Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs: Draft Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Assessing the Irritation
and Sensitization
Potential of Transdermal
and Topical Delivery
Systems for ANDAs
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the 	Federal Register 	of the notice announcing the availability of the draft
guidance. Submit electronic comments to 	https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the 	Federal Register.
For questions regarding this draft document, contact (CDER) Susan Levine at 240-402-7936.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
July 2026
Generic Drugs
Revision 2

Assessing the Irritation
and Sensitization
Potential of Transdermal
and Topical Delivery
Systems for ANDAs
Guidance for Industry
Additional copies are available from:
Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
Phone: 855-543-3784 or 301-796-3400
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
July 2026
Generic Drugs
Revision 2

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TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	GENERAL CONSIDERATIONS ................................................................................... 3
IV. 	EVALUATIONS OF SKIN IRRITATION AND SENSITIZATION 	.......................... 4
A. 	Study Design and Conduct 	............................................................................................................ 4
1. 	Study Design Recommendations ...................................................................................................... 4
2. 	Study Conduct Considerations 	......................................................................................................... 6
3. 	Recommended Inclusion and Exclusion Criteria 	............................................................................. 7
4. 	Scoring Scales for Dermal Responses ............................................................................................. 8
5. 	Calculating and Formatting Dermal Response Scores.................................................................... 9
B. 	Considerations for Statistical Analyses 	...................................................................................... 10
1. 	Irritation Analysis .......................................................................................................................... 10
2. 	Sensitization Analysis..................................................................................................................... 12
C. 	Vehicle TDS and Positive Control TDS ..................................................................................... 13
D. 	Partial (Cut) TDS 	......................................................................................................................... 14
V. 	OVERALL ASSESSMENT OF ADVERSE EVENT DATA...................................... 14
VI. 	FORMAT OF DATA SUBMISSIONS.......................................................................... 15

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1
Assessing the Irritation and Sensitization Potential of Transdermal	1
and Topical Delivery Systems for ANDAs	2
Guidance for Industry1
3
4
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	5
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	6
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	7
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	8
for this guidance listed on the title page.	9
10
11
12
13
I. 	INTRODUCTION	14
15
This guidance provides recommendations for the design and conduct of studies to evaluate the in	16
vivo skin irritation and sensitization potential of a proposed transdermal or topical delivery	17
system (collectively referred to as TDS2). The recommendations in this guidance relate to	18
studies submitted in support of an abbreviated new drug application (ANDA).3 	This guidance is	19
a second revision to the revised draft guidance 	Assessing the Irritation and Sensitization	20
Potential of Transdermal and Topical Delivery Systems for ANDAs 	(April 2023). This revision	21
provides the following updates to the April 2023 revision of the draft guidance:	22
(1) Clarifies recommendations for the design and conduct of studies to evaluate the in vivo	23
skin irritation (and sensitization, if applicable) potential of a proposed TDS.	24
(2) Clarifies when an in vivo study to assess the sensitization potential of a TDS product may	25
not be needed.	26
27
In this guidance, the letter 	T 	(representing 	Test) will refer to proposed generic products that are	28
the subject of an ANDA, and the letter 	R 	(representing 	Reference) will refer to the reference	29
listed drug (RLD) and/or reference standard (RS) product.	30
31
1 	This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research
(CDER) in cooperation with CDER’s Office of Translational Sciences at the Food and Drug Administration.
2 	The acronym 	TDS 	refers to both transdermal delivery systems and topical delivery systems and includes products
that may be described elsewhere or known as 	patches, 	topical patches, or 	extended-release films.
3 	The recommendations for studies characterizing the TDS irritation or sensitization potential in a new drug
application or a supplemental new drug application may be different than those submitted in support of an ANDA.
The design, conduct, and assessment of TDS irritation and sensitization in studies supporting a new drug application
are inherently different because TDS irritation/sensitization in that context is not typically evaluated in relation to a
reference listed drug. For a new drug application, please refer to FDA’s guidance for industry 	Contact Dermatitis
from Topical Drug Products for Cutaneous Application: Human Safety Assessment 	(March 2020). We update
guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

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FDA recommends that applicants consult this guidance in conjunction with any relevant product-	32
specific guidances (PSGs)4 	and in conjunction with any relevant guidances for industry5 	when	33
considering the design and conduct of studies that may be appropriate to support the	34
bioequivalence of a proposed generic TDS product to its RLD. FDA also recommends that	35
applicants routinely refer to FDA’s website, since additional guidances may become available	36
that could assist in the development of a generic TDS product.	37
38
FDA encourages an applicant who seeks to use an alternative approach to FDA’s	39
recommendations in the relevant PSG for the design and conduct of studies evaluating the in	40
vivo irritation (and sensitization, if applicable) potential of a TDS between T and R products to	41
contact the Agency to discuss the proposed alternative approach for that drug product.6	
42
43
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	44
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	45
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	46
the word 	should 	in Agency guidances means that something is suggested or recommended but	47
not required.	48
49
50
II. 	BACKGROUND	51
52
The components and composition of a TDS formulation, including the nature of the drug	53
substance and/or the degree to which the TDS materials occlude the transmission of water vapor	54
from the skin, in conjunction with other factors such as the environmental humidity or the	55
condition of the skin, may have the potential to irritate the skin or lead to a sensitization	56
reaction.7 	Such reactions can be unpleasant to the patient and may affect patient compliance,	57
skin permeability, and/or adhesion of the TDS to the skin. The collective consequence of these	58
potential effects could create uncertainty about the resulting drug delivery profile and the rate	59
and extent of drug absorption from the TDS. Therefore, when appropriate, applicants should	60
perform a comparative assessment of the T and R TDS products using an appropriately designed	61
skin irritation study or combined skin irritation and sensitization study with human subjects to	62
4 	Generic drug PSGs are available at the Product-Specific Guidances for Generic Drug Development web page,
available at 	https://www.fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-development.
5 	For example, relevant guidances include the draft guidances for industry 	Assessing Adhesion With Transdermal
and Topical Delivery Systems for ANDAs 	(April 2023) and 	Transdermal and Topical Delivery Systems—Product
Development and Quality Considerations 	(November 2019). When final, these guidances will represent FDA’s
current thinking on these topics.
6 	See Manual of Policies and Procedures (MAPP) 5220.8 	Evaluating Requests for and Conducting Product
Development and Pre-Submission Pre-ANDA Meetings 	https://www.fda.gov/media/130874/download. See also
FDA’s guidances for industry 	Controlled Correspondence Related to Generic Drug Development 	(March 2024) and
Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA 	(October 2022) for
additional information on how to obtain Agency feedback on the development of a specific drug product.
7 	Skin sensitization reaction refers to an allergic skin reaction (i.e., allergic contact dermatitis) to a substance
resulting from previous exposure, and is usually characterized by redness, swelling, and itching.

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demonstrate that the potential for a skin irritation or sensitization reaction with the T TDS is no	63
worse than the reaction observed with the R TDS (see General Considerations below for	64
information about when such a study may be appropriate).	65
66
67
III. 	GENERAL CONSIDERATIONS	68
69
Skin irritation and sensitization studies are designed to compare the similarity between the T and	70
R TDS products for the potential to cause irritation and sensitization reactions, respectively. A	71
TDS may elicit these reactions in only some of the patients using the product, but even if the	72
frequency of this occurrence were low, the adverse reactions could affect thousands of	73
individuals.	74
75
Changes in environmental temperature or humidity, including the daily exposure of the TDS to	76
heat and water during routine showering, may transiently affect the rate at which components of	77
the TDS formulation are released and permeate through skin. Such changes may also affect	78
entrapped moisture in and/or under the TDS, which could alter skin hydration and impact the	79
bioavailability of formulation components, which may, in turn, change irritation and/or	80
sensitization reactions. Therefore, applicants should consider any conditions of labeled use for	81
the RLD that may impact the irritation or sensitization potential of a TDS product (e.g.,	82
incidental exposure of the TDS to water, such as while bathing or showering, particularly for a	83
TDS with a duration of wear that is up to or greater than 24 hours).	84
85
In addition to irritation and sensitization reactions that may arise from the corrosive or	86
immunomodulatory nature of formulation components or from the pharmacodynamic response	87
of the skin to the occlusion by the TDS, the skin may also become irritated in response to the	88
physical insults that can occur during the removal of a TDS. For example, if the adhesive	89
properties of the TDS are such that it strips away substantial portions of the stratum corneum	90
during removal, the damage to the skin barrier may lead to irritation at the site of TDS removal.	91
Accordingly, applicants should also consider the adhesive components of the TDS and physical	92
insults from removal of the TDS that may impact the irritation potential of a TDS product.	93
94
FDA generally recommends applicants conduct an in vivo study to evaluate the irritation	95
potential of a T product, unless a difference in an inactive ingredient as compared to the RLD	96
warrants an in vivo study to evaluate both the irritation and sensitization potential of the T	97
product. Specifically, if a T product contains an inactive ingredient not contained in the RLD	98
that is known to be sensitizing,8 	or at an amount not previously used in an FDA-approved drug	99
product with a similar context of use, FDA recommends conducting a combined irritation and	100
sensitization study. FDA encourages an applicant who has questions related to if a sensitization	101
8 	FDA has determined that conducting a sensitization assessment is unnecessary or unethical where the active
ingredient is known to be a skin sensitizer, or the components and composition of the TDS is the same as the RLD.

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study would be necessary for a proposed product (with a proposed formulation composition) to	102
seek the Agency’s feedback through controlled correspondences or pre-ANDA meetings.9	
103
104
105
IV. 	EVALUATIONS OF SKIN IRRITATION AND SENSITIZATION	106
107
A. 	Study Design and Conduct	108
109
1. 	Study Design Recommendations	110
111
In general, the Agency recommends that applicants conduct an evaluator-blinded, randomized	112
study to support their comparative evaluation of the skin irritation characteristics of the T and R	113
products. The study population should typically include healthy males and nonpregnant,	114
nonlactating females, unless product-specific considerations consistent with the RLD’s labeled	115
conditions of use for certain TDS products indicate otherwise.10 	In the study protocol, the choice	116
of TDS strength intended to be used should be prespecified and should be justified, as	117
appropriate, based upon the use of the TDS in the proposed study population. When evaluating	118
the irritation potential only, applicants should compare the T and R TDS products in a minimum	119
of 40 evaluable subjects, or a sufficient number of subjects to power the study at a level of 0.80	120
or higher, whichever sample size is greater. To evaluate the irritation potential only, the study	121
should consist of a single 21-day induction phase under provocative conditions (repeated	122
removal and reapplication of the TDS on the same skin site) to maximize the potential for the	123
occurrence of an irritation in accordance with the recommendations described below.	124
125
When a sensitization study is appropriate, the Agency recommends that applicants evaluate both	126
skin irritation and sensitization in a single study using the same evaluator-blinded, randomized	127
study design, study population, and prespecified choice of TDS strength as described in the	128
paragraph above. However, a combined irritation and sensitization study should compare the T	129
and R TDS products in at least 200 evaluable subjects and be conducted under provocative	130
conditions (repeated removal and reapplication of the TDS on the same skin site) to maximize	131
the potential for the occurrence of an irritation and/or sensitization reaction in the subject	132
population during the study. FDA recommends a combined irritation and sensitization study to	133
consist of both a 21-day induction phase and, after a 14- to 17-day rest period, a challenge phase	134
in accordance with the recommendations described below.11	
135
136
9 	For information on submitting controlled correspondence or a pre-ANDA meeting request, see guidance for
industry 	Controlled Correspondence Related to Generic Drug Development 	(March 2024) and guidance for industry
Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA 	(October 2022).
10 	For product-specific considerations, refer to the relevant sections in current RLD labeling, including BOXED
WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS
sections, and the recommended inclusion and exclusion criteria of the relevant PSG.
11 	The challenge phase of the recommended study provides data to evaluate whether sensitization to the drug product
has occurred after introducing the drug product in the induction phase.

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During the induction phase, applicants should simultaneously apply all TDS units (i.e., every	137
whole or partial12 	T product and every whole or partial R product) to each subject. T and R	138
products should be applied at contralateral locations of the same anatomical site (e.g., T product	139
on the left buttock and R product on the right buttock); applicants should select the anatomical	140
site based on the recommendations for dosing in the RLD labeling.	141
142
For 21 consecutive days, TDS units should be worn, removed, and replaced by a new	143
TDS unit, for repeated durations to the same skin site as the initial application; each	144
duration should be representative of the RLD’s labeled wear period, unless otherwise	145
noted within the relevant PSG. For example, a TDS with a 3-day wear period may be	146
removed every 3 days, assessed for irritation, and replaced to the same skin site every 3	147
days, for a total of 21 days.	148
149
Applicants should evaluate the subject’s irritation response at the time of each TDS	150
change by individually assessing the subject’s “dermal response” and “other effects”	151
scores (both of which are described below) by using a separate scoring scale.	152
153
For subjects who experience excessive irritation,13 	the TDS may be moved to a new site	154
to complete the 21-day induction phase and to continue with the sensitization part (when	155
appropriate) of the study. Applicants should predefine in their protocol what criteria	156
would trigger the movement of a TDS to a new site (due to skin reactions that are	157
determined to represent excessive irritation). For example, the criteria may specify that	158
TDS may be moved to a new site if the combined score is equal to or greater than 3.	159
160
When evaluating the sensitization potential is appropriate, completion of the induction phase	161
should be followed by a 14- to 17-day rest period before beginning the challenge phase of the	162
study. During the challenge phase, applicants should simultaneously apply all TDS units (i.e.,	163
every whole or partial T product and every whole or partial R product) to each subject. T and R	164
products should be applied at contralateral locations of the same anatomical site (e.g., T product	165
on the left buttock and R product on the right buttock); applicants should select the anatomical	166
site based on the recommendations for dosing in the RLD labeling.	167
168
The TDS units should be applied for a 48-hour duration at a naïve skin site (i.e., a site	169
onto which a TDS was not applied during the induction phase) and then removed.	170
171
Applicants should assess the subject’s skin reactions at 30 minutes, 24 hours, 48 hours,	172
and 72 hours after removal of the TDS.	173
174
Applicants should record any skin reactions observed with a narrative description of the	175
subject’s “dermal response” and “other effects” scores (both of which are described	176
below) by using a separate scoring scale for each.	177
178
12 	Partial 	refers to a matrix TDS that is cut into smaller sizes.
13 	This score may vary for different TDS products or different scenarios.

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Applicants should document the opinion of the investigator about whether the skin	179
reaction(s) are indicative of a sensitization reaction. Applicants should prespecify, in	180
their study protocol how the investigators will be instructed to determine whether or not	181
there is a sensitization reaction.	182
183
For all subjects who exhibit a potential sensitization reaction, applicants should conduct a	184
rechallenge test 4 to 8 weeks following the original challenge and conducted in the same	185
manner as described above for the challenge phase.	186
187
2. 	Study Conduct Considerations	188
189
Applicants should randomize their assignment of the T and R products to skin sites, describe	190
their method of randomization in the protocol, and provide the randomization schedule as a SAS	191
transport data set in XPT format.	192
193
A trained observer should score the TDS’s adherence and the subject’s skin reactions at each	194
TDS removal, and applicants should try to ensure that the same scorer is used for all	195
observations. If the same scorer is not used for all observations, applicants should provide	196
evidence to ensure that the scoring is consistent across different scorers. Because of likely	197
differences in the appearance of the TDS between the T product and the R product, blinding of	198
the observer may not be possible, especially for monitoring TDS adhesion, which requires direct	199
observation of the TDS. However, applicants should try to blind the evaluation of irritation and	200
sensitization when possible.	201
202
If applicants believe that use of tape or an overlay may be needed to maintain maximum contact	203
of the TDS with the skin throughout the relevant duration of an irritation or combined irritation	204
and sensitization study, then the use of tape or an overlay may be appropriate. Applicants should	205
prespecify, in their study protocol, their criteria for using tape or an overlay to reinforce any TDS	206
that is lifting. If a TDS is reinforced with tape or an overlay, skin irritation of the tape or overlay	207
area should be reported separately from the skin irritation associated with the TDS application	208
area.	209
210
Applicants should evaluate adhesion of the TDS to the skin at each time point before TDS	211
removal throughout the entire study period to monitor the adequacy of skin contact, which is	212
necessary for a suitably provocative induction of irritation and sensitization. Accordingly, even	213
where tape or an overlay is used, adhesion should be evaluated based on the surface area of the	214
TDS (not including any tape or overlay) to ensure that the TDS is adhering well throughout the	215
induction phase and challenge phase. FDA’s recommendations for evaluating the adhesion of	216
the TDS are described in the draft guidance for industry 	Assessing Adhesion with Transdermal	217
and Topical Delivery Systems for ANDAs 	(April 2023).14	
218
219
If a TDS completely detaches, the subject should replace the new TDS within 24 hours and	220
continue in the study. The subject should note the date and time of detachment as soon as it	221
occurs, and applicants should maintain the source document generated by the subject (e.g.,	222
14 	When final, this guidance will represent FDA’s current thinking on this topic.

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subject diaries). If a TDS completely detaches for more than 24 hours during the 21-day	223
induction phase, applicants should exclude the subject from both the irritation and sensitization	224
(if appropriate) analyses for that product unless the subject intentionally removed the TDS	225
because of excessive irritation. If a TDS completely detaches for more than 24 hours during the	226
48-hour challenge phase, applicants should exclude the subject from the sensitization analysis	227
unless the subject intentionally removed the TDS because of excessive irritation.	228
229
In general, a subject’s body movement should not be restricted during the study. For products	230
with a wear period of up to or greater than 24 hours, the Agency recommends that subjects be	231
permitted to bathe or shower routinely during the study, in a manner consistent with the labeled	232
use of the RLD, and that the TDS should not be protected from direct exposure to water during	233
such routine activities.	234
235
Subjects should not apply makeup, creams, lotions, powders, alcohol, or other topical products to	236
the skin area where the TDS will be placed because these products could affect the adhesive	237
performance or irritation potential of the TDS. Also, the subject’s hair at the application site	238
should be clipped (not shaved) before TDS application. In addition, applicants should advise	239
subjects to avoid exposing the TDS application site to external sources of direct heat, such as	240
heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water beds, and/or prolonged	241
direct sunlight.	242
243
3. 	Recommended Inclusion and Exclusion Criteria	244
245
The following lists specify some inclusion and exclusion criteria that applicants can use to select	246
test subjects; however, these lists are not exhaustive, and applicants can use other criteria to	247
select subjects, as appropriate. Applicants should describe, as part of the protocol, the rationale	248
for inclusion and/or exclusion criteria that are in addition to or different from those identified	249
below.	250
251
Inclusion criteria:	252
253
- 	Healthy15 	male and female (nonpregnant, nonlactating) subjects between 18 and 65	254
years of age (inclusive).	255
256
- 	Females of childbearing potential must be prepared to either abstain from sexual	257
intercourse or use a reliable barrier method of contraception (e.g., female condom,	258
diaphragm, intrauterine system, contraceptive sponge, or have their partner use a	259
barrier method (condom with spermicide)) for at least 14 days before and throughout	260
the duration of study or have used a hormonal method of contraception for at least 30	261
days before the study and will continue to use the same type of hormonal	262
contraceptive during the study.	263
264
Exclusion criteria:	265
15 	Healthy subjects are in general nonsmoking adults 18 years of age or older without existing medical conditions or
required medications that exert physiological effects.

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266
- 	Subject is pregnant or lactating	267
268
- 	Medical history of significant dermatologic diseases or conditions, such as atopy,	269
psoriasis, vitiligo, or conditions known to alter skin appearance or physiologic	270
response (e.g., diabetes or porphyria)	271
272
- 	Medical history of a condition that would significantly influence the immune	273
response (e.g., primary or acquired immunodeficiencies such as HIV or AIDS;	274
allergic diseases such as anaphylaxis, asthma, or generalized drug reaction;	275
neoplasms such as lymphoma or leukemia; rheumatoid arthritis; or systemic lupus	276
erythematosus)	277
278
- 	Medical history of significant dermatologic cancers (e.g., melanoma or squamous cell	279
carcinoma), except basal cell carcinomas that were superficial and did not involve the	280
TDS application sites	281
282
- 	Within 3 weeks of the start of study treatment, use of medications or treatments that	283
would either: (1) significantly influence or exaggerate responses to the T or R	284
product or (2) alter the inflammatory or immune response to the T or R product (e.g.,	285
cyclosporine, tacrolimus, systemic or topical corticosteroids, cytotoxic drugs, immune	286
globulin, Bacillus Calmette-Guerin immunotherapy, monoclonal antibodies, or	287
radiation therapy)	288
289
- 	Within 72 hours of the start of study treatment, use of antihistamines or use of topical	290
drugs at the TDS site	291
292
- 	Subject has an obvious difference in skin color between arms or the presence of a	293
skin condition, excessive hair at the application sites, scar tissue, tattoos, open sores, a	294
recent sunburn, or body piercing that would interfere with the placement of the test	295
articles, the skin assessment, or the subject’s reactions to the TDS	296
297
Applicants should provide a list of the prescription and over-the-counter drug products that will	298
be contraindicated for subjects during the study, such as medications or treatments that would	299
significantly influence or exaggerate the subject’s responses to the T or R product or that would	300
alter the subject’s inflammatory or immune response to the product (e.g., antihistamines,	301
systemic or topical corticosteroids, cyclosporine, tacrolimus, cytotoxic drugs, immune globulin,	302
Bacillus Calmette-Guerin immunotherapy, monoclonal antibodies, or radiation therapy).	303
304
4. 	Scoring Scales for Dermal Responses	305
306
During both the induction phase and challenge phase, applicants should score the subjects’	307
dermal responses according to the two scales shown below.	308
309
Scale 1. Dermal Response.	310

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Skin Appearance 	Score
No evidence of irritation 	0
Minimal erythema that is barely perceptible 	1
Definite erythema that is readily visible or minimal edema or minimal papular response 	2
Erythema and papules 	3
Definite edema 	4
Erythema, edema, and papules 	5
Vesicular eruption 	6
Strong reaction spreading beyond the application site 	7
311
Scale 2. Other Effects.	312
Observation
Score
(Numerical
Equivalent)
No other effects or only a slightly glazed appearance 	A (0)
Markedly glazed appearance 	B (1)
Glazing with peeling and cracking 	C (2)
Glazing with fissures 	F (3)
Film of dried serous exudates covering all or part of the TDS site 	G (3)
Small petechial erosions and/or scabs 	H (3)
313
When one or more “other effects” are observed, applicants should report each score as a dermal	314
response number, a letter combination score, and as a numerical total (i.e., numerical “dermal	315
response” score + numeric equivalent for the “other effects” lettered score). For example, the	316
dermal response of 6 with glazing with fissure (F (3)) will equal to the score of 9. When no	317
“other effects” are observed, score zero should be applied to an observed “other effects.”	318
319
Applicants intending to utilize an alternative scale other than these two scales should request a	320
meeting with FDA to discuss the alternative scale and the proposed statistical analysis plan	321
before conducting the study (i.e., submit a pre-ANDA meeting request).16 	If applicants use a	322
scale other than these two scales (e.g., a single numerical scale that captures the progressive	323
changes in skin reactions) to score the skin reactions observed, they should report each score	324
according to their selected alternate scale as well as the score according to these two scales.	325
326
5. 	Calculating and Formatting Dermal Response Scores	327
328
FDA’s recommended primary endpoint for evaluating irritation is the mean irritation score	329
(MIS). At each assessment time point for each subject and for each product, applicants should	330
calculate a combined irritation score by adding the “dermal response” score and the numeric	331
equivalent for “other effects” letter score. For each subject and each product, applicants should	332
calculate the MIS as the sum of the combined irritation scores over the assessment time points	333
divided by the total number of assessments. A separate MIS should be calculated in the same	334
16 	See footnote 7.

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manner for dermal response scores from the challenge phase (or rechallenge phase, if applicable)	335
to determine the subjects who are potentially sensitized.	336
337
Applicants should submit descriptive irritation score data in a frequency table illustrating the	338
number and proportion of each TDS unit with each combination of the dermal response	339
numerical score and the “other effects” letter score at each evaluation time point. If a TDS is	340
moved or removed because of excessive irritation, the last irritation score(s) observed at the	341
original application site prior to removal is considered a reasonable representation of the degree	342
of irritation with the TDS at that site for the remaining time points. This approach is referred to	343
as the last observation carried forward (LOCF) from the original application site. The frequency	344
table should reflect the irritation scores after the LOCF. The table below provides an example of	345
a frequency table.	346
347
Frequency of Irritation Scores for a Per-Protocol Population (Hypothetical Data) (N=153	348
TDS Units for T, and N=152 TDS Units for R).	349
Day:
TDS
“Dermal Response” and “Other Effects” Scores
0 	0A * 	1** 	1A 	2 	2A 	3 	4
n 	% 	n 	% 	n 	% 	n 	% 	n 	% 	n 	% 	n 	% 	n 	%
3:T 	151 	98.7 	0 	0.0 	2 	1.3 	0 	0.0 	0 	0.0 	0 	0.0 	0 	0.0 	0 	0.0
3:R 	151 	99.3 	0 	0.0 	1 	0.7 	0 	0.0 	0 	0.0 	0 	0.0 	0 	0.0 	0 	0.0
7:T 	149 	97.4 	0 	0.0 	4 	2.6 	0 	0.0 	0 	0.0 	0 	0.0 	0 	0.0 	0 	0.0
7:R 	145 	95.4 	0 	0.0 	7 	4.6 	0 	0.0 	0 	0.0 	0 	0.0 	0 	0.0 	0 	0.0
10:T 	140 	91.5 	0 	0.0 	10 	6.5 	1 	0.7 	1 	0.7 	0 	0.0 	1 	0.7 	0 	0.0
10:R 	141 	92.8 	0 	0.0 	9 	5.9 	0 	0.0 	2 	1.3 	0 	0.0 	0 	0.0 	0 	0.0
14:T 	142 	92.8 	0 	0.0 	7 	4.6 	2 	1.3 	1 	0.7 	0 	0.0 	1 	0.7 	0 	0.0
14:R 	139 	91.5 	0 	0.0 	11 	7.2 	0 	0.0 	1 	0.7 	0 	0.0 	1 	0.7 	0 	0.0
17:T 	120 	78.4 	1 	0.7 	23 	15.0 	2 	1.3 	3 	2.0 	0 	0.0 	4 	2.6 	0 	0.0
17:R 	129 	84.9 	0 	0.0 	16 	10.5 	0 	0.0 	3 	2.0 	1 	0.7 	2 	1.3 	1 	0.7
21:T 	112 	73.2 	5 	3.3 	25 	16.3 	4 	2.6 	3 	2.0 	0 	0.0 	4 	2.6 	0 	0.0
21:R 	121 	79.6 	2 	1.3 	20 	13.2 	3 	2.0 	3 	2.0 	0 	0.0 	2 	1.3 	1 	0.7
* The combination 	0A 	means that the “dermal response” score is 0 and the “other effects” score is A.
** The number 	1 	means that the “dermal response” score is 1 and the “other effects” score is 0.
B. 	Considerations for Statistical Analyses	350
351
1. 	Irritation Analysis	352
353
For an irritation analysis, applicants should define, in the protocol, their per-protocol (PP)	354
population per TDS instead of per subject. The PP population should include all TDS units	355
applied sequentially to the same anatomical site for the entire 21-day induction phase without	356
any period of detachment longer than 24 hours. If a TDS is moved or removed because of	357

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excessive irritation, it should be included in the PP population, using the LOCF from the original	358
application site.	359
360
Applicants should compare the overall mean of the per-subject MIS (i.e., the primary endpoint	361
described above) for the T and R products. To demonstrate the noninferiority (NI) of the T	362
product compared to the R product with respect to the MIS, the T product should be shown to be	363
statistically noninferior to the R product based on evaluating the difference in the T and R	364
products’ overall mean MIS, with an NI margin of 0.20 	20). The NI margin of 0.20	365
represents the difference of the mean MIS between the T and R products based on the irritation	366
scales as previously described; this NI margin may not be appropriate to use for either the	367
difference of the mean MIS based on other irritation scales or data transformations (e.g., a	368
logarithmic transformation or the addition of a constant to all irritation scores) or the difference	369
of the median MIS between the T and R products.	370
371
Applicants should test the following hypotheses at the significance level of 0.05:	372
373
0:	374
1: 	<	375
376
Here, 	and 	are the population means for the MIS for the T and R products, respectively, and	377
the alternative hypothesis 	1 	represents the NI of the T product’s irritation relative to the R	378
product’s irritation. These hypotheses can also be written as follows:	379
380
:	381
: 	<	382
383
where 	is equal to the difference of the population mean for the MIS for the T and R products:	384
= 	. When there is no missing data, in a matched pairs study, 	is the same as the	385
population mean for the difference 	between the paired T per-subject MIS ( 	) 	and R per-	386
subject MIS ( 	) 	for individual subject 	= 	, 	= 	.	387
388
To demonstrate an acceptable irritation response for the T product, applicants should design and	389
conduct an irritation study as described in section IV.A of this guidance. If an irritation-only	390
study is designed, applicants should enroll a minimum of 40 evaluable subjects, or a sufficient	391
number of subjects to power the study at a level of 0.80 or higher, whichever sample size is	392
greater. Because of the discrete nature of irritation scales and other potential complications of	393
the irritation data, FDA recommends that applicants use a large enough sample size to ensure the	394
validity of any large-sample (asymptotic) Gaussian assumptions, if used.	395
396
Applicants should finalize their statistical analysis plan, describing all aspects of the planned	397
analysis in detail, before the data are unblinded; the statistical analysis plan should be provided	398
to the Agency when the ANDA is submitted.	399
400
Incomplete data and data associated with noncompliance can seriously affect the validity of an	401
NI study. Therefore, FDA recommends good study design and conduct to prevent patient	402

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dropout and noncompliance. If either occur, applicants should document, in detail, the reasons	403
for the dropout and/or noncompliance. Although FDA recommends using the PP population as	404
the primary analysis population for NI studies, the Agency also has significant concerns with the	405
possibility of informative dropout and noncompliance. If methods other than LOCF will be used	406
to impute data for a TDS that is moved or removed due to excessive irritation, applicants should	407
prespecify these imputation methods in their protocol. FDA recommends that applicants conduct	408
a prespecified sensitivity analysis to evaluate the potential impact of any unbalanced or	409
informative dropout and noncompliance on the conclusion of NI.	410
411
For the irritation evaluation, FDA also considers other clinically relevant data, including the	412
number of TDS unit applications that reach a maximum irritation score and the number of	413
subjects who discontinue product application because of excessive irritation. The same MIS	414
could be reached with a small number of high scores (e.g., 3 or higher), which may be of greater	415
clinical concern, or with a larger number of low scores (e.g., 1), which may be of lesser clinical	416
concern. Thus, it is difficult to determine the clinical meaningfulness of a given MIS or a given	417
difference between products with respect to their MIS.	418
419
Therefore, in addition to MIS, FDA recommends the applicant evaluate the proportion of	420
subjects with excessive irritation for each product. The proportion of subjects with excessive	421
irritation should be no higher for the T product than for the R product, and irritation should not	422
occur earlier in the application period for the T product than for the R product. The T product	423
should be noninferior to the R product with respect to the MIS, and the T product should show	424
no meaningful difference, compared to the R product, with respect to the degree of irritation.	425
426
2. 	Sensitization Analysis	427
428
As previously noted, generally an in vivo sensitization evaluation of a TDS product may be	429
needed where there is a difference in an inactive ingredient between the T product as compared	430
to the RLD. Specifically, if a T product contains an inactive ingredient not contained in the RLD	431
that is known to be sensitizing, or at an amount not previously used in an FDA-approved drug	432
product with a similar context of use, a sensitization assessment may be needed to show that the	433
T product is not likely to be more sensitizing than the RLD.	434
435
When an in vivo sensitization evaluation is appropriate, a combined irritation and sensitization	436
study should compare the T and R TDS products in at least 200 evaluable subjects. Applicants	437
should define, in the protocol, the PP population for the sensitization analysis per TDS instead of	438
per subject.	439
440
The PP population for the sensitization analysis should include all TDS units worn (without any	441
period of detachment longer than 24 hours) for the full 21-day induction phase and the entire 48-	442
hour challenge phase. Each subject should return for at least one of the scheduled evaluations at	443
48 and 72 hours after removal of the challenge TDS. If a TDS unit is removed before the end of	444
the 48-hour challenge phase because of excessive irritation, the application site should be	445
evaluated at 24 hours, 48 hours, and 72 hours after TDS removal and be included in the	446
sensitization analysis using the LOCF from the original application site.	447

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448
For each TDS unit, each PP subject with a combined score of 2 or greater at 48 or 72 hours after	449
TDS removal during the challenge phase should be individually evaluated for potential	450
sensitization. Applicants should consider a subject 	potentially sensitized 	if all the following	451
criteria are met:	452
453
The subject has at least one evaluation timepoint occurring at more than 24 hours (e.g., at	454
48 or 72 hours) after the removal of the challenge phase TDS.	455
456
The subject has a combined irritation score of at least 2 at their last evaluation during the	457
challenge phase.	458
459
If the subject completed a rechallenge phase, the above two criteria were met during both	460
the challenge phase and the rechallenge phase.	461
462
Skin reactions that resolve before 48 hours are generally considered to be caused by irritation	463
instead of sensitization. For any potential sensitization reaction observed during the challenge or	464
rechallenge phase, applicants should provide a justification to support that the rate of	465
sensitization of the T product is comparable to that observed with the use of the R product.	466
467
Applicants should report the respective numbers of subjects considered to be potentially	468
sensitized to the T and/or R products.	469
470
Applicants should provide descriptive statistics comparing both the number and the proportion of	471
subjects potentially sensitized to each TDS unit and both the number and the proportion of	472
subjects sensitized to each TDS unit.	473
474
Applicants should provide a frequency table showing the number of applications of each TDS	475
unit during the challenge phase, with each specific combined “dermal response” numerical score	476
and “other effects” letter score at each evaluation time point.	477
478
For all subjects with at least one combined irritation score of 2 or more at 48 or 72 hours after	479
TDS removal in the challenge phase, applicants should provide a table showing the actual scores	480
for each subject at each evaluation time point during the induction and challenge phases.	481
482
483
C. 	Vehicle TDS and Positive Control TDS	484
485
If safety concerns preclude the usual comparative studies, which include the use of the T and R	486
products, the evaluation of skin irritation (and sensitization, if applicable) by the T product can	487
be evaluated by testing a vehicle TDS versus a positive control TDS that produces mild irritation	488
(e.g., 	0.1% sodium lauryl sulfate). The vehicle TDS should contain all the inactive ingredients	489
in the T product and be identical to the T product in every manner except for the absence of the	490
active ingredient. If the inactive ingredients in the vehicle TDS are different than those	491
contained in the T product or are in different amounts than in the T product, then the applicant	492

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should clearly describe the differences and provide data to show that the differences will not	493
affect the safety of the T product or the applicant’s interpretation of the study results.	494
495
For a skin irritation (or combined irritation and sensitization) study that compares the vehicle	496
TDS to a positive control TDS, applicants should utilize essentially the same approach as is	497
recommended for the comparison of T and R products in sections IV.A. and B. of this guidance,	498
except that the vehicle TDS should serve as the T product and the positive control TDS should	499
serve as the R product.	500
501
Applicants should ensure that the positive control is consistently able to elicit and maintain an	502
irritation response during the induction phase. A positive control that is either unable to	503
consistently elicit an irritation response, or unable to maintain that response, may confound the	504
interpretation of study results and undermine the validity of the study.	505
506
It is not recommended to include multiple candidate positive control TDS products in the	507
irritation (or combined irritation and sensitization) study and post-hoc select one as the positive	508
control TDS to compare with the vehicle TDS in the statistical analysis. Rather, it is	509
recommended to preselect one appropriate positive control to use as the positive control TDS	510
prior to the irritation (or combined irritation and sensitization) study.	511
512
D. 	Partial (Cut) TDS	513
514
If a safety concern prevents the simultaneous application of two whole TDS on the same subject	515
during the 21-day irritation-only study or 21-day induction phase of a combined irritation and	516
sensitization study, a matrix TDS can be cut to a smaller size.17 	In such situations, the T and R	517
products should both have designs that can be safely cut to a smaller size. Applicants should not	518
manufacture a separate batch of product to use a smaller TDS in this study. When using a cut	519
TDS, the general recommendations provided in sections IV.A and IV.B in this guidance apply.	520
521
522
V. 	OVERALL ASSESSMENT OF ADVERSE EVENT DATA	523
524
Applicants should include, in their analysis, all subjects who receive at least one dose of TDS.	525
This analysis should include a comparison of all TDS units (e.g., the T product and the R	526
product) with respect to any application site adverse events. Applicants should report all adverse	527
events, including systemic adverse events. For any application site-related adverse events,	528
applicants should report whether or not the adverse event is related to the T product or the R	529
product.	530
531
Applicants should document, in their study report, all application site reactions (including subject	532
complaints such as dryness, itching, burning, pain, or soreness) separate from the “dermal	533
response” and “other effects” scores. In addition, applicants should include details about any	534
application site to which the complaint applies. The study report should also include a frequency	535
17 	The recommended cut size for a matrix TDS is product specific and included in the relevant PSG.

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table listing application site reactions and comparing the severity of application site reactions	536
between the T product and the R product.	537
538
539
VI. 	FORMAT OF DATA SUBMISSIONS	540
541
Applicants should refer to the Study Data for Submission to CDER web page18 	for information	542
about data standards.	543
544
Applicants should provide SAS transport data sets in XPT format with the define file. If	545
applicants apply imputation, they should submit both raw data and the analysis data after the	546
imputation.	547
18 	Available at 	https://www.fda.gov/industry/study-data-standards-resources/study-data-submission-cder-and-cber.