GUIDELINES FOR EFFECTIVENESS TESTING OF

OTC ANTIPERSPIRANT DRUG PRODUCTS

1\. [BACKGROUND]{.underline}.

The Food and Drug Administration (FDA) is offering suggested guidelines
for testing the effectiveness of an OTC antiperspirant drug product in
finished product form in accordance with § 350.60 (21 CFR 350.60) of the
final monograph (final rule) for OTC antiperspirant drug products,
published in the FEDERAL REGISTER on June 9, 2003 (68 FR 34273). These
guidelines set forth criteria for the test subjects, test conditions,
test procedures, and treatment of the data obtained. FDA recognizes that
alternate methods may be appropriate to qualify an antiperspirant drug
product as effective. These guidelines do not preclude the use of
alternate methods that provide scientifically valid results, subject to
FDA approval. To qualify as effective, an antiperspirant drug product in
finished product form should meet the criteria established in these
guidelines. These guidelines apply to all antiperspirant formulations.
Because minor variations in formulation, such as adding emollients or
buffers, can alter the effectiveness of an antiperspirant ingredient,
FDA encourages the use of these guidelines to test the product whenever
a change is made, except for the addition or change in color or perfume
ingredients. In testing OTC antiperspirant drug products, the agency
believes it is important to assure that the perspiration reduction that
is achieved can be readily perceived by the majority of users. Merely
reducing the level of perspiration by a statistically significant amount
will not assure a reduction that will be noticeable to the user. The
agency considers this factor in the data treatment in these guidelines.

2\. [TEST SUBJECTS]{.underline}.

\(a\) Test subjects must be sufficiently representative so that the
differences between the highest and lowest rates of sweating among the
test subjects must exceed 600 milligrams in 20 minutes per axilla.
Information on the sweating rate will be obtained during pretreatment
sweat collections or by sweat collections taken from the control axilla
during treatment.

\(b\) Test subjects are required to abstain from using all
antiperspirant and deodorant materials (except those deodorants,
furnished by the investigator, that have been tested and found to have
no antiperspirant effect on axillary sweating) for at least 17 days
prior to pretreatment or treatment sweat collections.

3\. [TESTING CONDITIONS]{.underline}.

Either hotroom or ambient conditions may be used to obtain gravimetric
measurements of axillary perspiration rate.

\(a\) [Hotroom conditions]{.underline}. (1) Test subjects are placed in
a controlled environment (temperatures at 100°F, plus or minus 2°, and
relative humidity of 30 to 40 percent) to thermally induce perspiration.

\(2\) Care must be taken to insure that factors which are known to
influence axillary sweating (i.e., air movement, mental or emotional
stimuli, position of the trunk and extremities) are properly controlled.

\(b\) [Ambient conditions]{.underline}. Test subjects are allowed to go
about their normal daily routines during the collection period.

\(c\) [Baseline perspiration rate]{.underline}. Test subjects must
produce at least 100 milligrams of sweat from the untreated or placebo
control axilla in a 20‑minute collection in the controlled environment.

4\. [TEST PROCEDURES]{.underline}.

\(a\) [Hotroom procedure]{.underline}. (1) For gravimetric user
perception testing, treatments consist of the application of the test
formulation to one axilla and the application of a placebo control
formulation to the other axilla of each test subject. Except for the
active ingredient, the placebo control formulation should be as similar
as possible to the test formulation.

\(2\) Half of the test subjects are randomly assigned to receive the
test formulation under the left axilla and the placebo control
formulation under the right axilla, leaving the remaining test subjects
to be assigned oppositely.

\(3\) The quantity of each formulation applied to all test subjects must
reflect the amount that a typical person would apply under normal use
conditions.

\(4\) Treatment applications are made once daily. The number of
treatments preceding the collections of axillary perspiration for
evaluation must be recorded. At least one daily treatment should be
carried out before the test. For claims of enhanced duration of effect,
the test should be conducted at least two times during the period of the
claim, such as 1 hour and 24 hours after the last daily treatment for 24
hour claims.

\(5\) Test subjects are placed in the controlled environment as defined
in paragraph (a)(1) under \"TESTING CONDITIONS\" for a 40‑minute warmup
period.

\(6\) Preweighed absorbent pads are placed in both axillae of each test
subject at the end of the warmup period.

\(7\) Test subjects remain in the controlled environment for a period of
20 minutes, perspiration is collected on the absorbent pads, and the
pads are again weighed at the end of the collection period. Perspiration
is collected during one of two successive 20‑minute periods for
evaluation.

\(8\) If a pretreatment evaluation is made to determine the ratio of
right to left axillary sweating rate of each test subject, the placebo
control formulation, if used, is applied to both axillae of each test
subject.

\(b\) [Ambient procedure]{.underline}. The ambient procedure is
performed in the same manner as the hotroom procedure except that test

subjects are allowed to go about their normal daily routines, and the
collection period lasts 3 to 5 hours.

5\. [DATA TREATMENT TO DEMONSTRATE STANDARD ANTIPERSPIRANT]{.underline}
[EFFICACY]{.underline}.

\(a\) When there is no pretreatment observation, the unadjusted ratio of
right axilla to left axilla is determined by the formula:

Unadjusted right‑to‑left ratio = R/L.

Where R is the raw milligram weight measure of moisture from the right
axilla and L is the corresponding quantity from the left axilla.

To adjust for 20 percent reduction due to treatment, the measure of
moisture for the control axilla is multiplied by 0.80. For subjects
treated on the right axilla, the adjusted right‑to‑left ratio is
determined by the formula:

Adjusted right‑to‑left ratio = X = R/(0.8L)

Where X is the adjusted value for a subject treated on the right axilla.
For subjects treated on the left axilla, the corresponding adjustment is
defined by the formula:

Adjusted right‑to‑left ratio = Y = (0.8R)/L

Where Y is the adjusted value for a subject treated on the left axilla.
Thus, if the product is effective, X should be a relatively small number
(less than one), and Y should be a relatively large number (greater than
one). The hypothesis that reduction in perspiration exceeds 20 percent
is tested statistically by comparing X to Y using the Wilcoxon Signed
Rank Test. In statistical terminology, the test is of the null
hypothesis: Median X [\>]{.underline} Median Y versus the alternative
hypothesis: Median X \< Median Y. This is a test of the null against a
one‑sided alternative at a predetermined level of significance, usually
taken to be 0.05. Rejection of the null hypothesis at significance level
0.05 will justify the conclusion that at least 50 percent of the target
population will obtain a sweat reduction of at least 20 percent. An
error will be committed in no more than 5 percent of the cases in which
the sweat reduction does not exceed 20 percent.

\(b\) When pretreatment observations are recorded, the ratio of treated
axilla to control axilla adjusted for the ratio of right‑to‑left
axillary sweating rate is defined for each subject by the formula:

Z = (PC x T) / (PT x C).

Where Z is the adjusted ratio, PC is the pretreatment measure of
moisture for the control axilla, PT is the pretreatment measure for the
test axilla, T is the treated measure for the test axilla, and C is the
corresponding quantity for the control axilla.

The hypothesis that reduction in perspiration exceeds 20 percent is
tested statistically by subtracting 0.80 from Z for all subjects. The
Wilcoxon Signed Rank Test is applied to compare the adjusted ratio to
0.80, the value which corresponds to a 20‑percent reduction in moisture
due to treatment. In statistical terminology, this is a test of the null
hypothesis: Median Z [\>]{.underline} 0.80, versus the alternative
hypothesis: Median Z \< 0.80.

Again, the null is being tested against a one‑sided alternative at a
predetermined level of significance. Rejection of the null hypothesis
will justify the conclusion that at least 50 percent of the target
population will obtain a sweat reduction of at least 20 percent.

\(c\) For both testing situations the rank tests are 95 percent as
efficient as the appropriate t‑test when the data are normal. When the
data are nearly normally distributed, the rank tests and the t‑test are
nearly identical in efficiency. Estimates of sample size can therefore
be based on calculations or tables for the t‑test.

\(d\) The test will demonstrate that, with high probability, at least 50
percent of the target population will obtain a sweat reduction of at
least 20 percent.

6\. [DATA TREATMENT TO DEMONSTRATE EXTRA‑EFFECTIVE]{.underline}
[ANTIPERSPIRANT EFFICACY]{.underline}.

\(a\) When there is no pretreatment observation, the hypothesis that
reduction in perspiration exceeds 30 percent is tested statistically by
the Wilcoxon Signed Rank Test (see 5.(a) above). To adjust for 30
percent reduction in perspiration due to treatment, the measure of
moisture for the control axilla is multiplied by 0.70, and X and Y
values calculated accordingly.

\(b\) When pretreatment observations are recorded, the hypothesis that
reduction in perspiration exceeds 30 percent is tested statistically by
subtracting 0.70 from Z for all subjects and applying the Wilcoxon
Signed Rank Test (see 5.(b) above).

\(c\) The test will demonstrate that, with high probability, at least 50
percent of the target population will obtain a sweat reduction of at
least 30 percent.

7\. [DATA TREATMENT TO DEMONSTRATE ENHANCED DURATION ANTIPERSPIRANT
EFFICACY]{.underline}.

\(a\) As noted in section 4.(a)(4), for claims of enhanced duration of
effect, the test should be conducted at least two times during the
period of the claim, such as 1 hour and 24 hours after the last daily
treatment for 24 hour claims.

\(b\) Products having an enhanced duration of effect may be either
standard efficacy of extra-effective antiperspirant products. For
standard efficacy products, the data treatment methods in section 5. of
the guidelines shall be used. For extra-effective products, the data
treatment methods in section 6. of the guidelines shall be used.