Assessment of Adhesion for 
Topical and Transdermal 
Systems Submitted in New 
Drug Applications 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Margaret Kober at 301-796-0934.  
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
July 2021 
Clinical/Medical 
 
38107412dft.docx 
06/29/21   
Assessment of Adhesion for 
Topical and Transdermal 
Systems Submitted in New 
Drug Applications 
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) 
 
 
July 2021 
Clinical/Medical 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION ........................................................................................... 1 
II.  BACKGROUND.............................................................................................. 2 
III.  EVALUATING ADHESION ........................................................................... 2 
A.  Selecting the Trial Drug Product and Conducting an Adhesion Trial ..................... 2 
B.  Inpatient Clinical Wear Trial Design ................................................................... 3 
C.  Data Assessment ................................................................................................ 5 
D.  Other Trial Design Considerations ...................................................................... 6 
APPENDIX:  FORMAT OF DATA SUBMISSION ................................................... 8 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Assessment of Adhesion for Topical and Transdermal Systems 
2  Submitted in New Drug Applications 
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 clinical trials designed to assess the adhesion 
18  performance of transdermal and topical delivery systems (collectively referred to as TDS). 
19  Adhesion performance is defined in this guidance as whether the TDS fully adheres to the 
20  subject in the applied location for the duration of use of the TDS. Adhesion performance can 
21  affect both safety and effectiveness of TDS products because adhesion failures can result in 
22  reduced effectiveness caused by suboptimal dosing or potentially increased exposure when a new 
23  TDS needs to be applied sooner than the scheduled dose. Additionally, partial or full detachment 
24  of a TDS from a patients skin may result in unintentional exposure of the active pharmaceutical 
25  ingredient to a partner, child, or other individual, potentially exposing them to the drugs 
26  toxicity. Adhesion performance may also inform the Dosage and Administration section of 
27  labeling. 
28   
29  The recommendations in this guidance relate to studies to be submitted in support of a new drug 
30  application (NDA) or supplemental new drug application (sNDA) for human prescription and 
31  nonprescription drug products under Section 505 of the Federal Food, Drug, and Cosmetic Act 
32  (21 U.S.C.  355) and 21 CFR Part 314. Because biological products are often more complex 
33  and of a higher molecular weight, it is likely that these products would not be absorbed across 
34  the skin, requiring a different approach for administration, so they are outside the scope of this 
35  guidance. 
36   
37  Sponsors are encouraged to contact the appropriate clinical review division in advance of 
38  conducting these adhesion performance studies to discuss specific design and methodology 
39  issues. 
40   
 
1 This guidance has been prepared by the Office of New Drugs in the Center for Drug Evaluation and Research 
(CDER) and CDERs Office of Pharmaceutical Quality, Office of Translational Sciences, and Office of Generic 
Drugs at the Food and Drug Administration. 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
41  The contents of this document do not have the force and effect of law and are not meant to bind 
42  the public in any way, unless specifically incorporated into a contract. This document is intended 
43  only to provide clarity to the public regarding existing requirements under the law. FDA 
44  guidance documents, including this guidance, should be viewed only as recommendations, unless 
45  specific regulatory or statutory requirements are cited. The use of the word should in Agency 
46  guidances means that something is suggested or recommended, but not required. 
47   
48   
49  II.  BACKGROUND 
50   
51  Transdermal delivery systems are designed to deliver an active pharmaceutical ingredient across 
52  the skin and into systemic circulation, whereas topical delivery systems are designed to deliver 
53  the active ingredient to local tissue.2 The amount of drug delivered into and through the patients 
54  skin from a TDS depends, in part, on the surface area in direct contact with the TDS. The TDS 
55  should remain consistently and uniformly adherent to the patients skin throughout the duration 
56  of wear. During the products wear period, a TDS is reasonably expected to encounter torsional 
57  strains arising from body movements, changes in environmental temperature or humidity such as 
58  daily exposure to water (e.g., during routine showering), and contact with clothing, bedding, or 
59  other surfaces. When a TDS loses its adhesion during wear, the amount of drug delivered to the 
60  patient may be reduced, potentially compromising effectiveness.  
61   
62  TDS development has evolved over the years, especially with respect to expected adhesion 
63  performance. TDS products developed today may use technologies that were not available when 
64  the first TDS products were approved. This guidance takes these developments into 
65  consideration. When final, this draft guidance will expand upon the recommendation for in vivo 
66  adhesion studies in section V., Special Topics, subsection A., Product Adhesion Considerations, 
67  in the draft guidance for industry Transdermal and Topical Delivery Systems  Product 
68  Development and Quality Considerations (November 2019).3 
69   
70   
71  III.  EVALUATING ADHESION 
72   
73  A.  Selecting the Trial Drug Product and Conducting an Adhesion Trial 
74   
75  Sponsors should conduct an in vivo clinical adhesion trial as outlined in sections B and D of this 
76  guidance as part of an NDA or sNDA in certain circumstances. Examples include, but are not 
77  limited to, the following: 
78   
 
2 Topically administered liquid and semisolid drug products (e.g., gels, creams, lotions, foams, ointments, or sprays) 
are not considered to be TDS and are not covered by this guidance, even though they can be formulated to provide 
local, or in some cases, transdermal delivery of the drug. 
 
3 See the draft guidances for industry Transdermal and Topical Delivery Systems  Product Development and 
Quality Considerations and Assessing Adhesion With Transdermal and Topical Delivery Systems for ANDAs 
(October 2018). When final, these guidances will represent the FDAs current thinking on these topics. 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. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
79    A new TDS submitted in an NDA 
80   
81    An sNDA for an approved TDS proposing a different population, application site or sites, 
82  wear time, or higher strength from the approved conditions of use 
83   
84    A postapproval change to a TDS, such as a reformulation, change in excipient, or change 
85  in critical process parameters that may affect adhesion unless there is strong scientific 
86  justification for why another trial is not needed4  
87   
88  Sponsors should use the following criteria to select the product for the adhesion trial: 
89   
90    Use the proposed commercial product 
91   
92    Studying a placebo formulation is not appropriate because the active pharmaceutical 

93  ingredient can influence the adhesive properties of the finished product. 
94   
95    Altering the product design, the qualitative or quantitative composition, or the 

96  manufacturing process can affect the adhesion properties of a TDS. 
97   
98    Use the largest proposed size of the proposed commercial TDS. 
99   
100    A larger TDS may be more sensitive to detachment than a smaller one because a 

101  larger TDS may be subjected to greater conformational and torsional strains arising 
102  from increased anatomical curvatures or a greater magnitude of flexion across a larger 
103  sized product.  
104   
105  B.  Inpatient Clinical Wear Trial Design 
106   
107  Sponsors should conduct an inpatient clinical wear trial as outlined in this section and, when 
108  appropriate, an outpatient clinical trial using patient diary data (as outlined in section D). The 
109  inpatient clinical wear trial may be conducted as a dedicated trial or in conjunction with a 
110  planned pharmacokinetic trial. Sponsors should account for the following product application 
111  and wear techniques when designing and conducting the inpatient clinical wear trial:  
112   
113    The use of overlays or taping of the edges of the system should be prohibited. 
114   
115    The product should be applied to the proposed application site or sites. 
116   
117    In cases where multiple anatomical application sites are proposed for the products 

118  use: 
119   
 
4 Only in rare instances, such as the addition of a new manufacturing site, would a noninferiority adhesion study 
design similar to that outlined in the draft guidance for industry Assessing Adhesion with Transdermal and Topical 
Delivery Systems for ANDAs apply. 
 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
120    Sponsors should study the anatomical site or sites of greatest expected torsional 
121  strain and/or potential to be impacted by clothing or changing of clothes (e.g., for 
122  multiday wear products where clothing may stick to the edges and cause partial 
123  detachment). If a TDS is reformulated in response to previously noted issues with 
124  adhesion and multiple anatomical sites are permitted, sponsors should ensure that 
125  subjects apply the TDS to the sites that have been reported to have the most 
126  adhesion issues. 
127   
128    If the product is proposed to be used at multiple anatomical sites, sponsors should 
129  make additional evaluations at more than one anatomical site. 
130   
131    The application site should be prepared in a manner consistent with the proposed use of 
132  the TDS. 
133   
134    Subjects should not apply makeup, creams, lotions, powders, or other topical products 

135  to the skin area where the TDS is to be placed. 
136   
137    Hair at the application site should be clipped (not shaved) before TDS application. 

138  Shaving is not recommended because of the possibility of resulting skin abrasion. 
139   
140    The subjects movements should not be restricted during the trial. Subjects should be 
141  allowed to freely conduct normal activities and wear normal attire within the trial unit or 
142  facility site. 
143   
144    For products with a wear period of 24 hours or more, subjects should be permitted to 
145  bathe or shower routinely during the trial. 
146   
147    The TDS should not be protected (e.g., do not apply a water-resistant covering over 

148  the product) or wholly excluded from direct exposure to water (e.g., do not restrict 
149  bathing to only a sponge bath) during such routine activities. 
150   
151    Activities that are thought to potentially impact adhesion, including bathing or 

152  showering, should be recorded for each subject (i.e., activity, duration, and timing 
153  relative to TDS application). 
154   
155    Deliberate actions with the intent to reapply or reattach a detached area of the TDS, to 
156  apply pressure to the TDS, or to inappropriately inhibit detachment (e.g., by the constant 
157  pressure of a chair back on the TDS) should be prohibited. 
158   
159  Sponsors should include the following adhesion assessment techniques: 
160   
161    Adhesion should be evaluated at multiple, equally spaced time points following TDS 
162  application throughout the wear period. The adhesion of a TDS with a 7-day wear period 
163  should be assessed at least daily; the adhesion of a TDS with a 72-hour wear period 
164  should be assessed at least every 12 hours; and the adhesion of a TDS with a wear period 
165  of 24 hours or less should be assessed at least every 4 hours. 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
166   
167    Adhesion should be assessed in person by a trained observer, and measurements or 
168  assessments of adhesion should be based on an estimate of the percentage of the total 
169  surface area that is adhered to the skin. 
170   
171    With each consecutive measurement, observers should record the percentage based 

172  upon the actual measurement at each time point with the observer blinded to the 
173  previous recorded percentage finding.  
174   
175    For a product that fully detaches (i.e., 0 percent adhered), the time of detachment 

176  should be recorded, and 0 percent should be assigned for that and all remaining time 
177  points. 
178   
179    To assist in objectively estimating the percentage of adhesion, sponsors may use aids 

180  such as grids or dot matrices; however, provisions in the protocol should ensure 
181  tactile pressure is not applied to the TDS during the observations. 
182   
183    At each adhesion assessment time point, sponsors should also record photographic 

184  evidence showing the extent of TDS adhesion to the skin. This additional 
185  photographic information generally supports the visual observation of percentage of 
186  adhesion and is not intended to be used for automated or photometric analysis. 
187   
188  C.  Data Assessment 
189   
190  Sponsors should conduct a statistical evaluation, as outlined below, in conjunction with other 
191  information (e.g., photographs, trends, narratives, and patient diaries), and the impact of the 
192  findings on effectiveness and safety should be considered as part of the benefit-risk framework.5 
193   
194  The statistical assessment should consider the following: 
195   
196    The statistical analysis for adhesion should be performed for the prespecified per-
197  protocol population. The adhesion analysis should include all TDS except those that were 
198  intentionally removed early in the trial (e.g., because of unacceptable irritation) or 
199  subjects who discontinued use of the TDS before the end of the proposed duration of 
200  wear for reasons unrelated to adhesion (e.g., because of a protocol violation or an adverse 
201  event). Sponsors should include individual case reports describing any subjects who were 
202  excluded from the per-protocol population, and the reasons for their exclusion, in the trial 
203  report. 
204   
205    Let p denote the probability that a randomly selected TDS maintains at least % of a 
206  TDSs total surface area adhesion during its entire wear period. In general,  should be at 
207  least 75. 
 
5 See Benefit-Risk Assessment in Drug Regulatory Decision-Making: Draft PDUFA VI Implementation Plan (FY 
2018-2022) available at https://www.fda.gov/media/112570/download. Also, see the appendix at the end of this 
document for guidance for formatting and submitting statistical information for NDA adhesion studies. 
 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
208   
209    p is estimated by the proportion of TDS in the wear trial that maintains a surface area 
210  adhesion of at least % at every time point. 
211   
212    A statistical assessment of the adhesion of a TDS should be evaluated via the following 
213  hypothesis test: 
214   
215    versus   

216     should be set at no less than 0.80 

217    HH0: ipps rejppec0t ed if thHHe 19:5pp%> loppw0er confidence limit for p is greater than   

218    pp0
219    SpoHHns0ors should specify how the 95% lower confidence limit is calculateppd0 and provide 
220  justification for the chosen method. 
221   
222    Sponsors should enroll a sufficient number of subjects to ensure at least 80% power. 
223  FDA generally recommends using a larger sample size than that calculated under 
224  standard assumptions to ensure the intended power can be maintained to account for 
225  dropouts and noncompliance. 
226   
227  Depending on the proposed indication and drug safety profile, TDS assessments may warrant 
228  a higher threshold for either  or  than outlined above. Sponsors should discuss the 
229  thresholds with the clinical division before conducting the trial. 
230    pp0 
231  D.  Other Trial Design Considerations 
232   
233  Although the inpatient setting of a clinical wear trial informs the adhering capability of the TDS, 
234  the actual user experience may differ. Therefore, in addition to the clinical wear trial described 
235  above, if subsequent larger clinical trials are conducted (e.g., a phase 2 or phase 3 trial), sponsors 
236  should collect information on product adhesion. Sponsors should obtain this information by 
237  using patient diaries describing their user experience with product adhesion. This information is 
238  especially important when a novel transdermal or topical system is being studied, when the TDS 
239  contains a drug substance (e.g., an opioid) that has a higher risk associated with accidental 
240  exposure, or when the clinical wear trial may not adequately capture use in the intended 
241  population. The following information should be included in the diaries in these trials: 
242   
243    Subjects should record the application site in their diaries. 
244   
245    Subjects should record multiple, equally spaced timed assessments throughout the wear 
246  period. 
247   
248    Subjects should estimate the percentage of surface area adhered and record the 
249  percentage in their diaries. Sponsors should provide clear instructions to subjects on how 
250  to determine the percentage of surface area. Alternative methodologies to collect the 
251  percentage surface area in diaries can be considered, but sponsors should first discuss the 
252  approach with the appropriate review division. 
253   
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
254    Subjects should record how often (i.e., the date and time) they pressed the detached parts 
255  back on, smoothed the product out over the wear period, removed their TDS, or replaced 
256  their TDS.  
257   
258    Subjects should record the time and date of any unscheduled TDS placement or 
259  replacement and the reason (e.g., It was itching, I preferred a different location on my 
260  body, It fell off).  
261   
262    If a subject removes the TDS for localized discomfort, the time should be recorded and 
263  the site photographed if possible by the subject or caregiver. 
264   
265    Subjects should record in diaries those events associated with daily activities that may 
266  impact adhesion, such as the following: 
267   
268    Shower, bath, or water immersion (e.g., swimming) 

269   
270    Activities that caused sweating (e.g., strenuous exercise, mowing the lawn) 

271   
272    Subjects should record localized issues encountered during wear (e.g., itching or burning, 
273  difficulty removing from the body, adhesive residue after TDS removal from site or 
274  sites). Sponsors should designate a specific electronic case report form (eCRF) module 
275  that collects this adverse-event information (i.e., type/appearance of local reaction, 
276  duration, intensity, additional local symptoms, outcome (resolved, ongoing, trial drug 
277  interrupted, patient continuing in trial, patient withdrawn from trial, etc.)). 
278   
7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
279  APPENDIX:  FORMAT OF DATA SUBMISSION 
280   
281  Sponsors should submit trial data in standardized format and refer to the FDA web page on 
282  Study Data for Submission to CDER and CBER1 for more information about trial data standards. 
283  In addition, sponsors should provide SAS transport datasets in XPT format with the define file. If 
284  imputation is applied, sponsors should also submit analysis data after the imputation. The 
285  information should be submitted in Module 5 of the electronic common technical document. 
286   
287  For ease of evaluation, sponsors should submit an Excel, csv, or XPT file with each row 
288  representing the observations of the percentage of adhesion of a TDS on a subject for all subjects 
289  in the per-protocol population, including subject ID, application site, actual date and time of each 
290  evaluation, and percentage of adhesion at the time of each evaluation. Sponsors may omit 
291  application site information if a single application site is used in the trial. An example is shown 
292  in the table below. 
293   
Subject  Application  Date and  Percentage  Date and  Percentage 
ID  site  time of first  of adhesion  time of  of adhesion 
evaluation  of first  second  of second 
evaluation  evaluation  evaluation 
XXX  Site 1  YYYY- XX%  YYYY- XX% 
MM-DD:  MM-DD: 
hh:mm  hh:mm 
294   
 
1 The web page is available at https://www.fda.gov/industry/study-data-standards-resources/study-data-submission-
cder-and-cber. 
8