, developmental and reproductive toxicity
studies, and toxicokinetic studies described in sections II.B.1 through
II.B.3 should provide the information needed to characterize both the
potential dermal and systemic toxic effects and the levels of exposure
at which they occur. These data, when viewed in the context of human
exposure data, can be used to determine a margin of safety for use of
ecamsule in OTC sunscreens.
Data Available for Ecamsule: Nonclinical (Animal) Studies Generally
The ecamsule submission included reports of the following types of
nonclinical safety studies:

Single-dose toxicity studies
[cir] Oral toxicity (rat, mouse) (Note 9)
[cir] Dermal toxicity (rat, mouse) (Note 10)
[cir] Intravenous toxicity (rat, mouse) (Note 11)
[cir] Mucosal and skin irritation (rabbit) (Note 12)
[cir] Skin irritation and sensitization (guinea pig) (Note 13)
[cir] Photoirritation and photosensitization (guinea pig) (Note 14)
Repeat-dose toxicity studies
[cir] 4-week bridging dermal (mouse) (Note 15)
[cir] 13-week dermal (mouse) (Note 16)
[cir] 9-month dermal (minipig) (Note 17)
Genotoxicity and mutagenicity assays
[cir] Ames test (Salmonella typhimurium, Escherichia coli) (Note
18)
[cir] Chromosomal aberration assay (Chinese hamster ovary (CHO
cells)) (Note 19)
[cir] Micronucleus test (rat) (Note 20)
[cir] Photomutagenicity (E. coli) (Note 21)
[cir] HPRT test (CHO cells) (Note 22)
[cir] Photochromosomal aberration assay (CHO cells) (Note 23)
Reproductive and developmental toxicity studies
[cir] Fertility and early embryonic development, oral (rat) (Note
24)
[cir] Pre/postnatal development, oral (rat) (Note 25)
[cir] Embryotoxicity/teratogenicity, dermal (rabbit) (Note 26)

[[Page 10040]]

[cir] Embryofetal development/teratogenicity, oral (rat) (Note 27)
[cir] Embryofetal development/teratogenicity, oral (rabbit) (Note
28)
Carcinogenicity and photocarcinogenicity
[cir] 104 weeks dermal carcinogenicity (mouse) (Note 29)
[cir] 12 months photocarcinogenicity (mouse) (Note 30)
Pharmacokinetics
[cir] Pharmacokinetic study, oral (rat) (Note 31)
[cir] Pharmacokinetic study, dermal (mouse, rat) (Note 32)
[cir] Microsome metabolism (interspecies, in vitro) (Note 33)
[cir] Excretion, oral and dermal (rat) (Note 34)

The submission includes summary reports of nonclinical studies that
are of the types FDA requests as a basis for evaluating whether
ecamsule is GRAS for use in sunscreen (chronic toxicity,
carcinogenicity, reproductive and developmental toxicity, and
toxicokinetics). However, the submission did not provide the full
reports and full comprehensive data sets that would be needed for an
adequate review of the data for these studies. Because the summary data
provided can support only tentative conclusions about these studies,
full final study reports and data sets need to be made available to
support a final GRASE determination.
Additional discussion of study findings and data gaps are provided
in the following subsections.
1. Carcinogenicity Studies: Dermal and Systemic
FDA guidance recommends that carcinogenicity studies be performed
for any pharmaceutical that is expected to be clinically used
continuously or ``repeatedly in an intermittent manner'' for a total of
6 months of exposure (Refs. 6, 7, and 8). Because the proposed use of
ecamsule in OTC sunscreens falls within this category, these studies
should be conducted to help establish that ecamsule is GRAS for its
proposed use. Carcinogenicity studies assist in characterizing
potential dermal and systemic risks by identifying the type of toxicity
observed, the level of exposure at which toxicity occurs, and the
highest level of exposure at which no adverse effects occur (i.e.,
NOAEL). The NOAEL would then be used in determining the safety margin
for human exposure to sunscreens containing ecamsule.
Systemic carcinogenicity studies can also help to identify other
systemic or organ toxicities that may be associated with ecamsule, such
as hormonal effects. For example, the effect of persistent disruption
of particular endocrine gland systems (e.g., hypothalamic-pituitary-
adrenal axis), if any, can be captured by these assays.
Data Available for Ecamsule: Genotoxicity Studies
The ecamsule submission included some information regarding
genotoxicity studies. Based on the reviewable genotoxicity data
included in the ecamsule data submission, ecamsule appears to be
negative for causing genotoxic activity under the conditions studied
(Notes 35 through 43). As we believe that data from the recommended
systemic carcinogenicity and developmental and reproductive toxicology
(DART) studies will provide an adequate and appropriate measure of
potential long-term effects of systemic or dermal exposure to ecamsule,
we do not request further genotoxicity studies.
Data Available for Ecamsule: Carcinogenicity Studies
We have reviewed study summaries for four dermal carcinogenicity
and photocarcinogenicity studies, which appear to be negative (Notes 44
through 47). However, full final study reports need to be made
available to support a final GRASE determination. In addition, we did
not receive any systemic carcinogenicity data, which are recommended to
support the safety of long-term use of ecamsule. We request that the
sponsor provide a systemic carcinogenicity study, as well as make
available full final study reports for the previously conducted
carcinogenicity studies that were submitted in a summarized form.
2. DART Studies (Ref. 9)
FDA recommends conducting DART studies to evaluate the potential
effects that exposure to ecamsule may have on developing offspring
throughout gestation and postnatally until sexual maturation, as well
as on the reproductive competence of sexually mature male and female
animals. Gestational and neonatal stages of development may also be
particularly sensitive to active ingredients with hormonal activity.
For this reason, we recommend that these studies include assessments of
endpoints such as vaginal patency, preputial separation, anogenital
distance, and nipple retention, which can be incorporated into
traditional DART study designs to assess potential hormonal effects of
ecamsule on the developing offspring. We also recommend conducting
behavioral assessments (e.g., mating behavior) of offspring, which may
also detect neuroendocrine effects.
Data Available for Ecamsule: DART Studies
We received study summaries for five developmental and reproductive
toxicity assays (Notes 48 through 52), which appear to be negative for
the potential to cause adverse developmental or reproductive effects.
However, comprehensive data sets were not provided.
We request that the sponsor make available full final study
reports, including full comprehensive datasets, to support a final
GRASE determination.
3. Toxicokinetics (Ref. 10)
We recommend conducting animal toxicokinetic studies because they
provide an important bridge between toxic levels seen in animal studies
and potential human exposure. Data from these studies can be correlated
to potential human exposure via clinical dermal pharmacokinetic study
findings. Toxicokinetic data could be collected as part of animal
studies being conducted to assess one or more of the safety parameters
described previously.
Data Available for Ecamsule: Toxicokinetics
We reviewed single-dose pharmacokinetic studies conducted in animal
models which showed that systemic exposure was achieved under the
conditions of the conducted studies (Notes 53 and 54). However, we did
not receive any pharmacokinetic data reflecting drug levels following
long-term exposure, which are usually collected from repeat toxicity
studies such as chronic (systemic or dermal) studies. We recommend that
a time course toxicokinetic study be conducted following repeat-dose
exposure (via the oral and dermal routes) to evaluate the steady-state
exposure level of ecamsule. Data obtained from this study could be used
to compare drug levels in animals to those in humans under maximal
exposure conditions to establish a margin of safety for human exposure.

III. Effectiveness Data Considerations for OTC Sunscreen Products
Containing Ecamsule

FDA's evaluation of the effectiveness of active ingredients under
consideration for inclusion in an OTC drug monograph is governed by the
following regulatory standard: Effectiveness means a reasonable
expectation that, in a significant proportion of the target population,
the pharmacological effect of the drug, when used under adequate
directions

[[Page 10041]]

for use and warnings against unsafe use, will provide clinically
significant relief of the type claimed. Proof of efficacy shall consist
of controlled clinical investigations as defined in 21 CFR 314.126(b).
Investigations may be corroborated by partially controlled or
uncontrolled studies, documented clinical studies by qualified experts,
and reports of significant human experience during marketing. Isolated
case reports, random experience, and reports lacking the details that
permit scientific evaluation will not be considered. General
recognition of effectiveness shall ordinarily be based upon published
studies which may be corroborated by unpublished studies and other data
(Sec. 330.10(a)(4)(ii)). For convenience, this order uses the term
``generally recognized as effective'' (GRAE) when referring to this
aspect of the GRASE determination.
To evaluate the efficacy of ecamsule for use in OTC sunscreen
products, FDA requests evidence from at least two adequate and well-
controlled SPF studies showing that ecamsule effectively prevents
sunburn. To determine that ecamsule is GRAE for use in OTC sunscreens
at concentrations in a range with the proposed maximum strength of 10
percent as requested, two adequate and well-controlled SPF studies of
ecamsule at a lower concentration should be conducted according to
established standards.\3\ These SPF studies should demonstrate that the
selected concentration (below 10 percent) provides an SPF of 2 or more.
---------------------------------------------------------------------------

\3\ The upper bound of any concentration of ecamsule ultimately
established in the OTC sunscreen monograph will be governed by the
safety data, as well as by efficacy.
---------------------------------------------------------------------------

The current standard procedure for SPF testing is described in
FDA's regulations in Sec. 201.327(i).\4\ Further SPF tests for
ecamsule should be performed as described in these regulations, using a
test formulation containing ecamsule as the only active ingredient to
identify its contribution to the overall SPF test results. (See the
following subsection Data Available for Ecamsule: Effectiveness for
further discussion of submitted SPF tests.) The study should also
include a vehicle control arm to rule out any contribution the vehicle
may have on the SPF test results. Finally, as described in Sec.
201.327(i), an SPF standard formulation comparator arm should be
another component of the study design.
---------------------------------------------------------------------------

\4\ Although the SPF testing procedure is used primarily for
final formulation testing of finished products marketed without
approved NDAs, under the sunscreen monograph, it is equally
applicable for determining whether or not a sunscreen active
ingredient is GRAE.
---------------------------------------------------------------------------

Although current sunscreen testing and labeling regulations also
specify a ``broad spectrum'' testing procedure to support related
labeling claims for certain OTC sunscreen products marketed without
approved new drug applications that contain specific ingredients
included in the OTC sunscreen monograph, those additional claims are
permitted, but not required, for these products (Sec. 201.327(c)(2)
and (j)). Under current regulations, sunscreen active ingredients need
only be effective for the labeled indication of sunburn prevention, for
which the SPF test can provide sufficient evidence. Consistent with
this approach, we here do not request broad spectrum testing for
ecamsule. Broad spectrum protection is often, although not always, the
result of the combined contribution of multiple active ingredients in a
final sunscreen formulation. Thus, under the current regulations
applicable to other sunscreens, the determination of whether an
individual sunscreen product may be labeled as broad spectrum and bear
the related additional claims is made on a product-specific basis,
applying standard testing methods set forth in those regulations. If
ecamsule is established to be GRASE for use in nonprescription
sunscreens (based in part on the efficacy data requested here), the
final sunscreen order can likewise address broad-spectrum testing and
related labeling conditions for final sunscreen formulations containing
ecamsule.

Data Available for Ecamsule: Effectiveness

Study reports were submitted for two studies that assessed SPF of
formulations containing ecamsule, at a concentration of either 2
percent or 3 percent (Notes 55 and 56, respectively), in combination
with other active ingredients. Neither of these studies provides a
direct evaluation of the efficacy of ecamsule alone. These studies were
not adequately designed to provide evidence of efficacy on which to
base a GRAE determination for ecamsule. No adequately designed studies
of ecamsule efficacy were identified in our search of the published
literature. To support the finding that ecamsule is GRAE when used at
concentrations up to 10 percent, we request submission of data from two
adequate and well-controlled SPF studies conducted according to
established standards to demonstrate that the lowest selected
concentration provides an SPF of 2 or more. Because no study has been
identified that assesses the effectiveness of ecamsule at a
concentration of 10 percent, it is recommended that such a study be
conducted and submitted.

IV. Summary of Current Data Gaps for Ecamsule

Based on our review of the available safety and efficacy data as
discussed previously, we request the types of data listed in this
section of the proposed order, at minimum, for us to reverse our
tentative determination that ecamsule is not GRASE and is misbranded
because the data are insufficient to classify ecamsule as GRASE and not
misbranded, and additional data are necessary to allow us to determine
otherwise. Note that, in some cases, as discussed in section II of this
proposed order, the ecamsule data submission provided some information
from nonclinical studies of the type FDA requests as part of the basis
for a GRAS determination, but only in summary form. Were complete study
data generally available from these previously conducted studies, they
might address several aspects of our GRASE consideration. If data from
these previously conducted studies are not made available, further
studies of those types would be needed to support a finding that
ecamsule is GRASE for use in sunscreens. Further, as summarized in the
following subsections, some additional studies of other types are
needed. For additional information about the purpose and design of
studies recommended to address present data gaps, please refer to the
earlier sections of this proposed order referenced in parentheses. We
welcome discussions on the design of any of the studies prior to their
commencement. We request the following types of data:

Safety Data (see section II)

A. Human Clinical Studies

1. Skin irritation/sensitization, and photosafety (see section
II.A.1)
2. Human dermal pharmacokinetic (bioavailability) studies (see
section II.A.2)

B. Human Safety Data To Establish Adverse Event Profile (see Section
II.A.3)

1. A summary and analysis of all available reported adverse events
potentially associated with ecamsule
2. A summary and analysis of all available documented case reports
of serious side effects
3. A summary and analysis of any available safety information from
studies of the safety and effectiveness of sunscreen products
containing ecamsule in humans

[[Page 10042]]

4. A summary and analysis of relevant medical literature describing
adverse events associated with ecamsule
Alternatively, the results of a literature search that found no
reports of adverse events may be provided. In that case, detailed
information on how the search was conducted should be provided.

C. Nonclinical (Animal) Studies

Full study reports will be needed for the following studies:
1. Systemic and dermal carcinogenicity (see section II.B.1)
2. Reproductive and developmental toxicity studies (see section
II.B.2)
3. Toxicokinetics (see section II.B.3)
Effectiveness Data (see section III)
For concentrations of ecamsule up to 10 percent to be found to be
GRASE for use in nonprescription sunscreen products as requested, at
least two SPF studies showing effectiveness of a selected concentration
lower than 10 percent should be conducted. An efficacy study of
ecamsule at 10 percent is also recommended.

V. Administrative Procedures

A copy of this proposed order will be filed in the Division of
Dockets Management in Docket No. FDA-2008-N-0474. To inform FDA's
evaluation of whether this ingredient is GRASE and not misbranded for
use in sunscreen products, we encourage the sponsor and other
interested parties to submit additional data regarding the safety and
effectiveness of this ingredient for use as an OTC sunscreen product.
We also encourage the sponsor and other interested parties to notify us
in writing of their intent to submit additional data. However, as noted
previously, because the data submitted to date are not sufficient to
support a determination that ecamsule is GRASE for use as an active
ingredient in OTC sunscreen drug products, at present, OTC sunscreen
products containing ecamsule may not be marketed without approval of an
NDA or ANDA (see section 586C(e)(1)(A) of the FD&C Act, as amended by
the SIA). Data submissions relating to this proposed order should be
submitted to Docket No. FDA-2008-N-0474 at the Division of Dockets
Management (see ADDRESSES). In addition, you can submit the data
through the Federal eRulemaking Portal at http://www.regulations.gov.
Follow the instructions for submitting comments.
Section 586C(b)(7) of the FD&C Act, as amended by the SIA, provides
that the sponsor may, within 30 days of publication of a proposed order
(see DATES), submit a request to FDA for a meeting to discuss the
proposed order. Submit meeting requests electronically to http://www.regulations.gov or in writing to the Division of Dockets Management
(see ADDRESSES), identified with the active ingredient name ecamsule,
Docket No. FDA-2008-N-0474, and the heading ``Sponsor Meeting
Request.'' To facilitate your request, please also send a copy to
Kristen Hardin (see FOR FURTHER INFORMATION CONTACT).

VI. Proposed Effective Date

FDA proposes that any final administrative order based on this
proposal become effective on the date of publication of the final order
in the Federal Register.

VII. Comments

Similarly, section 586C(b)(6) of the FD&C Act, as amended by the
SIA, establishes that a proposed sunscreen order shall provide 45 days
for public comment. Interested persons wishing to comment on this
proposed order may submit either electronic comments to http://www.regulations.gov or written comments to the Division of Dockets
Management (see ADDRESSES). It is only necessary to send one set of
comments. Identify comments with the active ingredient name (ecamsule)
and the docket number found in brackets in the heading of this proposed
order. Received comments on this proposed order may be seen in the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday, and will be posted to the docket at http://www.regulations.gov.

VIII. Notes

1. FDA-2008-N-0474-0012 and FDA-2008-N-0474-0013, Volumes 6 and
7, dated November 14, 2008.
2. FDA-2008-N-0474-0015 and FDA-2008-N-0474-0016, Volumes 9 and
10, dated November 14, 2008.
3. FDA-2008-N-0474-0007, Volume 1, dated November 14, 2008, FDA-
2008-N-0474-0006, TEA submission.
4. FDA-2008-N-0474-0008, Volume 2, Study no. 16039/G2347.
5. FDA-2008-N-0474-0014, Volume 8, Study no. V3156.
6. FDA-2008-N-0474-0014, Volume 8, Study no. V99.1203.
7. FDA-2008-N-0474-0014, Volume 8, Study no. CG.03.SRE.2607.
8. FDA-2008-N-0474-0007, Volume 1, dated November 14, 2008.
9. FDA-2008-N-0474-0009, Volume 3, Study no. 3667-109/309, Study
no. 1.CG.03.SRE.12160.
10. FDA-2008-N-0474-0009, Volume 3, Study no. 4222-109/310,
Study no. 1.CG.03.SRE.12156.
11. FDA-2008-N-0474-0009, Volume 3, Study no. 1.CG.03.SRE.12158,
Study no. 1.CG.03.SRE.12157.
12. FDA-2008-N-0474-0009, Volume 3, Study no. 712332, Volume 4,
Study no. 712320.
13. FDA-2008-N-0474-0010, Volume 4, Study no. 802410, Study no.
3697-109/313.
14. FDA-2008-N-0474-0010, Volume 4, Study no. 1.CG.03.SRE.12163,
Study no. 1.CG.03.SRE.12164.
15. FDA-2008-N-0474-0010, Volume 4, Study no. RDA.03.SRE.12268.
16. FDA-2008-N-0474-0009, Volume 3, Study no. 93/LOL/007/0971.
17. FDA-2008-N-0474-0009, Volume 3, Study no. 1.CG.03.SRE.12183.
18. FDA-2008-N-0474-0011, Volume 5, Study no. G185-109/314.
19. FDA-2008-N-0474-0011, Volume 5, Study no. G220-109/381,
Study no. G220-109/381A, Study no. 12174MIC, Study no. 413/52-D6172.
20. FDA-2008-N-0474-0011, Volume 5, Study no. 12639MAR.
21. FDA-2008-N-0474-0011, Volume 5, Study no. EU1REBRP.031.
22. FDA-2008-N-0474-0011, Volume 5, Study no. LRL 170/921503.
23. FDA-2008-N-0474-0011, Volume 5, Study no. ICHUREBRP.031.
24. FDA-2008-N-0474-0010, Volume 4, Study no. 1.CG.03.SRE.12181.
25. FDA-2008-N-0474-0011, Volume 5, Study no. 1.CG.03.SRE.12182.
26. FDA-2008-N-0474-0011, Volume 5, Study no. 10297 RSL.
27. FDA-2008-N-0474-0010, Volume 4, Study no. 1412 RMR/064.89.
28. FDA-2008-N-0474-0011, Volume 5, RCC Project 682874.
29. FDA-2008-N-0474-0010, Volume 4, Study no. 95/LOL/008/1217,
Study no. LOL/011/980150.
30. FDA-2008-N-0474-0010, Volume 4, Study no. C-1012-001, Study
no. RDS.03.SRE.12215.
31. FDA-2008-N-0474-0009, Volume 3, Study no. 10225PAR, Study
no. 1.CG.03.SRE.12269/RDS.03.SRE.12269.
32. FDA-2008-N-0474-0009, Volume 3, Study no. 10507 PAS, Study
no. RDS.03.SRE 12268, Study no. RDS.03.SRE.12269/1.CG.03.SRE.12269.
33. FDA-2008-N-0474-0009, Volume 3, Study no. 2.CG.03.SRE.11029.
34. FDA-2008-N-0474-0009, Volume 3, Study no. 1.CG.03.SRE.12270.
35. FDA-2008-N-0474-0011, Volume 5, Study no. G185-109/314.
36. FDA-2008-N-0474-0011, Volume 5, Study no. G220-109/381.
37. FDA-2008-N-0474-0011, Volume 5, Study no. G220-109/381A.
38. FDA-2008-N-0474-0011, Volume 5, Study no. 12174MIC.
39. FDA-2008-N-0474-0011, Volume 5, Study no. 413/52-D6172.
40. FDA-2008-N-0474-0011, Volume 5, Study no. 12639MAR.
41. FDA-2008-N-0474-0011, Volume 5, Study no. EU1REBRP.031.
42. FDA-2008-N-0474-0011, Volume 5, Study no. LRL 170/921503.
43. FDA-2008-N-0474-0011, Volume 5, Study no. ICHUREBRP.031.

[[Page 10043]]

44. FDA-2008-N-0474-0010, Volume 4, Study no. 95/LOL/008/1217.
45. FDA-2008-N-0474-0010, Volume 4, Study no. LOL/011/980150.
46. FDA-2008-N-0474-0010, Volume 4, Study no. C-1012-001.
47. FDA-2008-N-0474-0010, Volume 4, Study no. RDS.03.SRE.12215.
48. FDA-2008-N-0474-1000, Volume 4, Study no. 1.CG.03.SRE.12181.
49. FDA-2008-N-0474-0011, Volume 5, Study no. 1.CG.03.SRE.12182,
Study no. 1412 RMR/064.89.
50. FDA-2008-N-0474-0011, Volume 5, RCC Project 682874.
51. FDA-2008-N-0474-0011, Volume 5, RCC Project 682874.
52. FDA-2008-N-0474-0011, Volume 5, Study no. 1.CG.03.SRE.12182.
53. FDA-2008-N-0474-0009, Volume 3, Study no. 10225PAR.
54. FDA-2008-N-0474-0009, Volume 3, Study no. 1.CG.03.SRE.12269/
RDS.03.SRE.12269.
55. FDA-2008-N-0474-0017, Volume 11, Study no. PEN.810.02.
56. FDA-2008-N-0474-0017, Volume 11, Study no. PEN.810.06.

IX. References

The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday,
and are available electronically at http://www.regulations.gov. (FDA
has verified the Web site addresses in this reference section, but FDA
is not responsible for any subsequent changes to the Web sites after
this document publishes in the Federal Register.)

1. FDA, Guidance for Industry, ``Photosafety Testing,'' May 2003
(available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079252.pdf).
2. Leonard, F., B. Kalis, H. Adamski, et al., ``The New Standard
Battery of Photopatch Test in France.'' Nouvelles Dermatologiques,
vol. 15, pp. 343-348, 1996.
3. Schauder, S., and H. Ippen, ``Contact and Photocontact
Sensitivity to Sunscreens. Review of a 15-Year Experience and of the
Literature.'' Contact Dermatitis, vol. 37(5), pp. 221-232, 1997.
4. Schmidt, T., J. Ring, and D. Abeck, ``Photoallergic Contact
Dermatitis Due to Combined UVB (4-Methylbenzylidene Camphor/Octyl
Methoxycinnamate) and UVA (Benzophenone-3/Butyl
Methoxydibenzoylmethane) Absorber Sensitization.'' Dermatology, vol.
196(3), pp. 354-357, 1998.
5. FDA, Guidance for Industry, ``Guideline for the Format and
Content of the Human Pharmacokinetics and Bioavailability Section of
an Application,'' February 1987 (available at http://www.fda.gov/downloads/drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072112.pdf).
6. International Conference on Harmonization (ICH), Guidance for
Industry, ``The Need for Long-Term Rodent Carcinogenicity Studies of
Pharmaceuticals S1A,'' March 1996 (available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance/UCM074911.pdf).
7. ICH, Guidance for Industry, ``S1B Testing for Carcinogenicity
of Pharmaceuticals,'' July 1997 (available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074916.pdf).
8. ICH, ``S1C(R2) Dose Selection for Carcinogenicity Studies''
(Revision 1), September 2008 (available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074919.pdf).
9. ICH Harmonized Tripartite Guideline for Industry, ``Detection
of Toxicity to Reproduction for Medicinal Products & Toxicity to
Male Fertility S5(R2),'' 2005 (available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S5_R2/Step4/S5_R2__Guideline.pdf).
10. ICH, Guideline for Industry, ``Toxicokinetics: The
Assessment of Systemic Exposure in Toxicity Studies S3A,'' March
1995 (available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074937.pdf).

Dated: February 20, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-03883 Filed 2-24-15; 8:45 am]
BILLING CODE 4164-01-P