Ulcerative Colitis: 
Developing Drugs for 
Treatment  
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Kelly Richards at 240-402-4276. 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
April 2022 
Clinical/Medical 
44354222dft_Ulcerative Colitis.docx 
4/29/2022   
Ulcerative Colitis:  
Developing Drugs 
for Treatment 
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 
 
or  
 
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https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
biologics/biologics-guidances  
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
April 2022 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  DEVELOPMENT PROGRAM ............................................................................2 
A.  Trial Population ................................................................................................................. 2 
B.  Trial Design ........................................................................................................................ 3 
C.  Efficacy Considerations .................................................................................................... 4 
1. Efficacy Assessments ........................................................................................................... 4 
2. Statistical Considerations .................................................................................................... 7 
3. Future Patient-Reported Outcome Instrument Development, ............................................. 8 
D.  Safety Considerations ........................................................................................................ 8 
REFERENCES .................................................................................................................10 
APPENDIX .......................................................................................................................11 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Ulcerative Colitis: Developing Drugs for Treatment  
2  Guidance for Industry1 
3   
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  The purpose of this guidance is to help sponsors in the clinical development of drugs to treat 
18  adults with ulcerative colitis (UC).2  This guidance addresses the Food and Drug 
19  Administrations (FDAs) current recommendations on clinical trials for drugs being developed 
20  under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355), section 351 of 
21  the Public Health Service Act (42 U.S.C. 262) and 21 CFR parts 312, 314, and 601 for treating 
22  UC.  Specifically, this guidance addresses FDAs current thinking about the necessary attributes 
23  of clinical trials for drugs being developed for treating UC, including trial population, trial 
24  design, efficacy considerations, and safety assessments.3,4   
25   
26  This guidance does not address extraintestinal manifestations of UC, pediatric drug development, 
27  or the treatment or prevention of long-term complications of UC (e.g., this guidance is not 
28  intended to discuss endpoints for prevention or reduction in risk of colorectal cancer).  
29   
30  This guidance replaces the withdrawn draft guidance for industry Ulcerative Colitis: Clinical 
31  Trial Endpoints (August 2016).  
 
1 This guidance has been prepared by the Division of Gastroenterology (the Division) in the Center for Drug 
Evaluation and Research at the Food and Drug Administration and the Center for Biologics Evaluation and Research 
(CBER).  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified.  
 
3 In addition to consulting guidances, sponsors are encouraged to contact the appropriate review division to discuss 
specific issues that arise during the development of drugs to treat UC. 
 
4 For cellular and gene therapy products, there may be additional considerations. Sponsors should discuss their 
development program with the Office of Tissues and Advanced Therapies. For clinical trials involving gene therapy 
products, sponsors should consult the guidance for industry Long Term Follow-Up After Administration of Human 
Gene Therapy Products (January 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. 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
32   
33  The contents of this document do not have the force and effect of law and are not meant to bind 
34  the public in any way, unless specifically incorporated into a contract. This document is intended 
35  only to provide clarity to the public regarding existing requirements under the law. FDA 
36  guidance documents, including this guidance, should be viewed only as recommendations, unless 
37  specific regulatory or statutory requirements are cited. The use of the word should in Agency 
38  guidances means that something is suggested or recommended, but not required. 
39   
40   
41  II.  BACKGROUND 
42   
43  UC is a chronic, relapsing, and remitting inflammatory bowel disease characterized by diffuse 
44  mucosal inflammation of the colon.   
45   
46  UC involves the rectum, and it may extend proximally in a contiguous pattern to affect part of 
47  the colon or the entire colon. Clinical manifestations of active UC include bloody diarrhea (with 
48  or without mucus), urgency, tenesmus, abdominal pain, weight loss, fever, and malaise. In 
49  patients with extensive or severe inflammation, acute complications such as severe bleeding and 
50  toxic megacolon, which can lead to perforation, may occur (Danese and Fiocchi 2011).   
51   
52  The treatment goals of UC include resolution or reduction of the signs and symptoms of active 
53  disease to provide relief to the patient and healing or control of the underlying mucosal 
54  inflammation and its complications.   
55   
56   
57  III.  DEVELOPMENT PROGRAM 
58   
59  A.  Trial Population 
60   
61  Sponsors developing drugs to treat UC should consider the following: 
62   
63    Subjects should have a confirmed diagnosis of UC based on documented findings on 
64  endoscopy and histopathology. 
65   
66    For clinical trials for drugs intended to treat moderately to severely active UC: 
67   
68    Subjects should have a score of 5 to 9 on the modified Mayo Score (mMS),5 
69  including an endoscopy subscore of at least 2. 
70   
71    Sponsors should enroll subjects across the whole range of both moderately and 

72  severely active disease categories. 
73   
 
5 The mMS is a composite endpoint consisting of rectal bleeding, stool frequency, and endoscopy subscores, adapted 
from the originally published Mayo Score. The previously used physician global assessment component is excluded 
to reduce subjectivity and focus the evaluation on the subjects directly reported symptoms and directly observable 
endoscopic findings. See Table 1 in the Appendix.  
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74    We recommend a balanced representation of subjects who have never received 

75  treatment with a biologic and subjects who have failed prior therapy with one or more 
76  biologics or other advanced therapies. 
77   
78    For drugs intended to support an indication of mildly to moderately active UC, sponsors 
79  should enroll subjects with a score of at least 4 on the mMS, including an endoscopy 
80  subscore of at least 2 and a rectal bleeding subscore of at least 1. 
81   
82    Sponsors should enroll subjects who reflect the characteristics of clinically relevant 
83  populations, including with regard to race and ethnicity, and should consider clinical trial 
84  sites that include higher proportions of racial and ethnic minorities to recruit a diverse 
85  study population.6 
86   
87  B.  Trial Design 
88   
89  Sponsors developing drugs to treat UC should consider the following: 
90   
91    We recommend a randomized, double-blind, placebo-controlled trial design that would 
92  be able to demonstrate that beneficial effects observed initially with treatment are 
93  continued long term to support chronic administration. This goal may be achieved 
94  through various study designs, and the overall design of a program should be agreed upon 
95  with the appropriate review division before trial initiation.   
96   
97    One approach (induction followed by randomized withdrawal maintenance) is to 

98  conduct a randomized, placebo-controlled induction trial to assess clinical benefit in 
99  the short term, followed by a maintenance trial in which all subjects who achieve 
100  initial clinical response7 to active drug at the end of induction are re-randomized to 
101  receive either active treatment or placebo, and efficacy is evaluated again at the end 
102  of the maintenance phase (e.g., 52 weeks).8 
103   
104    Another approach (treat-through design) is to randomize subjects once at the start of 

105  the trial to one of the treatment arms (i.e., a dosing regimen or placebo), and subjects 
106  are then treated continuously without rerandomization through 52 weeks. Sponsor 
107  should assess the primary endpoint at the end of treatment (e.g., 52 weeks). Earlier 
108  periodic assessments throughout the trial are useful to characterize the time to onset 
109  of initial clinical improvement. Early escape criteria should be incorporated to ensure 
110  that subjects who are worsening or not improving after a reasonable time frame have 
111  the opportunity to receive active treatment.  
 
6 For additional recommendations, refer to the guidance for industry Enhancing the Diversity of Clinical Trial 
Populations  Eligibility Criteria, Enrollment Practices, and Trial Designs (November 2020). 
 
7 As defined in section C, Efficacy Considerations. 
 
8 Placebo responders at the end of induction should continue to receive blinded placebo in maintenance. Early 
escape criteria should be incorporated to ensure that subjects who are worsening or not improving after a reasonable 
time frame are discontinued from blinded study treatment and offered either rescue dosing or an alternative active 
treatment. 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
112   
113    For drugs intended to be administered chronically, we recommend a total controlled 
114  treatment period of at least 1 year in duration to adequately assess both early efficacy and 
115  durability of response over time and to adequately characterize the safety profile. 
116  Sponsors should discuss with the appropriate review division the number of subjects 
117  exposed to the to-be-marketed dosing regimen for a minimum of 1 year that should be 
118  available at the time of application submission. 
119   
120    We encourage active controlled trials designed to demonstrate superiority to an approved 
121  therapy.  
122   
123    Sponsors can consider noninferiority studies, but we recommend that sponsors reach 
124  agreement on an acceptable noninferiority margin with the appropriate review division 
125  before initiating clinical trials.9  
126   
127  C.  Efficacy Considerations 
128   
129  1.  Efficacy Assessments 
130   
131  Sponsors developing drugs to treat UC should consider the following:  
132   
133    We recommend evaluating the proportion of subjects achieving clinical remission as the 
134  primary endpoint.  
135   
136    Clinical remission: Defined as an mMS score of 0 to 2, including the following three 

137  components:10 
138   
139  1)  Stool frequency subscore = 0 or 111 
140   
141  2)  Rectal bleeding subscore = 0 
142   
143  3)  Centrally read endoscopy subscore = 0 or 1 (score of 1 modified to 
144  exclude friability)  
145   
146    Sponsors should explore the proportion of subjects in clinical remission who had 
147  a stool frequency subscore of 0 versus 1. Although a stool frequency subscore of 
148  0 or 1 is allowable for individual subjects, a subscore of 1 in a significant number 
149  of subjects may not be considered adequate evidence of stool normalization, and 
150  this limitation may be noted in the label. 
 
9 For additional information, see the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness 
(November 2016). 
  
10 See Table 2 in the Appendix for sample instructions for patients to accurately capture patient-reported outcome 
data for stool frequency and rectal bleeding subscores. 
 
11 For products intended to treat mildly to moderately active UC, the recommended definition of remission should be 
modified to include a stool frequency subscore of 0 or 1 and no greater than baseline (start of trial). 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
151   
152    Although historically sponsors have used sigmoidoscopy for the endoscopic 
153  assessment, we recommend that colonoscopy be used to document disease 
154  activity in all involved segments of the colon. 
155   
156    We recommend using centralized reading of endoscopies as the primary approach 
157  to scoring the endoscopic component of the primary and secondary endpoint 
158  assessments. Both the endoscopist performing the procedure and the central 
159  readers reviewing high-definition video recordings of the procedure should be 
160  blinded to treatment assignment and should document the endoscopic findings. 
161  The protocol should specify clearly how discrepancies between the findings by 
162  the endoscopist and the central reader will be handled in the efficacy analyses 
163  (e.g., adjudication by a third reader). Efforts should be made to minimize bias and 
164  standardize reading of endoscopy across trial sites and among investigators 
165  through training and education on the definition of each item described in the 
166  scale. Sponsors should draft charters that standardize procedures, video 
167  recordings/equipment, and endoscopy assessment early in drug development and 
168  share them with FDA for comment.   
169   
170    For calculation of the mMS stool frequency and rectal bleeding subscores (at 
171  baseline and prespecified timepoints for efficacy assessment), the following 
172  considerations apply: 
173   
174    To calculate the stool frequency subscore and the rectal bleeding subscore, we 
o
175  recommend defining a 7-day period during which daily subscores are 
176  collected before the specified study visit when the mMS (or partial MS) is 
177  calculated. 
178   
179    The subscores should be calculated by averaging the daily subscores from 
o
180  within this 7-day period, excluding the day of bowel preparation and day of 
181  endoscopy (for visits that include an endoscopy). 
182   
183    A minimum of 3 consecutive days of completed diary entries or 4 
o
184  nonconsecutive days are necessary (otherwise the score should be considered 
185  missing and the subjects result imputed as nonresponder). 
186   
187    We recommend the following secondary endpoints:   
188   
189    Clinical response:12 Defined as a decrease from baseline in the mMS of greater than 

190  or equal to 2 points and at least a 30 percent reduction from baseline, and a decrease 
191  in rectal bleeding subscore of greater than or equal to 1 or an absolute rectal bleeding 
192  subscore of 0 or 1.  
193   
 
12 Although clinical response is not the final treatment goal, this definition may be used as a criterion at the end of 
induction to rerandomize subjects who are demonstrating improvement to continue into a maintenance phase in the 
induction/maintenance design.  
5  Contains Nonbinding Recommendations 
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194    Corticosteroid-free remission: Defined as subjects who are in clinical remission at 

195  the conclusion of the controlled trial (e.g., 52 weeks) and having no corticosteroid 
196  exposure during a prespecified period (e.g., at least 8 to 12 weeks) before that 
197  assessment.  
198   
199  The proportion of subjects achieving corticosteroid-free remission, of those who were 
200  using corticosteroids at enrollment, is of interest and should be reported.  
201   
202    Endoscopic improvement: Defined as a centrally read endoscopy subscore of 0 or 1 

203  (score of 1 modified to exclude friability).  
204   
205    Endoscopic remission: Defined as a centrally read endoscopy subscore of 0.  

206   
207  We do not recommend the use of the term mucosal healing at this time, as there is no 
208  consensus as to how best to define this concept.   
209   
210    Maintenance of remission: We recommend the following to demonstrate the 

211  durability of benefit: 
212   
213    For trial designs in which subjects who achieve clinical response at the end of the 
214  induction phase are rerandomized in the maintenance phase, we recommend that 
215  sponsors assess remission within the subset of subjects who enter the maintenance 
216  phase in remission to support the ability of the therapy to maintain a durable state 
217  of remission.  
218   
219    For trial designs in which subjects are treated continuously without 
220  rerandomization (treat-through design), sponsors should assess the proportion of 
221  subjects who individually achieve clinical remission at both early (e.g., 8 weeks) 
222  and late (e.g., 52 week) time points to demonstrate that a clinical benefit was 
223  attained and was durable.   
224   
225    We recommend the following exploratory endpoints, each of which should be discussed 
226  with FDA before trial initiation: 
227   
228    Histologic response/remission: At this time, there is no scientific consensus on a 

229  definition of, or scoring system for, histologic resolution of mucosal inflammation in 
230  subjects who achieved endoscopic remission in UC. Sponsors should provide 
231  adequate justification for the proposed endpoint definitions, grading scales, and 
232  scoring techniques. 
233   
234    Interim clinical assessments based on noninvasive measures: Sponsors should 

235  incorporate interim clinical assessments based on the noninvasive components of the 
236  mMS (such as stool frequency and rectal bleeding subscores) at prespecified time 
237  points during the trial, up until and including the last visit (e.g., 52 weeks), to support 
238  maintenance of remission.  
239   
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240    Additional Endpoints: We encourage sponsors to explore the effect of an 

241  investigational drug on additional symptoms of UC identified by subjects as 
242  important but that are not captured within the mMS (e.g., abdominal pain, urgency) 
243  using fit-for-purpose patient-reported outcome (PRO) instruments (see section III. C. 
244  3., Future Patient-Reported Outcome Instrument Development).   
245   
246  2.  Statistical Considerations 
247   
248  Sponsors developing drugs to treat UC should consider the following:  
249   
250    To gain precision in evaluating overall treatment effects (e.g., the overall difference in 
251  remission rates), we recommend statistical analyses adjust for subject characteristics at 
252  baseline that may affect efficacy outcomes (e.g., duration of disease, disease severity, 
253  concurrent use of corticosteroids, prior biologic use). 
254   
255    Sponsors should conduct efficacy analyses in all randomized subjects.  
256   
257    Sponsors should prespecify methods to handle intermittent missing data (e.g., lack of at 
258  least 3 consecutive diary days, or 4 nonconsecutive diary days, during the 7 days before a 
259  visit).  
260   
261    Subjects who drop out before the end of treatment should be considered treatment 
262  failures.  
263   
264    Sponsors should prespecify a primary estimand of interest for each endpoint and justify 
265  that it is meaningful and that it can be estimated with minimal and plausible assumptions 
266  with the proposed analysis. The estimand is a precise description of the treatment effect, 
267  reflecting the clinical question posed by a given clinical trial objective. See the 
268  International Council for Harmonisation harmonized guideline E9 R1 Addendum on 
269  Estimands and Sensitivity Analysis in Clinical Trials to the guideline on Statistical 
270  Principles for Clinical Trials.13 The following considerations apply:  
271   
272    The important intercurrent events that should be considered when defining the 

273  estimand include treatment discontinuation attributable to lack of efficacy or adverse 
274  events, use of rescue medication, and UC-related surgery.   
275   
276    Potential strategies for defining and handling intercurrent events include the 

277  following: 
278   
279    A treatment policy strategy in which outcomes are collected after the intercurrent 
280  event and used in analyses. 
281   
282    A composite strategy in which subjects who experience the intercurrent event are 
283  considered to have an unfavorable outcome (e.g., to have not achieved remission). 
 
13 Available at https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf.  
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284   
285    Sponsors should continue to follow subjects after the occurrence of all intercurrent 

286  events, regardless of the strategy used in the primary analysis, to facilitate important 
287  analyses using a treatment policy strategy. The protocol should distinguish between 
288  reasons for treatment discontinuation and reasons for study withdrawal and should 
289  include plans to follow subjects for collection of relevant data after treatment 
290  discontinuation and use of rescue therapies. 
291   
292    Sponsors should prespecify sensitivity analyses to evaluate whether the results from the 
293  primary and secondary analyses are robust to the missing data assumptions. These 
294  sensitivity analyses should comprehensively explore the space of plausible assumptions. 
295   
296  3.  Future Patient-Reported Outcome Instrument Development14,15 
297   
298    Sponsors wishing to develop additional novel PRO instruments (or adapt existing 
299  instruments for use in UC patients) to assess concepts that are relevant to UC patients but 
300  not captured within the mMS can submit a PRO instrument development proposal for 
301  FDA review. 
302   
303    Sponsors pursuing PRO instrument development may need to collect additional 

304  qualitative information from patients to support the relevance of the selected 
305  symptom(s), and document that patients understand and can use the instruments 
306  proposed items.  
307   
308    To support potential labeling claims, an adequate number of patients should 

309  demonstrate the presence of the additional symptom(s) at baseline, with sufficient 
310  degree of severity in order to be able to measure a clinically meaningful improvement 
311  over the course of treatment. 
312   
313    Additionally, sponsors may need to collect evidence that captures clinically important 

314  improvement at the individual patient level to inform the definition of response using 
315  the PRO instrument, preferably by including anchor-based analyses but also by other 
316  methods. 
317   
318  D.  Safety Considerations 
319   
320  Sponsors developing drugs to treat UC should consider the following: 
 
14 For general recommendations regarding PRO assessments (as well as information relevant for other 
clinical outcome assessments), see the guidance for industry Patient-Reported Outcome Measures: Use in 
Medical Product Development to Support Labeling Claims (December 2009). 
 
15 For general recommendations regarding PRO assessments (as well as information relevant for other clinical 
outcome assessments), see the FDA Patient-Focused Drug Development Guidance Series for Enhancing the 
Incorporation of the Patients Voice in Medical Product Development and Regulatory Decision Making web page at 
https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-
series-enhancing-incorporation-patients-voice-medical. 
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321   
322    In general, FDA has recommended a washout period of 5 half-lives for prior therapies or 
323  undetectable serum levels (when available) for trial subjects. To promote timely 
324  enrollment of subjects with active disease and reduce the potential need for escalation of 
325  corticosteroids as bridging therapy, sponsors may propose shorter washout periods, with 
326  appropriate justification.   
327   
328    Sponsors proposing a shorter washout period should acknowledge within the protocol 

329  and informed consent the potential increased risk of adverse events (e.g., serious 
330  infections) in the early portion of the trial, and sponsors should include appropriate 
331  close monitoring and risk mitigation plans.  
332   
333    For drugs intended for long-term treatment, such as for UC, a sufficient number of 
334  subjects should be exposed to the to-be-marketed dosing regimen (selected induction 
335  dose, followed by selected maintenance dose, when applicable) for at least 52 weeks to 
336  characterize the safety profile of the drug.16   
337   
338    Drug-specific considerations may alter the minimum acceptable size of the safety 
339  database, including whether the drug in question is a new molecular entity or has relevant 
340  supportive safety data from other populations, the known and anticipated adverse events 
341  of the drug and drug class, and nonclinical findings.  
342   
343    For trials of therapeutic protein products, such as monoclonal antibodies, sponsors should 
344  consider recommendations in the guidance for industry Immunogenicity Assessment for 
345  Therapeutic Protein Products (August 2014). Sponsors should evaluate neutralizing 
346  capabilities of antidrug antibodies and their impact on clinical efficacy and safety. 
347   
348    Sponsors should prospectively plan for safety analyses to compare treatment groups with 
349  respect to risk (e.g., with a risk difference, relative risk, rate ratio, or hazard ratio) along 
350  with a confidence interval for the chosen metric to help quantify the uncertainty in the 
351  treatment comparison. Sponsors should stratify by study any analyses of integrated data 
352  from multiple studies. 
 
16 For recommendations about duration of exposure and number of patients to be included in the safety database, see 
the guidance for industry Premarketing Risk Assessment (March 2005). 
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353  REFERENCES 
354   
355  Literature 
356   
357  Danese S and Fiocchi C, 2011, Ulcerative Colitis, N Engl J Med, 365(18):17131725. 
358   
359   
360  Guidances1 
361   
362  Guidance for industry and FDA staff Qualification Process for Drug Development Tools 
363  (November 2020) 
364   
365  Guidance for industry, FDA staff, and other stakeholders Patient-Focused Drug Development:  
366  Collecting Comprehensive and Representative Input (June 2020) 
367   
368  Guidance for industry Enhancing the Diversity of Clinical Trial Populations  Eligibility 
369  Criteria, Enrollment Practices, and Trial Designs (November 2020) 
370   
371  Guidance for industry Immunogenicity Assessment for Therapeutic Protein Products (August 
372  2014) 
373   
374  Guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 
375  2016) 
376   
377  Guidance for industry Patient-Reported Outcome Measures: Use in Medical Product 
378  Development to Support Labeling Claims (December 2009) 
379   
380  Guidance for industry Premarketing Risk Assessment (March 2005)  
381   
382  International Council for Harmonisation harmonized guideline E9 R1 Addendum on Estimands 
383  and Sensitivity Analysis in Clinical Trials to the guideline on Statistical Principles for Clinical 
384  Trials (November 2019)2 
 
1 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. 
 
2 Available at https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf. 
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385  APPENDIX 
386   
387  The modified Mayo Score (mMS) (see Table 1) is a composite endpoint consisting of rectal 
388  bleeding, stool frequency, and endoscopy subscores, adapted from the originally published Mayo 
389  Score. Table 2 provides an example of instructions for subjects to accurately capture patient-
390  reported outcome data for stool frequency and rectal bleeding subscores. 
391   
392  Table 1. Modified Mayo Score (mMS) 
393   
mMS Subscores by Category   
 
Stool Frequency* 
0  Normal number of stools for this patient 
1  12 more stools than normal 
2  34 more stools than normal 
3  5 or more stools more than normal 
 
Rectal Bleeding**  
0  No blood seen  
1  Stool with streaks of blood 
2  Stool with more than streaks of blood 
3  Blood alone passed 
Endoscopy   
0  Normal appearance of mucosa  
1  Mild disease (erythema, decreased vascular pattern), no 
friability  
2  Moderate disease (marked erythema, absent vascular pattern, 
friability, erosions) 
3  Severe disease (spontaneous bleeding, ulcerations) 
394  * Each patient provides own baseline against which to compare the degree of abnormality in stool frequency. 
395  ** Represents the worst bleeding score for that day. 
396   
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397  Table 2. Example of Standardized Instructions for Recording Number of Stools and Worst 
398  Rectal Bleeding (Each in a 24-Hour Period)* 
399   
Category of Instructions  Specific Instructions to Patients 
  Patients should be instructed to report the number of trips to the toilet 
Definition of stool 
when the patient had a bowel movement (including passing feces, 
frequency 
blood alone, blood and mucus, or mucus only). 
  The patient should be asked to identify at the screening visit how many 
stools he or she had in a 24-hour period when in remission from 
ulcerative colitis (UC). 
  If the patient does not report achieving remission, then the patient 
should be asked to identify the number of stools he or she had in a 24-
hour period before initial onset of signs and symptoms of UC. If the 
patient has not experienced remission, this value will be used to 
Reference remission stool 
calculate the stool frequency endpoint.  
frequency (in a 24-hour 
  Sponsors should record if the reference remission stool frequency 
period) 
is based on reported stool frequency when the patient was in 
remission or reported stool frequency before initial onset of signs 
and symptoms of UC.  
  Both the remission and the pre-UC stool frequency should be 
collected at baseline when feasible. This allows exploration of the 
natural history of prediagnosis stool frequency versus remission 
stool frequency. 
  Patients should be instructed to indicate the most severe category that 
describes the amount of blood they had in their stools for a given 24-
hour period. 
  Categories of rectal bleeding should be defined as follows (in order of 
Most severe category of 
increasing severity): 
rectal bleeding (in a given 
  Not applicable; no bowel movement** 
24-hour period) 
  No blood seen 
  Stool has streaks of blood 
  Stool has more than just streaks of blood  
  Blood alone passed 
  Patients should be trained on the completion of the event log or diary. 
Completion of event log    The instructions for completion of the stool frequency and rectal 
or diary  bleeding assessments should be incorporated into the event log or 
diary for ready reference by the patient. 
Recording of rectal    Patients should be directed to capture their rectal bleeding and stool 
bleeding and stool  frequency assessments in event logs or daily diaries for a minimum of 
frequency assessments  7 days before each visit. 
400  * FDA encourages sponsors to propose an electronic data collection method (e.g., electronic diary, web-based 
401  system) as an alternative to pen and paper data collection. If an electronic data collection method is proposed, 
402  sponsors should provide site training and instructions for subjects and investigators. To minimize missing data, 
403  sponsors should implement a web- or paper-based backup plan and reminder or alarm functions on the electronic 
404  device. To ensure proper recall period for the assessment, sponsors should consider exploring inclusion of 
405  reasonable lock-out times before and after which no entries can be made.   
406  ** If the event log or diary is set up to include the option of no bowel movement occurred, then this rectal 
407  bleeding response is not necessary. 
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