Development of Locally 
Applied Corticosteroid 
Products for the Short-Term 
Treatment of Symptoms 
Associated with Internal or 
External Hemorrhoids 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Benjamin Vali at 301-796-4261.  
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2019 
Clinical/Medical 
   
Development of Locally 
Applied Corticosteroid 
Products for the Short-Term 
Treatment of Symptoms 
Associated with Internal or 
External Hemorrhoids 
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) 
 
 
December 2019 
Clinical/Medical  
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  TRIAL POPULATION .........................................................................................2 
IV.  DEVELOPMENT PROGRAM ............................................................................3 
A.  Trial Design ........................................................................................................................ 3 
B  Efficacy Considerations .................................................................................................... 4 
C.  PRO Endpoints .................................................................................................................. 4 
D.  Safety Considerations ........................................................................................................ 6 
E.  Additional Considerations ................................................................................................ 6 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Development of Locally Applied Corticosteroid Products for the 
2  Short-Term Treatment of Symptoms Associated with Internal or 
3  External Hemorrhoids1 
4  Guidance for Industry 
5   
6   
7   
8   
9  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
10  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
11  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
12  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
13  for this guidance as listed on the title page. 
14   
15   
16   
17   
18  I.  INTRODUCTION  
19   
20  The purpose of this guidance is to assist sponsors in the clinical development of locally applied 
21  corticosteroid products (including suppositories or products that require an applicator) for the 
22  short-term treatment of symptoms associated with internal or external hemorrhoids.  Specifically, 
23  this guidance describes FDAs current thinking regarding the recommended attributes of patients 
24  for enrollment, efficacy assessments, and safety assessments.2 
25   
26  This guidance does not address the clinical development of drugs for the chronic treatment of 
27  signs and symptoms associated with internal or external hemorrhoids or drugs for the treatment 
28  of an underlying disease. 
29   
30  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
31  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
32  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
33  the word should in Agency guidances means that something is suggested or recommended, but 
34  not required. 
35   
36   
                                                 
1 This guidance has been prepared by the Division of Gastroenterology and Inborn Error Products (Division) in the 
Center for Drug Evaluation and Research at the Food and Drug Administration. 
 
2 In addition to consulting guidances, sponsors are encouraged to contact the Division to discuss specific issues that 
arise during the development of products. 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
37  II.  BACKGROUND 
38   
39  Hemorrhoids represent one of the most common medical and surgical disease conditions in the 
40  United States, accounting for over 2.5 million outpatient evaluations per year.3  Hemorrhoids are 
41  dilated arteriovenous connective tissues that are normally present between the anal mucosa and 
42  underlying internal sphincter and are usually categorized as internal or external hemorrhoids 
43  based upon their location with respect to the dentate line. 
44   
45  Because the pathogenesis of hemorrhoids involves anatomic structural changes in the vascular 
46  cushions (hemorrhoidal arteriovenous plexus), surrounding supportive muscles, connective 
47  tissues, and skin, rectal bleeding commonly associated with internal hemorrhoids is unlikely to 
48  be improved with locally applied corticosteroid products.  However, many patients have one or 
49  more additional perirectal symptoms (e.g., itch, discomfort, pain, or burning) because of 
50  secretions from inflamed hemorrhoids that irritate the skin.  These perirectal symptoms are 
51  common in patients with both external and internal hemorrhoids and may be mitigated by locally 
52  applied corticosteroid products. 
53   
54  Fit-for-purpose4  patient-reported outcome (PRO) instruments5 for evaluating symptomatic 
55  treatment response in internal or external hemorrhoids should be identified and agreed upon with 
56  FDA for regulatory use. 
57   
58   
59  III.  TRIAL POPULATION 
60   
61  Sponsors developing locally applied corticosteroid products for the short-term treatment of 
62  symptoms associated with internal or external hemorrhoids should consider the following for 
63  clinical trial populations: 
64   
65    To be enrolled, patients should be sufficiently symptomatic, with a minimum level of 
66  symptomatology (e.g., severity or frequency) to allow observation of a clinically 
67  meaningful improvement.  We recommend that sponsors include a screening period 
                                                 
3 Peery AF, SD Crockett, CC Murphy, JL Lund, ES Dellon, JL Williams, ET Jensen, NJ Shaheen, AS Barritt, SR 
Lieber, B Kochar, EL Barnes, YC Fan, V Pate, J Galanko, TH Baron, and RS Sandler, 2019, Burden and Cost of 
Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2018, Gastroenterology, 156(1):254
272. 
 
4 A conclusion that the level of validation associated with a tool is enough to support its context of use.  See the 
glossary of the Biomarkers, EndpointS and other Tools (BEST) Resource: 
https://www.ncbi.nlm.nih.gov/books/NBK338448/. 
 
5 A PRO is a type of clinical outcome assessment that is a measurement based on a report that comes directly from a 
patient (i.e., trial subject) about the status of a patients health condition without amendment or interpretation of the 
patients response by a clinician or anyone else.  A PRO can be measured by self-report or by interview, provided 
that the interviewer records only the patients response.  Symptoms or other unobservable concepts known only to 
the patient can be measured only by PRO measures.  PROs can also assess the patient perspective on functioning or 
activities that may also be observable by others.  See the glossary of the BEST Resource. 
 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
68  before randomization to document persistence of symptoms and train patients to collect 
69  PRO data appropriately. 
70   
71    As symptoms are more likely to be present in patients with grade 3 or grade 4 internal 
72  hemorrhoids and external hemorrhoids, we recommend that sponsors enroll adequate 
73  numbers of such patients. 
74   
75    Sponsors should diagnose and classify internal hemorrhoids by proctoscopy or anoscopy 
76  and document internal hemorrhoids by photograph or video recording as per clinical 
77  practice guidelines of the American Society of Colon and Rectal Surgeons.6 
78   
79    Patients with perirectal conditions, such as perianal warts, anorectal fistula, and anal 
80  fissure, which may present with perirectal symptoms similar to those accompanying 
81  hemorrhoids (e.g., itch, discomfort, pain, or burning), should be excluded. 
82   
83    Because narcotics use is known to cause constipation and exacerbate symptoms 
84  associated with hemorrhoids and could influence efficacy assessment, sponsors should 
85  exclude patients using narcotics. 
86   
87    Because intake of extra fiber and water could improve constipation and symptoms 
88  associated with hemorrhoids, patients should not make dietary changes before enrollment 
89  and throughout the duration of the trial. 
90   
91   
92  IV.  DEVELOPMENT PROGRAM 
93   
94  A.  Trial Design 
95   
96  Sponsors developing locally applied corticosteroid products for the short-term treatment of 
97  symptoms associated with internal or external hemorrhoids should consider the following for 
98  clinical trial design: 
99   
100    We recommend a multicenter, randomized, double-blind, vehicle-controlled, parallel 
101  group trial design with a prespecified screening period before randomization of patients 
102  to confirm eligibility criteria. 
103   
104    The trial duration and timing of efficacy assessments should be guided by the mechanism 
105  of action of the drug and its expected onset of action and the time frame in which a 
106  clinical benefit is expected to be observed.  We recommend a treatment period of at least 
107  2 weeks duration to assess efficacy. 
108   
                                                 
6 Davis BR, SA Lee-Kong, J Migaly, DL Feingold, and SR Steele, 2018, The American Society of Colon and Rectal 
Surgeons Clinical Practice Guidelines for the Management of Hemorrhoids, Dis Colon Rectum, 61(3):284292. 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
109    Following the randomized treatment phase, there should be a 2- to 3-week follow-up 
110  period off treatment (see section IV. D., Safety Considerations) to assess safety, 
111  durability of response, and the potential need for retreatment. 
112   
113    Where uncertainty exists regarding time to onset of clinical benefit, optimal dosage, and 
114  optimal duration of therapy, we strongly encourage a phase 2 trial to address these issues 
115  before embarking on a large phase 3 program. 
116   
117  B  Efficacy Considerations 
118   
119  Sponsors developing locally applied corticosteroid products for the short-term treatment of 
120  symptoms associated with internal or external hemorrhoids should consider the following 
121  regarding a drugs efficacy: 
122   
123    For the primary endpoints in phase 3 trials, sponsors should identify a response that 
124  represents meaningful improvement from baseline in symptoms, compared with vehicle 
125  control, using a well-defined and reliable PRO instruments endpoint scores. 
126   
127    Statistically significant but small group-level mean differences may not establish whether 
128  the effect is clinically meaningful. 
129   
130    To aid in interpreting the PRO endpoint results, sponsors should propose a range of 
131  thresholds that would constitute a clinically meaningful within-patient score change 
132  using anchor-based methods (e.g., patient global impression of symptom severity 
133  scale as an anchor) in conjunction with empirical cumulative distribution functions 
134  (eCDFs) of individual patient changes in scores using data pooled across trial arms 
135  with separate curves for each anchor response category. 
136   
137    Additionally, sponsors should submit for review a supportive graph (i.e., eCDF) 
138  of within-patient changes in scores from baseline with separate curves for each 
139  treatment arm. The graph will be used to assess whether the treatment effect 
140  occurs in the range that patients consider to be clinically meaningful. 
141   
142  C.  PRO Endpoints 
143   
144  Sponsors developing locally applied corticosteroid products for the short-term treatment of 
145  symptoms associated with internal or external hemorrhoids should consider the following when 
146  selecting a fit-for-purpose PRO instrument: 
147   
148    FDA encourages sponsors to seek FDA input as early as possible and at important 
149  milestones throughout the drug development process to ensure that fit-for-purpose PRO 
150  instruments are included in phase 3 trials.  For general recommendations regarding PRO 
151  instruments and the documents to be provided to FDA for review, see the guidance for 
152  industry relevant to patient-reported outcome measures or clinical outcome assessments. 
153   
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
154    FDA recommends selecting a PRO instrument based on patient input regarding the most 
155  important and bothersome perirectal symptoms of internal or external hemorrhoids (e.g., 
156  itch, discomfort, pain, or burning) and choosing for assessment symptoms that are 
157  expected to improve with the treatment.  FDA encourages sponsors to first explore using 
158  existing PRO instruments for assessing patients symptoms before developing a de novo 
159  PRO instrument. 
160   
161    Examples of patient-reported symptom severity assessment scales that may be fit-for-

162  purpose include an 11-point (i.e., 0 to 10) numeric rating scale or a verbal rating scale 
163  (e.g., none, mild, moderate, severe) that asks patients daily to rate their worst 
164  experience of one or several specific perirectal symptoms (e.g., itch, discomfort, pain, 
165  or burning) over the past 24 hours.  Additionally, a frequency scale for one or more of 
166  these items may also be considered (e.g., ranging from none of the time to all of 
167  the time). 
168   
169    To minimize patient recall error and measurement error, sponsors should use 

170  instruments that are administered daily (e.g., 24-hour recall period) and that focus on 
171  capturing patients symptoms.  Patients should complete the PRO instruments at the 
172  same time each day (e.g., evening before bedtime).  Improvement in, or resolution of, 
173  symptoms should be demonstrated for a meaningful, prespecified duration of time 
174  (e.g., one week), not based solely on a single days assessment. 
175   
176    For newly developed instruments, or existing instruments that have not been 
177  tested in the target patient population, it may be useful for sponsors to test the 
178  appropriateness and clarity of any proposed PRO instruments instructions, recall 
179  period, items, and response options by conducting cognitive interviews with a 
180  number of patients (e.g., 8 to 10 patients) matching the target population to 
181  decrease the possibility of introducing measurement error because of patients 
182  misunderstanding or incomplete understanding of the PRO instruments. 
183   
184    When modifying an existing instrument or developing a new PRO, sponsors 
185  should consider that phase 2 trials should help inform finalization of scoring 
186  algorithms and endpoint definitions.  Piloting the proposed PRO instrument in 
187  phase 2 trials can provide sponsors an opportunity to evaluate the instruments 
188  psychometric properties and performance (reliability, validity, and ability to 
189  detect change) as well as provide guidelines for interpreting clinically meaningful 
190  within-patient change in scores and confirm the endpoint definition.  Pilot results 
191  can further inform plans for implementing the proposed instruments in phase 3 
192  trials. 
193   
194    We recommend that sponsors analyze PRO endpoints as continuous or ordinal 
195  variables, with the choice justified based on the nature of the data, using baseline 
196  values as covariates.  FDA does not recommend a responder analysis endpoint or 
197  a percentage change from baseline endpoint unless the targeted response is 
198  complete resolution of symptoms.  The statistical analysis plan should include 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
199  prespecified alternative approaches for analysis if extreme outliers occur, such as 
200  analyses based on ranks. 
201   
202  D.  Safety Considerations 
203   
204  Sponsors developing locally applied corticosteroid products for the short-term treatment of 
205  symptoms associated with internal or external hemorrhoids should consider the following 
206  regarding safety in clinical trials: 
207   
208    For products being studied over a 2-week course of treatment, we recommend at least one 
209  interim assessment to capture potential adverse events (which can be completed by 
210  telephone) and a minimum follow-up period of 2 to 3 weeks after treatment is 
211  discontinued to adequately assess safety (duration, severity, progression or resolution of 
212  any reported adverse events). 
213   
214    Safety assessment at the end of the trial or at drop-out should include assessing changes 
215  in the perirectal skin, such as thinning or atrophy of skin. 
216   
217    We recommend that hypothalamic pituitary adrenal (HPA) axis suppression potential be 
218  studied by an adrenocorticotropic hormone (ACTH) stimulation test.  The ACTH 
219  stimulation test should be performed at preestablished time points with at least a 4-week 
220  interval between the pre- and posttreatment assessments.  For trials lasting less than 4 
221  weeks, the ACTH stimulation test for determining baseline status should be completed 
222  early in the screening period to permit an adequate amount of time between the pre- and 
223  posttreatment assessments.  The ACTH stimulation test may be performed in a dedicated 
224  study or during phase 2 or phase 3 trials.  Patients showing signs of HPA axis 
225  suppression or having abnormal ACTH stimulation test results at the end of treatment 
226  should be followed closely until complete resolution. 
227   
228  Sponsors intending to rely on another approved corticosteroid product to support absence 
229  of HPA axis suppression from the systemic absorption of the proposed product should 
230  demonstrate that the relative bioavailability of the proposed product is no greater than 
231  that of the approved corticosteroid product that has been shown to cause no HPA axis 
232  suppression. 
233   
234  E.  Additional Considerations 
235   
236  If the proposed drug product will be copackaged with a device (e.g., an applicator), it would 
237  probably be considered a drug-device combination product as defined in 21 CFR 3.2(e).  
238  Sponsors should meet with the Division about combination product status considerations early in 
239  the development process; sponsors are encouraged to consult the guidance for industry and FDA 
240  staff Current Good Manufacturing Practice Requirements for Combination Products (January 
241  2017).7 
                                                 
7 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
6