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DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Melissa Mannion at 301-796-2747.  
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
April 2023 
Generic Drugs 
Revision 1 
   
Assessing the Irritation 
and Sensitization 
Potential of Transdermal 
and Topical Delivery 
Systems for ANDAs 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD 20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
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) 
 
April 2023 
Generic Drugs 
Revision 1 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  GENERAL CONSIDERATIONS ................................................................................... 3 
IV.  COMBINED EVALUATIONS OF SKIN IRRITATION AND SENSITIZATION ... 4 
A.  Study Design and Conduct ............................................................................................................ 4 
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.......................................................................... 14 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Assessing the Irritation and Sensitization Potential of Generic 
2  Transdermal and Topical Delivery Systems for ANDAs 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance listed on the title page.  
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  This guidance provides recommendations for the design and conduct of studies to evaluate the in 
18  vivo skin irritation and sensitization (I/S) potential of a proposed transdermal or topical delivery 
19  system (collectively referred to as TDS2).  The recommendations in this guidance relate to 
20  studies submitted in support of an abbreviated new drug application (ANDA).3  This guidance 
21  revises the draft guidance for industry Assessing the Irritation and Sensitization Potential of 
22  Transdermal and Topical Delivery Systems for ANDAs (October 2018).  This revision provides 
23  the following updates to the original draft guidance: 
24   
25  (1) Clarifies recommendations for the design and conduct of studies to evaluate the in vivo 
26  skin I/S potential of a proposed TDS. 
27   
28  (2) Clarifies when an in vivo study to assess the sensitization potential of a TDS product may 
29  not be needed. 
30   
 
1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research 
(CDER) in cooperation with CDERs 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 the 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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31  (3) Provides guidance to applicants intending to utilize alternative scoring scales or 
32  alternative approaches to compare I/S between the test and reference TDS. 
33   
34  In this guidance, the letter T (representing Test) will refer to proposed generic products that are 
35  the subject of an ANDA, and the letter R (representing Reference) will refer to the reference 
36  listed drug (RLD) and/or reference standard product.   
37   
38  FDA recommends that applicants consult this guidance in conjunction with any relevant product-
39  specific guidances (PSGs)4 and in conjunction with any relevant guidances for industry5 when 
40  considering the design and conduct of studies that may be appropriate to support the 
41  bioequivalence of a proposed generic TDS product to its RLD.  FDA also recommends that 
42  applicants routinely refer to FDAs website, since additional guidances may become available 
43  that could assist in the development of a generic TDS product. 
44   
45  FDA encourages an applicant who seeks to use an alternative approach to FDAs 
46  recommendations in the relevant PSG for the design and conduct of studies evaluating the in 
47  vivo I/S potential of a TDS between T and R products to contact the Agency to discuss the 
48  proposed alternative approach to evaluate the I/S potential for that drug product.6 
49   
50  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
51  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
52  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
53  the word should in Agency guidances means that something is suggested or recommended, but 
54  not required. 
55   
56   
57  II.  BACKGROUND 
58   
59  The components and composition of a TDS formulation, including the nature of the drug 
60  substance and/or the degree to which the TDS materials occlude the transmission of water vapor 
61  from the skin, in conjunction with other factors such as the environmental humidity or the 
62  condition of the skin, may have the potential to irritate the skin or lead to a sensitization 
 
4 Generic drug product-specific guidances 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 the FDAs 
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 the 
guidances for industry Controlled Correspondence Related to Generic Drug Development (December 2020) 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. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
63  reaction.7  Such reactions can be unpleasant to the patient and may affect patient compliance, 
64  skin permeability, and/or adhesion of the TDS to the skin. The collective consequence of these 
65  potential effects could create uncertainty about the resulting drug delivery profile and uncertainty 
66  about the rate and extent of drug absorption from the TDS.  Therefore, when appropriate, 
67  applicants should perform a comparative assessment of the T and R TDS products using an 
68  appropriately designed skin I/S study with human subjects to demonstrate that the potential for a 
69  skin irritation or sensitization reaction with the T TDS is no worse than the reaction observed 
70  with the R TDS (see General Considerations below for information about when such a study may 
71  be appropriate).  
72   
73   
74  III.  GENERAL CONSIDERATIONS 
75   
76  Skin I/S studies are designed to compare the similarity between the T and R TDS products for 
77  the potential to cause irritation and/or sensitization reactions.  A TDS may elicit these reactions 
78  in only some of the patients using the product, but even if the frequency of this occurrence were 
79  low, the adverse reactions could affect thousands of individuals.  To evaluate this I/S potential, 
80  applicants should compare the T and R TDS products in at least 200 evaluable subjects (see 
81  section IV.A.), and the study should be conducted under provocative conditions (repeated 
82  removal and reapplication of the TDS on the same skin site) to maximize the potential for the 
83  occurrence of an irritation and/or sensitization reaction in the subject population during the 
84  study. 
85   
86  In some circumstances, an in vivo study to assess the sensitization potential of a TDS product 
87  submitted in an ANDA may not be necessary if adequate justification is provided or FDA has 
88  determined that conducting a sensitization assessment is unnecessary or unethical (e.g., where 
89  the active ingredient is known to be a skin sensitizer or based on information/data related to the 
90  components and composition of TDS products) to show that the T product is not likely to be 
91  more sensitizing than the R product.   
92   
93  Changes in environmental temperature or humidity, including the daily exposure of the TDS to 
94  heat and water during routine showering, may transiently affect the rate at which components of 
95  the TDS formulation are released and permeate through skin.  Such changes may also affect 
96  entrapped moisture in and/or under the TDS, which could alter skin hydration and impact the 
97  bioavailability of formulation components, which may, in turn, change I/S reactions.  Therefore, 
98  when designing their I/S studies, applicants should consider any conditions of labeled use for the 
99  RLD that may impact the I/S potential of a TDS product (e.g., incidental exposure of the TDS to 
100  water, such as while bathing or showering, particularly for a TDS with a duration of wear that is 
101  up to or greater than 24 hours). 
102   
103  In addition to I/S reactions that may arise from the corrosive or immunomodulatory nature of 
104  formulation components or from the pharmacodynamic response of the skin to the occlusion by 
105  the TDS, the skin may also become irritated in response to the physical insults that can occur 
 
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. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
106  during the removal of a TDS.  For example, if the adhesive properties of the TDS are such that it 
107  strips away substantial portions of the stratum corneum during removal, the damage to the skin 
108  barrier may lead to irritation at the site of TDS removal, which may also increase the potential 
109  for a sensitization reaction.  
110   
111   
112  IV.  COMBINED EVALUATIONS OF SKIN IRRITATION AND SENSITIZATION 
113   
114  A.  Study Design and Conduct 
115   
116  In general, the Agency recommends that applicants conduct an evaluator-blinded, randomized 
117  study to support their comparative evaluation of the skin I/S characteristics of the T and R 
118  products.  The study population should typically include healthy males and nonpregnant, 
119  nonlactating females, unless product-specific considerations consistent with the RLDs labeled 
120  conditions of use for certain TDS products indicate otherwise.8  In the study protocol, the choice 
121  of TDS strength intended to be used should be prespecified and should be justified, as 
122  appropriate, based upon the use of the TDS in the proposed study population.  
123   
124  The Agency recommends that applicants evaluate skin irritation and sensitization in a single 
125  study if a sufficient number of subjects are included to evaluate sensitization, as described 
126  herein.  The recommended study consists of the following two phases, which are each described 
127  in turn: 
128   
129  (1) A 21-day induction phase, followed by a 14- to 17-day rest period  
130  (2) A challenge phase9 
131   
132  During the induction phase, applicants should simultaneously apply all TDS units (i.e., every 
133  whole or partial10 T product and every whole or partial R product) to each subject.  T and R 
134  products should be applied at contralateral locations of the same anatomical site (e.g., T product 
135  on the left buttock and R product on the right buttock); applicants should select the anatomical 
136  site based on the recommendations for dosing in the RLD labeling.  
137   
138    For 21 consecutive days, TDS units should be worn, removed, and replaced by a new 
139  TDS unit, for repeated durations to the same skin site as the initial application; each 
140  duration should be representative of the RLDs labeled wear period, unless otherwise 
141  noted within the relevant PSG.  For example, a TDS with a 3-day wear period may be 
142  removed every 3 days, assessed for I/S, and replaced to the same skin site every 3 days, 
143  for a total of 21 days. 
 
8 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. 
 
9 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.   
 
10 Partial refers to a matrix TDS that is cut into smaller sizes. 
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144   
145    Applicants should evaluate the subjects irritation response at the time of each TDS 
146  change by individually assessing the subjects dermal response and other effects 
147  scores (both of which are described below) by using a separate scoring scale.  
148   
149    For subjects who experience excessive irritation,11 the TDS may be moved to a new site 
150  to complete the 21-day induction phase and to continue with the sensitization part of the 
151  study.  Applicants should predefine in their protocol what criteria would trigger the 
152  movement of a TDS to a new site (due to skin reactions that are determined to represent 
153  excessive irritation).  For example, the criteria may specify that TDS may be moved to a 
154  new site if the combined score is equal to or greater than 3. 
155   
156  During the challenge phase, applicants should simultaneously apply all TDS units (i.e., every 
157  whole or partial T product and every whole or partial R product) to each subject.  T and R 
158  products should be applied at contralateral locations of the same anatomical site (e.g., T product 
159  on the left buttock and R product on the right buttock); applicants should select the anatomical 
160  site based on the recommendations for dosing in the RLD labeling.   
161   
162    The TDS units should be applied for a 48-hour duration at a naive skin site (i.e., a site 
163  onto which a TDS was not applied during the induction phase) and then removed.  
164   
165    Applicants should assess the subjects skin reactions at 30 minutes, 24 hours, 48 hours, 
166  and 72 hours after removal of the TDS.  
167   
168    Applicants should record any skin reactions observed with a narrative description of the 
169  subjects dermal response and other effects scores (both of which are described 
170  below) by using a separate scoring scale for each.   
171   
172    Applicants should document the opinion of the investigator about whether the skin 
173  reaction(s) are indicative of a contact sensitization.  Applicants should prespecify, in their 
174  study protocol how the investigators will be instructed to determine whether or not there 
175  is a contact sensitization.  
176   
177    For all subjects who exhibit a potential sensitization reaction, applicants should conduct a 
178  rechallenge test 4 to 8 weeks following the original challenge and conducted in the same 
179  manner as described above for the challenge phase.   
180   
181  During both the induction phase and challenge phase, applicants should score the subjects skin 
182  responses according to the two scales shown below. 
183   
 
11 This score may vary for different TDS products or different scenarios. 
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184  Scale 1. Dermal Response. 
185   
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 
186   
187  Scale 2. Other Effects. 
188   
Score 
Observation  (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) 
189   
190  When one or more other effects are observed, applicants should report each score as a dermal 
191  response number, a letter combination score, and as a numerical total (i.e., numerical dermal 
192  response score + numeric equivalent for the other effects lettered score).  For example, the 
193  dermal response of 6 with glazing with fissure (F (3)) will equal to the score of 9. When no 
194  other effects are observed, score zero should be applied to an observed other effects.   
195   
196  Applicants intending to utilize an alternative scale other than these two scales should request a 
197  meeting with FDA to discuss the alternative scale and the proposed statistical analysis plan 
198  before conducting the study (i.e., submit a pre-ANDA meeting request).12  If applicants use a 
199  scale other than these two scales (e.g., a single numerical scale that captures the progressive 
200  changes in skin reactions) to score the skin reactions observed, they should report each score 
201  according to their selected alternate scale as well as the score according to these two scales. 
202   
203  If applicants believe that use of tape or overlay may be needed to maintain maximum contact of 
204  the TDS with the skin throughout the relevant duration of an I/S study, then the use of tape or an 
205  overlay may be appropriate.  Applicants should prespecify, in their study protocol, their criteria 
206  for using tape or an overlay to reinforce any TDS that is lifting.  If a TDS is reinforced with tape 
 
12 See footnote 7. 
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207  or an overlay, skin irritation of the tape or overlay area should be reported separately from the 
208  skin irritation associated with the TDS application 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 I/S.  Accordingly, even where tape or an 
213  overlay is used, adhesion should be evaluated based on the surface area of the TDS (not 
214  including any tape or overlay) to ensure that the TDS is adhering well throughout the induction 
215  phase and challenge phase.  FDAs recommendations for evaluating the adhesion of the TDS are 
216  described in the draft guidance for industry Assessing Adhesion With Transdermal and Topical 
217  Delivery Systems for ANDAs (April 2023).13 
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  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  analyses for that product unless the subject intentionally removed the TDS because of excessive 
225  irritation.  If a TDS completely detaches for more than 24 hours during the 48-hour challenge 
226  phase, applicants should exclude the subject from the sensitization analysis unless the subject 
227  intentionally removed the TDS because of excessive irritation.  
228   
229  For I/S studies, applicants should enroll an adequate number of subjects to ensure that at least 
230  200 evaluable subjects are included in their per protocol (PP) population; however, for irritation-
231  only studies, the number of evaluable subjects in the PP population can vary (see details in 
232  Section B.1. for sample size determination for the conduct of irritation-only studies).  Subjects 
233  should not apply makeup, creams, lotions, powders, alcohol, or other topical products to the skin 
234  area where the TDS will be placed because these products could affect the adhesive performance 
235  or irritation potential of the TDS.  Also, the subjects hair at the application site should be 
236  clipped (not shaved) before TDS application.  In addition, applicants should advise subjects to 
237  avoid exposing the TDS application site to external sources of direct heat, such as heating pads, 
238  electric blankets, heat lamps, saunas, hot tubs, heated water beds, and/or prolonged direct 
239  sunlight.  
240   
241  The following lists specify some inclusion and exclusion criteria that applicants can use to select 
242  test subjects; however, these lists are not exhaustive, and applicants can use other criteria to 
243  select subjects, as appropriate.  Applicants should describe, as part of the protocol, the rationale 
244  for inclusion and/or exclusion criteria that are in addition to or different from those identified 
245  below.  
246   
 
13 When final, this guidance will represent the FDAs current thinking on this topic.  
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247    Inclusion criteria: 
248   
249    Healthy14 male and female (nonpregnant, nonlactating) subjects between 18 and 65 
-
250  years of age (inclusive). 
251   
252    Females of childbearing potential must be prepared to either abstain from sexual 
-
253  intercourse or use a reliable barrier method of contraception (e.g., female condom, 
254  diaphragm, intrauterine system, contraceptive sponge, or have their partner use a 
255  barrier method (condom with spermicide)) for at least 14 days before and throughout 
256  the duration of study or have used a hormonal method of contraception for at least 30 
257  days before the study and will continue to use the same type of hormonal 
258  contraceptive during the study. 
259   
260    Exclusion criteria: 
261   
262    Subject is pregnant or lactating 
-
263   
264    Medical history of significant dermatologic diseases or conditions, such as atopy, 
-
265  psoriasis, vitiligo, or conditions known to alter skin appearance or physiologic 
266  response (e.g., diabetes or porphyria)  
267   
268    Medical history of a condition that would significantly influence the immune 
-
269  response (e.g., primary or acquired immunodeficiencies such as HIV or AIDS; 
270  allergic diseases such as anaphylaxis, asthma, or generalized drug reaction; 
271  neoplasms such as lymphoma or leukemia; rheumatoid arthritis; or systemic lupus 
272  erythematosus) 
273   
274    Medical history of significant dermatologic cancers (e.g., melanoma or squamous cell 
-
275  carcinoma), except basal cell carcinomas that were superficial and did not involve the 
276  TDS application sites 
277   
278    Within 3 weeks of the start of study treatment, use of medications or treatments that 
-
279  would either: (1) significantly influence or exaggerate responses to the T or R product 
280  or (2) alter the inflammatory or immune response to the T or R product (e.g., 
281  cyclosporine, tacrolimus, systemic or topical corticosteroids, cytotoxic drugs, immune 
282  globulin, Bacillus Calmette-Guerin immunotherapy, monoclonal antibodies, or 
283  radiation therapy)  
284   
285    Within 72 hours of the start of study treatment, use of antihistamines or use of topical 
-
286  drugs at the TDS site  
287   
288    Subject has an obvious difference in skin color between arms or the presence of a 
-
289  skin condition, excessive hair at the application sites, scar tissue, tattoos, open sores, a 
 
14 Healthy subjects are in general non-smoking adults 18 years of age or older without existing medical conditions or 
required medications that exert physiological effects. 
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290  recent sunburn, or body piercing that would interfere with the placement of the test 
291  articles, the skin assessment, or the subjects reactions to the TDS  
292   
293  Applicants should provide a list of the prescription and over-the-counter drug products that will 
294  be contraindicated for subjects during the study, such as medications or treatments that would 
295  significantly influence or exaggerate the subjects responses to the T or R product or that would 
296  alter the subjects inflammatory or immune response to the product (e.g., antihistamines, 
297  systemic or topical corticosteroids, cyclosporine, tacrolimus, cytotoxic drugs, immune globulin, 
298  Bacillus Calmette-Guerin immunotherapy, monoclonal antibodies, or radiation therapy). 
299   
300  In general, a subjects body movement should not be restricted during the study. For products 
301  with a wear period of up to or greater than 24 hours, the Agency recommends that subjects be 
302  permitted to bathe or shower routinely during the study, in a manner consistent with the labeled 
303  use of the RLD, and that the TDS should not be protected from direct exposure to water during 
304  such routine activities.   
305   
306  Applicants should randomize their assignment of the T and R products to skin sites, describe 
307  their method of randomization in the protocol, and provide the randomization schedule as a SAS 
308  transport data set in XPT format.   
309   
310  A trained observer should score the TDSs adherence and the subjects skin reactions at each 
311  TDS removal, and applicants should try to ensure that the same scorer is used for all 
312  observations.  If the same scorer is not used for all observations, applicants should provide 
313  evidence to ensure that the scoring is consistent across different scorers.  Because of likely 
314  differences in the appearance of the TDS between the T product and the R product, blinding of 
315  the observer may not be possible, especially for monitoring TDS adhesion, which requires direct 
316  observation of the TDS.  However, applicants should try to blind the evaluation of I/S when 
317  possible.  
318   
319  FDAs recommended primary endpoint for evaluating irritation is the mean irritation score 
320  (MIS).  At each assessment time point for each subject and for each product, applicants should 
321  calculate a combined irritation score by adding the dermal response score and the numeric 
322  equivalent for other effects letter score.  For each subject and each product, applicants should 
323  calculate the MIS as the sum of the combined irritation scores over the assessment time points 
324  divided by the total number of assessments. 
325   
326  Applicants should submit descriptive irritation score data in a frequency table illustrating the 
327  number and proportion of each TDS unit with each combination of the dermal response 
328  numerical score and the other effects letter score at each evaluation time point.  If a TDS is 
329  moved or removed because of excessive irritation, the last irritation score(s) observed at the 
330  original application site prior to removal is considered a reasonable representation of the degree 
331  of irritation with the TDS at that site for the remaining time points.  This approach is referred to 
332  as the last observation carried forward (LOCF) from the original application site.  The frequency 
333  table should reflect the irritation scores after the LOCF.  The table below provides an example of 
334  a frequency table.  
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335   
336  Frequency of Irritation Scores for a Per-Protocol Population (Hypothetical Data) (N=153 
337  patches for T, and N=152 patches for R). 
338   
Dermal Response and Other Effects Scores 
Day: 
0  0A *  1**  1A  2  2A  3  4 
TDS 
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.  
 
339  B.  Considerations for Statistical Analyses 
340   
341  1.  Irritation Analysis 
342   
343  For an irritation analysis, applicants should define, in the protocol, their per-protocol (PP) 
344  population per TDS instead of per subject.  The PP population should include all TDS units 
345  applied sequentially to the same anatomical site for the entire 21-day induction phase without 
346  any period of detachment longer than 24 hours.  If a TDS is moved or removed because of 
347  excessive irritation, it should be included in the PP population, using the LOCF from the original 
348  application site.  
349   
350  Applicants should compare the overall mean of the per-subject MIS (i.e., the primary endpoint 
351  described above) for the T and R products.  To demonstrate the noninferiority (NI) of the T 
352  product compared to the R product with respect to the MIS, the T product should be shown to be 
353  statistically noninferior to the R product based on evaluating the difference in the T and R 
354  products overall mean MIS, with an NI margin of 0.20 ( = 0.20).  The NI margin of 0.20 
355  represents the difference of the mean MIS between the T and R products based on the irritation 
356  scales as previously described; this NI margin may not be appropriate to use for either the 
357  difference of the mean MIS based on other irritation scales or data transformations (e.g., a 
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358  logarithmic transformation or the addition of a constant to all irritation scores) or the difference 
359  of the median MIS between the T and R products.  
360   
361  Applicants should test the following hypotheses at the significance level of 0.05:  
362   
363  :    
0
364  :   <  
1
TT RR
365    HH   
TT RR
366  Here,  and  are the population means fHHor the MIS for the T and R products, respectively, and 
367  the alternative hypothesis  represents the NI of the T products irritation relative to the R 
TT RR
368  products  irritati on.  These hypotheses can also be written as follows: 
1
369    HH  
370   
371   
372    HH0: DD  
373  where   is equal to the difference of the pHHop1u: laDDtio<n mean for the MIS for the T and R products: 
374  .  When there is no missing data, in a matched pairs study,   is the same as the 
375  populatiDDon mean for the difference  between the paired T per-subject MIS ( and R per-
DD = TT RR DD
376  subject MIS ( for individual subject    . 
DDjj  XXjjTT) 
377   
XXjjRR)  jj DDjj = XXjjTT XXjjRR,EEDDjj = DD
378  To demonstrate an acceptable irritation response for the T product, applicants should design and 
379  conduct an irritation study as described in section IV.A of this guidance. If an irritation-only 
380  study is designed, applicants should enroll a sufficient number of subjects to power the study at a 
381  level of 0.80 or higher. Because of the discrete nature of irritation scales and other potential 
382  complications of the irritation data, FDA recommends that applicants use a large enough sample 
383  size to ensure the validity of any large-sample (asymptotic) Gaussian assumptions, if used.  
384   
385  Applicants should finalize their statistical analysis plan, describing all aspects of the planned 
386  analysis in detail, before the data are unblinded; the statistical analysis plan should be provided 
387  to the Agency when the ANDA is submitted.   
388   
389  Incomplete data and data associated with noncompliance can seriously affect the validity of an 
390  NI study.  Therefore, FDA recommends good study design and conduct to prevent patient 
391  dropout and noncompliance.  If either occur, applicants should document, in detail, the reasons 
392  for the dropout and/or noncompliance.  Although the FDA recommends using the PP population 
393  as the primary analysis population for NI studies, the Agency also has significant concerns with 
394  the possibility of informative dropout and non-compliance.  If methods other than LOCF will be 
395  used to impute data for a TDS that is moved or removed due to excessive irritation, applicants 
396  should prespecify these imputation methods in their protocol.  FDA recommends that applicants 
397  conduct a prespecified sensitivity analysis to evaluate the potential impact of any unbalanced or 
398  informative dropout and noncompliance on the conclusion of NI.  
399   
400  For the irritation evaluation, FDA also considers other clinically relevant data, including the 
401  number of TDS unit applications that reach a maximum irritation score and the number of 
402  subjects who discontinue product application because of excessive irritation.  The same MIS 
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403  could be reached with a small number of high scores (e.g., 3 or higher), which may be of greater 
404  clinical concern, or with a larger number of low scores (e.g., 1), which may be of lesser clinical 
405  concern.  Thus, it is difficult to determine the clinical meaningfulness of a given MIS or a given 
406  difference between products with respect to their MIS.  
407   
408  Therefore, in addition to MIS, FDA recommends the applicant evaluate the proportion of 
409  subjects with excessive irritation for each product.  The proportion of subjects with excessive 
410  irritation should be no higher for the T product than for the R product, and irritation should not 
411  occur earlier in the application period for the T product than for the R product.  The T product 
412  should be noninferior to the R product with respect to the MIS, and the T product should show 
413  no meaningful difference, compared to the R product, with respect to the degree of irritation. 
414   
415  2.  Sensitization Analysis 
416   
417  Applicants should define, in the protocol, the PP population for the sensitization analysis per 
418  TDS instead of per subject.  
419   
420  The PP population for the sensitization analysis should include all TDS units worn (without any 
421  period of detachment longer than 24 hours) for the full 21-day induction phase and the entire 48-
422  hour challenge phase.  Each subject should return for at least one of the scheduled evaluations at 
423  48 and 72 hours after removal of the challenge TDS.  If a TDS unit is removed before the end of 
424  the 48-hour challenge phase because of excessive irritation, the application site should be 
425  evaluated at 24 hours, 48 hours, and 72 hours after TDS removal and be included in the 
426  sensitization analysis using the LOCF from the original application site. 
427   
428  For each TDS unit, each PP subject with a combined score of 2 or greater at 48 or 72 hours after 
429  TDS removal during the challenge phase should be individually evaluated for potential 
430  sensitization.  Applicants should consider a subject potentially sensitized if all the following 
431  criteria are met:  
432   
433    The subject has at least one evaluation timepoint occurring at more than 24 hours (e.g., at 
434  48 or 72 hours) after the removal of the challenge phase TDS. 
435   
436    The subject has a combined irritation score of at least 2 at their last evaluation during the 
437  challenge phase. 
438   
439    If the subject completed a rechallenge phase, the above two criteria were met during both 
440  the challenge phase and the rechallenge phase.  
441   
442  Skin reactions that resolve before 48 hours are generally considered to be caused by irritation 
443  instead of sensitization.  For any potential sensitization reaction observed during the challenge or 
444  rechallenge phase, applicants should provide a justification to support that the rate of 
445  sensitization of the T product is comparable to that observed with the use of the R product. 
446   
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447  Applicants should report the respective numbers of subjects considered to be potentially 
448  sensitized to the T and/or R products.  
449   
450  Applicants should provide descriptive statistics comparing both the number and the proportion of 
451  subjects potentially sensitized to each TDS unit and both the number and the proportion of 
452  subjects sensitized to each TDS unit. 
453   
454  Applicants should provide a frequency table showing the number of applications of each TDS 
455  unit during the challenge phase, with each specific combined dermal response numerical score 
456  and other effects letter score at each evaluation time point. 
457   
458  For all subjects with at least one combined irritation score of 2 or more at 48 or 72 hours after 
459  TDS removal in the challenge phase, applicants should provide a table showing the actual scores 
460  for each subject at each evaluation time point during the induction and challenge phases. 
461   
462  In some circumstances, an in vivo sensitization evaluation of a TDS product may be unnecessary 
463  if adequate justification is provided or FDA has determined that conducting a sensitization 
464  assessment is unnecessary or unethical (e.g., where the active ingredient is known to be a skin 
465  sensitizer or based on information/data related to the components and composition of TDS 
466  product) to show that the T product is not likely to be more sensitizing than the R product. 
467   
468  C.  Vehicle TDS and Positive Control TDS 
469   
470  If safety concerns preclude the usual comparative studies, which include the use of the T and R 
471  products, the evaluation of skin I/S by the T product can be evaluated by testing a vehicle TDS 
472  versus a positive control TDS that produces mild irritation (e.g., less than or equal to 0.1 percent 
473  sodium lauryl sulfate).  The vehicle TDS should contain all the inactive ingredients in the T 
474  product and be identical to the T product in every manner except for the absence of the active 
475  ingredient.  If the inactive ingredients in the vehicle TDS are different than those contained in the 
476  T product or are in different amounts than in the T product, then the applicant should clearly 
477  describe the differences and provide data to show that the differences will not affect the safety of 
478  the T product or the applicants interpretation of the study results. 
479   
480  For a skin I/S study that compares the vehicle TDS to a positive control TDS, applicants should 
481  utilize essentially the same approach as is recommended for the comparison of T and R products 
482  in sections IV.A. and B. of this guidance, except that the vehicle TDS should serve as the T 
483  product and the positive control TDS should serve as the R product.  
484   
485  Applicants should ensure that the positive control is consistently able to elicit and maintain an 
486  irritation response during the induction phase.  A positive control that is either unable to 
487  consistently elicit an irritation response, or unable to maintain that response, may confound the 
488  interpretation of study results and undermine the validity of the study. 
489   
490  It is not recommended to include multiple candidate positive control TDS products in the I/S 
491  study and post-hoc select one as the positive control TDS to compare with the vehicle TDS in the 
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492  statistical analysis.  Rather, it is recommended to pre-select one appropriate positive control to 
493  use as the positive control TDS prior to the I/S study. 
494   
495  D.  Partial (Cut) TDS 
496   
497  If a safety concern prevents the simultaneous application of two whole TDS on the same subject 
498  during the 21-day combined I/S study, a matrix TDS can be cut to a smaller size.15  In such 
499  situations, the T and R products should both have designs that can be safely cut to a smaller size.  
500  Applicants should not manufacture a separate batch of product to use a smaller TDS in this 
501  study.  When using a cut TDS, the general recommendations provided in sections IV.A and IV.B 
502  in this guidance apply. 
503   
504   
505  V.  OVERALL ASSESSMENT OF ADVERSE EVENT DATA 
506   
507  Applicants should include, in their analysis, all subjects who receive at least one dose of TDS.  
508  This analysis should include a comparison of all TDS units (e.g., the T product and the R 
509  product) with respect to any application site adverse events.  Applicants should report all adverse 
510  events, including systemic adverse events.  For any application site related adverse events, 
511  applicants should report whether or not the adverse event is related to the T product or the R 
512  product.  
513   
514  Applicants should document, in their study report, all application site reactions (including subject 
515  complaints such as dryness, itching, burning, pain, or soreness) separate from the dermal 
516  response and other effects scores.  In addition, applicants should include details about any 
517  application site to which the complaint applies.  The study report should also include a frequency 
518  table listing application site reactions and comparing the severity of application site reactions 
519  between the T product and the R product.   
520   
521   
522  VI.  FORMAT OF DATA SUBMISSIONS 
523   
524  Applicants should refer to the Study Data for Submission to CDER web page16 for information 
525  about data standards.  
526   
527  Applicants should provide SAS transport data sets in XPT format with the define file.  If 
528  applicants apply imputation, they should submit both raw data and the analysis data after the 
529  imputation.  
 
15 The recommended cut size for a matrix TDS is product specific and included in the relevant PSG.  
 
16 Available at https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/study-data-submission-cder.  
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