Assessing Adhesion 
With 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DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 2 
38572479dft.docx 
4/10/2023   
Assessing Adhesion 
With 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 2 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 3 
III.  EVALUATION OF ADHESION..................................................................................... 3 
A.  Study Design and Conduct ............................................................................................................ 3 
B.  Considerations for Statistical Analysis ........................................................................................ 8 
IV.  COMBINED EVALUATION OF ADHESION AND BIOEQUIVALENCE ............. 9 
V.  FORMAT OF DATA SUBMISSION ............................................................................ 10 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Assessing Adhesion With Transdermal  
2  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 as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  This guidance provides recommendations for the design and conduct of studies evaluating the 
18  adhesion performance of a transdermal or topical delivery system (collectively referred to as 
19  TDS2). The recommendations in this guidance relate to studies submitted in support of an 
20  abbreviated new drug application (ANDA).3 Depending on the objectives of a generic TDS 
21  product development program, applicants may choose to evaluate TDS adhesion in studies 
22  performed to evaluate TDS adhesion only, or in studies performed with a combined purpose 
23  (e.g., for the simultaneous evaluation of adhesion and bioequivalence (BE) with pharmacokinetic 
24  (PK) endpoints).  
25   
26  In this guidance, the letter T (representing Test) refers to proposed generic products that are the 
27  subject of an ANDA, and the letter R (representing Reference) refers to a reference listed drug 
28  (RLD) and/or reference standard product. 
 
1 This guidance has been prepared by the Office of Research and Standards in the Office of Generic Drugs in the 
Center for Drug Evaluation and Research (CDER) in cooperation with CDERs Office of New Drugs and Office of 
Pharmaceutical Quality at the Food and Drug Administration.  
 
2 The abbreviation 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 TDS adhesion in a new drug application or a supplemental new 
drug application may be different from those submitted in support of an ANDA and may involve the assessment of 
different ages and strengths of the TDS product, potentially dosed to different anatomical sites. Also, the design, 
conduct, and assessment of TDS adhesion in studies supporting a new drug application are inherently different 
because TDS adhesion in that context is not typically evaluated in relation to a reference product. See the draft 
guidance for industry Assessment of Adhesion for Topical and Transdermal Systems Submitted in New Drug 
Applications (July 2021) for further details. When final, this guidance will represent FDAs current thinking on this 
topic. 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-fdaguidance-documents. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
29  FDA recommends that applicants consult this guidance in conjunction with any relevant product-
30  specific guidances4 and in conjunction with any relevant guidances for industry,5 when 
31  considering the design and conduct of studies that may be appropriate to support the BE of a 
32  proposed generic TDS product to its RLD. FDA also recommends that applicants routinely refer 
33  to FDAs website,6 because additional guidances may become available that could assist in the 
34  development of a generic TDS product.  
35   
36  FDA encourages an applicant, who seeks to use an alternative approach to FDAs 
37  recommendations in the relevant product-specific guidance for the design and conduct of studies 
38  evaluating the adhesion performance of a TDS, to contact the Agency to discuss the proposed 
39  alternative approach to evaluate adhesion performance for that particular drug product.7  
40   
41  This guidance revises the draft guidance for industry Assessing Adhesion With Transdermal and 
42  Topical Delivery Systems for ANDAs issued in October 2018. This revision clarifies the 
43  appropriate methods for measuring the estimated percentage of the entire TDS surface area 
44  adhered to the skin and the statistical analysis of that data. Applicants are also encouraged to 
45  explore the use of alternative scales (other than the five-point adhesion scale described in section 
46  III.A., Study Design and Conduct) to estimate adhesion of the TDS to the skin and to discuss 
47  these alternative scales with FDA in a pre-ANDA meeting.8 Additionally, this revision clarifies 
48  that use of photographic evidence is not intended for automated or photometric analysis at this 
49  time but can be used to support the visual observation of percent adhesion reported at each time 
50  point. 
51   
52  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
53  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
54  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
55  the word should in Agency guidance means that something is suggested or recommended, but 
56  not required.  
57   
 
4 Generic drug product-specific guidances are available at the Product-Specific Guidances for Generic Drug 
Development web page 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 the Irritation and Sensitization 
Potential of 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 For newly posted draft guidances, or the most recent version of a guidance, check the FDA Drugs guidance web 
page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
7 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 
guidance for industry Controlled Correspondence Related to Generic Drug Development (December 2020) and the 
guidance for industry 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. 
 
8 See footnote 7. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
58   
59  II.  BACKGROUND 
60   
61  The amount of drug delivered by a TDS into and through the patients skin is dependent, in part, 
62  on the surface area dosed. The entire contact surface area of a TDS should remain consistently 
63  and uniformly adhered to the patients skin throughout the duration of wear under the conditions 
64  of use included in the RLD labeling. When a TDS loses its adhesion during wear, the amount of 
65  drug delivered to the patient may be reduced.   
66   
67  During the RLDs labeled wear period, a TDS is reasonably expected to encounter torsional 
68  strains arising from body movements; changes in environmental temperature or humidity such as 
69  the daily exposure to water (e.g., during routine showering); and contact with clothing, bedding, 
70  or other surfaces. TDS products that do not maintain consistent and uniform adhesion with the 
71  skin during the RLD labeled wear period can experience varying degrees of TDS detachment, 
72  including complete detachment, at different times during the product wear.   
73   
74  When the adhesion characteristics of a TDS are not sufficiently robust, as evaluated against the 
75  RLDs labeled conditions of use, the TDS may exhibit variability in the surface area that is in 
76  contact with the skin. For example, when a TDS is partially detached, there may be uncertainty 
77  about the resulting drug delivery profile and, hence, uncertainty about the rate and extent of drug 
78  absorption from the TDS, potentially affecting FDAs evaluation of bioequivalence for a 
79  proposed generic drug product. When the potential for complete detachment of the TDS 
80  increases, the risk of unintentional exposure of the drug product to an unintended recipient (e.g., 
81  a household member who may be a child) also increases.  
82   
83   
84  III.  EVALUATION OF ADHESION 
85   
86  A.  Study Design and Conduct 
87   
88  In general, the Agency recommends that applicants design their adhesion studies to support a 
89  comparative evaluation of the adhesion characteristics of the T and R TDS. 
90   
91  FDA recommends that applicants use a single-dose, randomized, two-treatment, two-period 
92  crossover study design where all subjects are dosed with the same strength of the T and R TDS. 
93  However, FDA may also consider the acceptability of a study using a single-period, two-
94  treatment-per-subject design (e.g., a matched pairs study), with the site of application 
95  randomized, if applicants appropriately justify such a study design. The population for the TDS 
96  adhesion study should typically be the same as the population enrolled, or recommended for 
97  enrollment, in the PK BE study for the product and should typically include healthy males and 
98  non-pregnant, non-lactating females unless product-specific considerations indicate otherwise.   
99    
100  Applicants should randomize subjects to receive either the T or R TDS product in a given study 
101  period. When possible, the TDS administered in the second study period should be applied to the 
102  same anatomical site as in the first study period, but on the contralateral side of the body.  
103   
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104  Because alterations in the product design, the active or inactive ingredients, the backing 
105  membrane, or the manufacturing process can affect the adhesion properties of a TDS, the study 
106  should use the to-be-marketed TDS product.  Postapproval changes to the TDS may necessitate 
107  confirmation that product quality attributes related to adhesion remain consistent with the 
108  product quality attributes characterized for the TDS product that demonstrated acceptable 
109  adhesion in the original ANDA approval. 
110   
111  Unless otherwise justified, when conducting an adhesion study, applicants should use the 
112  specific size/strength of the TDS that is recommended in the applicable product-specific 
113  guidance. A larger TDS may be more sensitive to detachment than a smaller one because the 
114  larger TDS may be subjected to greater conformational or torsional strains arising from 
115  potentially increased anatomical curvatures or from a greater magnitude of flexion across 
116  relatively greater anatomical distances across which the larger TDS may be adhered. It may also 
117  be possible for applicants to assess an adhesion score more precisely with a larger TDS than with 
118  a smaller one.  Applicants should not use an overlay or a cover for blinding because the overlay 
119  or cover may affect the products performance. 
120   
121  Applicants should evaluate the adhesion of each TDS at multiple time points following 
122  application of the TDS to provide sufficient temporal resolution to adequately compare the 
123  adhesion characteristics of the T and the R TDS throughout the duration of wear. For example, 
124  the adhesion of a TDS with a 7-day wear period should be assessed at least daily and at equally 
125  spaced time points (e.g., 24 hours (hrs), 48 hrs, 72 hrs, 96 hrs, 120 hrs, 144 hrs, and 168 hrs); the 
126  adhesion of a TDS with 72-hour wear period should be assessed at least every 12 hours (e.g., at 
127  12 hrs, 24 hrs, 36 hrs, 48 hrs, 60 hrs, and 72 hrs); the adhesion of a TDS with a wear period 
128  between 12 and 24 hours should be assessed at least every 4 hours; and the adhesion of a TDS 
129  with a wear period of less than 12 hours should be assessed at least hourly.  
130   
131  In addition, applicants should typically distribute these time points in a uniform manner, equally 
132  spaced throughout the entire RLDs labeled wear period because the mean adhesion score that is 
133  calculated from the individual assessments is intended to be representative of the entire wear 
134  period. For some TDS, adhesion during the earlier period of wear may be better than during the 
135  later period of wear; therefore, a greater number of adhesion assessments early in the TDS wear 
136  period may (1) disproportionately weight the calculation of the mean adhesion score by over-
137  representing the adhesion assessments during the initial period when TDS adhesion might be 
138  relatively better and (2) inappropriately decrease the mean adhesion score in a manner that is not 
139  representative of the entire wear duration for that TDS.  Applicants should calculate the mean 
140  adhesion score according to the recommendations described later on in this section. 
141   
142  When recording measurements of TDS adhesion, applicants may use appropriate methods (e.g., a 
143  trained visual assessment and/or dot matrix templates) and alternative scales (other than the five-
144  point adhesion scale described below) to estimate the percentage of the entire TDS surface area 
145  that is adhered to the skin. If applicants use a scale different from the five-point adhesion scale 
146  described below to record TDS adhesion measurements, they should report each TDS adhesion 
147  measurement as both the score according to the selected scale, as well as the corresponding score 
148  according to the five-point adhesion scale. For example, if the observer scores the TDS adhesion 
149  as a two on the five-point scale and estimates that the product appears to be 60 percent adhered, a 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
150  score of two and the estimate of 60 percent should both be reported for that time point. 
151  Information and/or analyses based upon scores from the alternative scale may be considered, 
152  provided that the use of the alternative scale is justified, and that information is submitted with 
153  the study to demonstrate that the scale has been adequately qualified. 
154   
155  For the comparative assessment of adhesion (i.e., for the noninferiority (NI) test described in 
156  section III.B.), applicants should use the following five-point adhesion scale, in which each score 
157  corresponds to a specified range of adhered surface area for the TDS:   
158   
159  Scale for Scoring the Comparative Assessment of Adhesion 
Score  Range of Adhered Surface Area for the TDS 
0   90% adhered (i.e., the TDS has essentially no lift off the skin) 
1   75% to < 90% adhered (e.g., only some edges of the TDS lift off the skin) 
2   50% to < 75% adhered (i.e., less than half of the TDS lifts off the skin) 
3  > 0% to < 50% adhered (i.e., the TDS is not detached, but more than half of it lifts off 
the skin without falling off) 
4  0% adhered (i.e., the TDS is detached and is completely off the skin) 
160   
161  At each adhesion assessment time point, applicants should also record photographic evidence 
162  showing the extent of TDS adhesion to the skin. Because percent adhesion can span a range and 
163  yet be classified as a single score, the photographic evidence can be used to support the visual 
164  observation of the percent adhesion reported at each time point but is not intended to be used for 
165  automated or photometric analysis at this time.    
166   
167  With each consecutive TDS adhesion measurement at each time point, applicants should record 
168  the score based upon the actual measurement of TDS adhesion at that time point (not carrying 
169  forward a score from a previous time point), regardless of whether the score increases or 
170  decreases relative to the preceding score. Successive TDS adhesion measurements should be 
171  made independent of the previous measurement, with the observer blinded to the previous 
172  measurement.  
173   
174  However, when analyzing the results for the comparative assessment of adhesion (i.e., for the NI 
175  test described in section III.B.), the highest adhesion score using the five-point adhesion scale 
176  described above (i.e., the score representing the greatest degree of detachment for that TDS) 
177  assessed at any time point after the baseline or time  should be used for subsequent time points 
0
178  until a higher score is assessed. For example, if the adhesion scores are 1, 2, 1, 3, then the 
179  imputed adhesion scores would be 1, 2, 2, 3. For a TDS that completely detaches, a score of 4 
180  should be assigned for any remaining assessments scheduled for that TDS across the study 
181  duration. 
182   
183  Applicants should use the mean adhesion score,  , as the primary endpoint for evaluating TDS 
184  adhesion. For a TDS, the mean adhesion score,  , should be derived from its individual adhesion 
185  scores at each assessment time point, averaged acXXross all the equally spaced time points (except 
186  the baseline time point, t ). Let  denote the obsXXerved mean adhesion score for a TDS across   
0
187  equally spaced time points after the baseline. It can be calculated as follows: 
xx  nn
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188  nn  
189  xx =   xxiinn
ii=1
190  Here,  is the observed mean adhesion score for a TDS across equally spaced time points after 
191  the baseline and   is the observed adhesion score at the ith measurement, or the highest observed 
192  score uxxp  to the ith measurement for a TDS as previously discussed. 
193    xxii
194  Although the recommendation in this guidance is to distribute time points in a uniform, equally 
195  spaced manner, if the data set contains scores from unequally spaced time points, a weighted 
196  average  , with weights corresponding to interval length, may be calculated as follows:   
197   
XXww
198    , where   
nn
199    nn ii=1(ttiittii1)xxii (ttiittii1)
xxww = ii=1wwiixxii = DD wwii = DD
200  Here,  is the observed weighted mean adhesion score for a TDS across   unequally spaced 
201  time points after the baseline;   is the observed adhesion score at the ith measurement;   is the 
202  corresxxpowwn ding weight for  ;  is the total duration of wear;   is the ith mennasurement time; and 
203   is the preceding (i-1)th mexxaiisurement time. Because of the potential round-off error wwofii 
204  computer software, FDA rxxeiicoDDm mends that applicants calculatttiie the sum in the numerator first, 
205  ttii1 , and then divide that sum by the total duration D. 
206    nn
207  Foii=r 1e(xttaiimpttliie, 1f)oxxr iia 24-hour-wear TDS, if an applicant measured adhesion at hours 2, 4, 8, 12, and 
208  24 after the baseline, the total duration of wear would be 24 hours. The coefficient   
209  corresponding to the ith measurement   (i = 1, 2, 3, 4, 5) would be (2-0), (4-2), (8-4), (12-8), and 
(ttii ttii1)
210  (24-12), respectively. The weighted mean  can be calculated by summing   
xxii
211  first, then dividing the sum by the total duration D (i.e., in this example, 24 hou5rs). The 
xxww  ii=1(ttii ttii1)xxii
212  corresponding weights for all five measurements would be   and  , which add up to 1. 
1 1 1 1 1
213   
12,12,6,6, 2
214  In addition to the primary endpoint, FDA recommends that applicants use the five-point adhesion 
215  scale described above to perform the following descriptive analyses for the evaluation of TDS 
216  adhesion to assess possible treatment group differences in potentially clinically meaningful 
217  values or events: 
218    
219  1.  Proportion of subjects with an observed adhesion score  2 at any time point, compared 
220  between T and R. 
221   
222  2.  Proportion of subjects with their T mean adhesion score greater than the corresponding R 
223  mean adhesion score by 1 or more, compared to the proportion of subjects with their R 
224  mean adhesion score greater than the corresponding T mean adhesion score by 1 or more. 
225   
226  3.  Time to an observed adhesion score  2 compared between T and R.  If there are a 
227  sufficient number of events, a Kaplan Meier cumulative incidence curve can be plotted. 
228   
229  In addition, applicants should submit descriptive adhesion score data in a frequency table 
230  illustrating the number and the proportion of the T and the R TDS with each adhesion score at 
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231  each evaluation time point and across all time points. An example of such a frequency table is 
232  shown below: 
233   
234  Frequency of Adhesion Scores for a Per-Protocol Population (Hypothetical Data) 
Time  T Score (N=100)  R Score (N=100) 
Point  n (%)  n (%) 
0  1  2  3  4  Mean  0  1  2  3  4  Mean 
1  95  5  0  0  0  0.05  82  16  2  0  0  0.20 
(95)  (5)  (0)  (0)  (0)  (82)  (16)  (2)  (0)  (0) 
2  90  10  0  0  0  0.10  68  30  2  0  0  0.34 
(90)  (10)  (0)  (0)  (0)  (68)  (30)  (2)  (0)  (0) 
3  87  13  0  0  0  0.13  57  41  2  0  0  0.45 
(87)  (13)  (0)  (0)  (0)  (57)  (41)  (2)  (0)  (0) 
4  86  14  0  0  0  0.14  46  51  3  0  0  0.57 
(86)  (14)  (0)  (0)  (0)  (46)  (51)  (3)  (0)  (0) 
5  85  15  0  0  0  0.15  42  55  2  1  0  0.62 
(85)  (15)  (0)  (0)  (0)  (42)  (55)  (2)  (1)  (0) 
All  443   57   0  0   0  0.11  295  193  11  1  0  0.44 
(88.6)  (11.4)  (0)  (0)  (0)  (59.0)  (38.6)  (2.2)  (0.2)  (0) 
235   
236  Applicants should note that both the T and the R TDS should be administered to study subjects 
237  in the manner described by the RLD label, and TDS adhesion should be assessed throughout the 
238  maximum labeled duration of wear for the RLD. In general, movement of study subjects should 
239  not be restricted during the study; instead, subjects should be allowed to freely conduct normal 
240  activities within the study unit and/or at home (e.g., to perform real-world activities like 
241  showering) that may reasonably be expected to occur during the labeled duration of use for the 
242  product. For products with a wear period of up to or greater than 24 hours, FDA recommends 
243  that subjects be permitted to bathe or shower routinely during the study, in a manner consistent 
244  with the labeled use of the RLD, and that the TDS should not be protected from direct exposure 
245  to water during such routine activities.   
246   
247  Generally, applicants should use only whole, intact T and R TDS for their assessment of 
248  comparative adhesion performance because altering the size or shape of the TDS may alter its 
249  adhesion characteristics. 
250   
251  Applicants should include provisions in their study protocol to ensure that deliberate actions with 
252  the intent to reapply a detached area of the TDS, to apply pressure to the TDS, or to reinforce 
253  TDS adhesion with the skin (e.g., overlays) are avoided throughout the study. The study protocol 
254  should include provisions to ensure that TDS detachment is not inappropriately inhibited (e.g., 
255  by the constant pressure of a chair back on the TDS).  
256   
257  Subjects should not apply makeup, creams, lotions, powders, or other topical products to the skin 
258  area where the TDS will be placed because they could affect adhesion performance. Also, hair at 
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259  the application site should be clipped (not shaved) before TDS application and the site should be 
260  prepared in a manner consistent with the labeled use of the RLD. 
261   
262  Applicants should describe the method of randomization in the study protocol and provide the 
263  randomization schedule as a SAS transport data set in XPT format (note that the randomization 
264  in this context refers to the sequence, not the treatment). FDA recommends that an independent 
265  third party generate and hold the randomization code throughout the conduct of the study to 
266  minimize bias. However, it may be appropriate for applicants to generate the randomization code 
267  if they are not involved in the packaging and labeling of the study medication. Applicants should 
268  ensure that a sealed copy of the randomization scheme is retained at the study site, and this 
269  sealed copy should be available to FDA investigators at the time of site inspection to allow for 
270  verification of the treatment identity for each application site on each subject. 
271   
272  B.  Considerations for Statistical Analysis 
273   
274  Applicants should prespecify the per-protocol (PP) population for the adhesion analysis and 
275  define it per TDS for each subject. The PP population for the adhesion analysis should include 
276  all TDS except those that were intentionally removed early in the study (e.g., because of 
277  unacceptable irritation) or those that were on subjects who discontinued use of the TDS before 
278  the end of the RLDs labeled duration of wear for reasons unrelated to adhesion (e.g., because of 
279  a protocol violation). Applicants should include individual case reports describing any subjects 
280  who were excluded from the PP population, and the reasons for the subjects exclusion, in their 
281  study report. 
282   
283  Applicants should compare the means of the per treatment group mean adhesion scores (i.e., the 
284  primary endpoint described above) for the T and R products. To calculate the mean adhesion 
285  score, applicants should carry forward the highest adhesion score at each time point after the 
286  baseline time point (t ) for subsequent time points until a higher score is assessed. To 
0
287  demonstrate adequate product adhesion, applicants should show that the T product is statistically 
288  noninferior to the R product based upon evaluating the difference in the T and R overall mean 
289  adhesion scores, with an NI margin of 0.15 ( = 0.15). The NI margin of 0.15 applies to the 
290  difference of the mean adhesion scores between the T and R products based on the five-point 
291  adhesion scale previously described; the NI margin of 0.15 does not apply to the difference of 
292  the mean adhesion scores based on other adhesion scales or non-location-based data 
293  transformations (e.g., a logarithmic transformation) or the difference of median adhesion scores 
294  between T and R. 
295   
296  Applicants should test the following hypotheses at the significance level of 0.05: 
297   
298   
299   
300    HH0: TT RR  
301  Here,  and  are the population meanHHs 1f:o r TTthe mRRea<n adhesion score for the T and R products, 
 
302  respectively,and the alternative hypothesis  represents the NI of the T products adhesion 
 
303  relative TTt o the RRR products adhesion.  These hypotheses correspond to the following: 
304       HH1 
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305   
306   
307    HH0: DD  
308  where   is the equal to the difference of thHHe1 p: opDDu<lation means for the mean adhesion score for 
309  the T and R products:  .  When there is no missing data, in a crossover or matched 
310  pairs stuDDdy,   is the same as the population mean for the difference  between the paired T 
DD = TT RR
311  ( and R ( mean adhesion score for individual subject    . 
DD DDjj 
312    
XXjjTT)  XXjjRR)  jj DDjj = XXjjTT XXjjRR,EEDDjj = DD
313  To demonstrate acceptable adhesion of the T product, applicants should design and conduct an 
314  adhesion study as described above and enroll a sufficient number of subjects to power the study 
315  at a level of 0.80 or higher.  Because of the discrete nature of adhesion scales and other potential 
316  complications of the adhesion data, FDA recommends that applicants use a large enough sample 
317  size to ensure the validity of any large-sample (asymptotic) Gaussian assumptions, if used.  
318   
319  Incomplete data and data associated with noncompliance can compromise the validity of an NI 
320  study. FDA recommends good clinical study design and conduct to prevent subject dropout and 
321  noncompliance. Nonetheless, when these events occur, applicants should document the detailed 
322  reasons for these events. Although FDA recommends using the PP population as the primary 
323  analysis population for NI studies, the Agency also has significant concerns with the possibility 
324  of informative dropout and noncompliance. If applicable, applicants should prespecify 
325  imputation methods in their protocol. FDA recommends that applicants conduct a prespecified 
326  sensitivity analysis to evaluate the potential effect of any unbalanced or informative dropout and 
327  noncompliance on the conclusion of the NI in adhesion. 
328   
329   
330  IV.  COMBINED EVALUATION OF ADHESION AND BIOEQUIVALENCE 
331   
332  If applicants elect to conduct a study evaluating both the adhesion performance and the PK BE of 
333  the T and R products in a single study, this study should be conducted in a population of 
334  sufficient size to adequately power the comparative evaluation of adhesion and to include a 
335  subpopulation of subjects of sufficient size to adequately power the evaluation of BE with 
336  appropriately selected PK endpoints. Applicants should select the participants for the PK BE 
337  evaluation according to a scheme prespecified in the protocol. 
338   
339  The study design and conduct recommendations described in section III.A., for a study 
340  performed exclusively for the purpose of evaluating TDS adhesion, also apply to a combined 
341  study evaluating adhesion and BE with PK endpoints.  
342   
343  The simultaneous application of multiple T TDS or of multiple R TDS to a subject may be 
344  appropriate in a combined study of TDS adhesion and PK BE when doing so is safe and justified, 
345  for example, by the potential need for increased drug delivery to compensate for an insufficient 
346  analytical sensitivity to measure the relevant analyte(s) in the PK samples. In such cases, when 
347  multiple TDS are simultaneously applied to a subject, the adhesion performance of each and all 
348  TDS should be assessed.  
349   
  9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
350  Applicants should collect and analyze PK samples from all subjects in the PK subpopulation, 
351  regardless of the subjects TDS adhesion scores, and report the sample concentrations for all 
352  time points as well as the PK results for all subjects in the PK study. All TDS units that are 
353  removed at the end of (or which detach during) the in vivo adhesion and/or PK BE study should 
354  be retained for analysis of residual drug content.9 
355   
356  Applicants should prespecify their inclusion criteria for the statistical analysis of PK endpoints 
357  and perform their primary PK analysis on the relevant population, which may be a subset of the 
358  PP population. We also recommend that applicants refer to the relevant product-specific 
359  guidance for FDAs recommendations on the BE criteria for PK analysis. 
360   
361   
362  V.  FORMAT OF DATA SUBMISSION 
363   
364  Applicants should submit study data in standardized format and refer to the FDA web page on 
365  Study Data for Submission to CDER10 for more information about study data standards.  
366   
367  In addition, applicants should provide SAS transport data sets in XPT format with the define file. 
368  If imputation is applied, applicants should submit both raw data and the analysis data after the 
369  imputation.   
 
9 See the guidance for industry Residual Drug in Transdermal and Related Drug Delivery Systems (August 2011) 
and the draft guidance for industry Transdermal and Topical Delivery Systems  Product Development and Quality 
Considerations (November 2019) (when final, this guidance will represent FDAs current thinking on this topic). 
 
10 This web page is available at https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/study-data-
submission-cder.  
  10