Crohns Disease: 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Jay Fajiculay at 301-796-9007.  
 
 
 
 
 
 
 
 
 
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 
44357485dft.docx 
04/29/22   
Crohns Disease:  
Developing Drugs 
for Treatment 
Guidance for Industry 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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or  
 
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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Draft  Not for Implementation 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 .......................................................................................................................12 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Crohns Disease: Developing Drugs for Treatment  
2  Guidance for Industry1 
3   
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
8  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page. 
11   
12   
13   
14  I.  INTRODUCTION 
15   
16  The purpose of this guidance is to help sponsors in the clinical development of drugs to treat 
17  adults with Crohns disease (CD).2 This draft guidance addresses the Food and Drug 
18  Administrations (FDAs) current recommendations on clinical trials for drugs being developed 
19  under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355), section 351 of 
20  the Public Health Service Act (42 U.S.C. 262) and 21 CFR parts 312, 314, and 601for treating 
21  CD. Specifically, this guidance addresses FDAs current thinking about the necessary attributes 
22  of clinical trials for drugs being developed for treating CD, including trial population, trial 
23  design, efficacy considerations, and safety assessments.3 
24   
25  This guidance does not address extraintestinal manifestations of CD, stricturing or fistulizing 
26  disease, pediatric drug development, or the treatment or prevention of long-term complications 
27  of CD. 
28   
29  The contents of this document do not have the force and effect of law and are not meant to bind 
30  the public in any way, unless specifically incorporated into a contract. This document is intended 
31  only to provide clarity to the public regarding existing requirements under the law. FDA 
32  guidance documents, including this guidance, should be viewed only as recommendations, unless 
33  specific regulatory or statutory requirements are cited. The use of the word should in Agency 
34  guidances means that something is suggested or recommended, but not required. 
35   
36   
 
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 CD. 
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37  II.  BACKGROUND 
38   
39  CD is a chronic, relapsing, and remitting inflammatory bowel disease characterized by 
40  transmural inflammation that may affect any area or areas of the gastrointestinal tract from the 
41  mouth to the anus. Clinical manifestations of active CD include abdominal pain, weight loss, 
42  diarrhea, fever, gastrointestinal bleeding, and anemia; some patients may also develop fistulae, 
43  fissures, and abscesses. The transmural inflammatory nature of CD may lead to fibrosis and 
44  strictures of the bowel, which are not typically seen in ulcerative colitis. 
45   
46  The treatment goals of CD include resolution or reduction of the signs and symptoms of active 
47  disease to provide relief to the patient and healing or control of the underlying mucosal 
48  inflammation and its complications. 
49   
50  Traditionally, the Crohns Disease Activity Index (CDAI),4 a weighted index comprising eight 
51  clinical and laboratory variables that estimate disease activity in CD, has been the most 
52  commonly used tool in trials intended to support approval of CD treatments. However, the CDAI 
53  has been shown to be poorly associated with intestinal inflammation (Levesque 2015; Peyrin-
54  Biroulet 2014). 
55   
56  Given the limitations of the CDAI, FDAs thinking on clinical endpoints for CD has evolved, 
57  and the recommended approach is to use coprimary endpoints to ensure that, in addition to 
58  relieving signs and symptoms, treatments have a meaningful impact on the underlying 
59  inflammation. Thus, coprimary endpoint assessment should include CDAI to evaluate signs and 
60  symptoms and an ileocolonoscopy to evaluate the impact of the drug on mucosal inflammatory 
61  changes. Although we currently recommend assessing signs and symptoms using the CDAI in 
62  the coprimary endpoint definition, sponsors are also encouraged to explore other methods for 
63  assessing clinically relevant signs and symptoms.  
64   
65  For general recommendations about patient-reported outcome (PRO) assessments (as well as 
66  information relevant for other clinical outcome assessments) and the documents to be provided 
67  to FDA for review, see the guidance for industry Patient-Reported Outcome Measures: Use in 
68  Medical Product Development to Support Labeling Claims (December 2009).5 
69   
70   
71  III.  DEVELOPMENT PROGRAM 
72   
73  A.  Trial Population 
74   
75  Sponsors developing drugs to treat CD should consider the following: 
76   
77    Subjects should have a confirmed diagnosis of CD based on documented findings on 
78  endoscopy and histopathology. 
 
4 See Appendix, Table 1. 
 
5 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
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79   
80    For clinical trials for drugs intended to treat moderately to severely active CD: 
81   
82    Subjects should have a CDAI score of at least 220 and a simple endoscopic score for 

83  Crohns disease (SES-CD) of at least 6 (or at least 4 if isolated ileal disease) at 
84  baseline. 
85   
86    Sponsors should enroll subjects across the whole range of both moderately and 

87  severely active disease categories. 
88   
89    We recommend a balanced representation of subjects who have never received 

90  treatment with a biologic and subjects who have failed prior therapy with one or more 
91  biologics or other advanced therapies. 
92   
93    For drugs intended to support an indication of mildly to moderately active CD, sponsors 
94  should discuss eligibility criteria with the appropriate review division. 
95   
96    Sponsors should enroll subjects who reflect the characteristics of clinically relevant 
97  populations, including with regard to race and ethnicity, and should consider clinical trial 
98  sites that include higher proportions of racial and ethnic minorities to recruit a diverse 
99  study population.6  
100   
101  B.  Trial Design 
102   
103  Sponsors developing drugs to treat CD should consider the following: 
104   
105    We recommend a randomized, double-blind, placebo-controlled trial design that would 
106  be able to demonstrate that beneficial effects observed initially with treatment are 
107  continued long term to support chronic administration. This goal may be achieved 
108  through various study designs, and the overall design of a program should be agreed upon 
109  with the appropriate review division before trial initiation. 
110   
111    One approach (induction followed by randomized withdrawal maintenance) is to 

112  conduct a randomized, placebo-controlled induction trial to assess clinical benefit in 
113  the short term, followed by a maintenance trial in which all subjects who achieve 
114  initial response (i.e., clinical or endoscopic response7) to active drug at the end of 
115  induction are re-randomized to receive either active treatment or placebo, and 
116  efficacy is evaluated again at the end of the maintenance phase (e.g., 52 weeks).8 
 
6 For additional recommendations, see 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. 
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117   
118    Another approach (treat-through design) is to randomize subjects once at the start of 

119  the trial to one of the treatment arms (i.e., a dosing regimen or placebo), and subjects 
120  are then treated continuously without rerandomization through 52 weeks. Sponsors 
121  should assess the coprimary endpoints at the end of treatment (e.g., 52 weeks). Earlier 
122  periodic assessments throughout the trial are useful to characterize the time to onset 
123  of initial clinical improvement. Early escape criteria should be incorporated to ensure 
124  that subjects who are worsening or not improving after a reasonable time frame have 
125  the opportunity to receive active treatment.  
126   
127    For drugs intended to be administered chronically, we recommend a total controlled 
128  treatment period of at least 1 year in duration to adequately assess both early efficacy and 
129  durability of response over time and to adequately characterize the safety profile. 
130  Sponsors should discuss with the appropriate review division the number of subjects 
131  exposed to the to-be-marketed dosing regimen for a minimum of 1 year that should be 
132  available at the time of application submission. 
133   
134    We encourage active controlled trials designed to demonstrate superiority to an approved 
135  therapy. 
136   
137  C.  Efficacy Considerations 
138   
139  1.  Efficacy Assessments 
140   
141  Sponsors developing drugs to treat CD should consider the following: 
142   
143    We recommend the following coprimary endpoints9 that evaluate a drugs effect on signs 
144  and symptoms and on underlying mucosal inflammation: 
145   
146    Clinical remission: Defined as a CDAI score of less than 150. 

147   
148    To calculate the CDAI stool frequency and abdominal pain subscores, we 
149  recommend defining a 7-day period during which the daily scores are collected 
150  before the specified study visit in which the CDAI is calculated. The scores 
151  should be calculated by averaging the daily scores from within this 7-day period 
152  then multiplied by 7, excluding the day of bowel preparation and day of 
153  endoscopy (for visits that include an endoscopy). A minimum of 3 consecutive 
154  days of completed diary entries or 4 nonconsecutive days are necessary 
155  (otherwise the score should be considered missing and the subjects result 
156  imputed as nonresponder). 
157   
 
9 Demonstrating treatment effects on both distinct endpoints is necessary to establish clinical benefit for this 
indication. See the draft guidance for industry Multiple Endpoints in Clinical Trials (January 2017). When final, 
this guidance will represent the FDAs current thinking on this topic. 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. 
 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
158    Endoscopic remission: Defined as SES-CD10 of 0 to 2 (Vuitton 2016). An 

159  alternative definition of SES-CD score of 0 to 4, with no individual subscore greater 
160  than 1, may also be acceptable.11 
161   
162    We recommend using centralized reading of endoscopies as the primary approach 
163  to scoring the endoscopic component of the primary and secondary endpoint 
164  assessments. Both the endoscopist performing the procedure and the central 
165  readers reviewing high-definition video recordings of the procedure should be 
166  blinded to treatment assignment and should document the endoscopic findings. 
167  The protocol should specify clearly how discrepancies between the findings by 
168  the endoscopist and the central reader will be handled in the efficacy analyses 
169  (e.g., adjudication by a third reader). Efforts should be made to minimize bias and 
170  standardize reading of endoscopy across trial sites and among investigators 
171  through training and education on the definition of each item described in the 
172  scale. Sponsors should draft charters that standardize procedures, video 
173  recordings/equipment, and endoscopy assessment early in drug development and 
174  share them with FDA for comment. 
175   
176    We recommend the following secondary endpoints: 
177   
178    Clinical response:12 Defined as a decrease from baseline of at least 100 points on the 

179  CDAI. 
180   
181    Endoscopic response:11,12 Error! Bookmark not defined.Defined as a 50 percent reduction 

182  from baseline on the SES-CD. 
183   
184    Corticosteroid-free remission: Defined as subjects who are in clinical remission at 

185  the conclusion of the controlled trial (e.g., 52 weeks) and having no corticosteroid 
186  exposure during a prespecified period (e.g., at least 8 to 12 weeks) before that 
187  assessment. 
188   
189  The proportion of subjects achieving corticosteroid-free remission, of those who were 
190  using corticosteroids at enrollment, is of interest and should be reported. 
191   
 
10 See Appendix, Table 2. 
 
11 We acknowledge that not all drugs may be able to achieve endoscopic remission within the duration of the clinical 
trial, and that there are currently limited data on the ability of available approved drugs to induce endoscopic 
remission. As a result, it may be acceptable to assess endoscopic response as the endoscopic component of the 
coprimary endpoint. If endoscopic response is included in the coprimary endpoints, then endoscopic remission 
should be assessed as a secondary endpoint. 
 
12 Although clinical or endoscopic response is not the final treatment goal, this definition may also 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. 
 
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192    Maintenance of remission: We recommend the following to demonstrate the 

193  durability of benefit:  
194   
195    For trial designs in which subjects who achieve clinical response at the end of the 
196  induction phase are rerandomized in the maintenance phase, we recommend that 
197  sponsors assess remission within the subset of subjects who enter the maintenance 
198  phase in remission to support the ability of the therapy to maintain a durable state 
199  of remission.  
200   
201    For trial designs in which subjects are treated continuously without 
202  rerandomization (treat-through design), sponsors should assess the proportion of 
203  subjects who individually achieve clinical remission (i.e., defined by CDAI) at 
204  both early (e.g., 8 weeks) and late (e.g., 52 week) time points to demonstrate that 
205  a clinical benefit was attained and was durable. A similar analysis should be 
206  performed for the SES-CD.  
207   
208    Composite endpoint of clinical remission and endoscopic remission:11 A 

209  secondary endpoint should assess the proportion of subjects who achieved both 
210  clinical remission and endoscopic remission. This endpoint should be assessed at the 
211  conclusion of the controlled trial (e.g., 52 weeks).  
212   
213    We recommend the following exploratory endpoints, each of which should be discussed 
214  with FDA before trial initiation: 
215   
216    Histologic response/remission: At this time, there is no scientific consensus on a 

217  definition of, or scoring system for, histologic resolution of mucosal inflammation in 
218  subjects who have achieved endoscopic remission in CD. Sponsors should provide 
219  adequate justification for the proposed endpoint definitions, grading scales, and 
220  scoring techniques. 
221   
222    Interim clinical assessments based on noninvasive measures: Sponsors should 

223  incorporate interim assessments of clinical remission (without endoscopic 
224  assessment) at prespecified time points during the trial, up until and including the last 
225  visit (e.g., 52 weeks), to support maintenance of remission. 
226   
227    Change from Baseline in the SES-CD Score: We recommend that sponsors 

228  evaluate the absolute change in the SES-CD score from baseline to the last visit (e.g., 
229  52 weeks). 
230   
231    Additional Endpoints: We encourage sponsors to explore the effect of an 

232  investigational drug on additional symptoms of CD identified by subjects as 
233  important but that are not captured within the CDAI (e.g., urgency) using fit-for-
234  purpose patient-reported outcome (PRO) instruments (see Section III. C. 3. Future 
235  Patient-Reported Outcome Instrument Development).   
236   
237   
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238  2.  Statistical Considerations 
239   
240  Sponsors developing drugs to treat CD should consider the following: 
241   
242    To support efficacy, the trial results should demonstrate statistical significance on both 
243  coprimary analyses (clinical endpoint and endoscopic endpoint). 
244   
245    To gain precision in evaluating overall treatment effects (e.g., the overall difference in 
246  remission rates), we recommend statistical analyses adjust for subject characteristics at 
247  baseline that may affect efficacy outcomes (e.g., duration of disease, disease severity, 
248  concurrent use of corticosteroids, prior biologic use). 
249   
250    Sponsors should conduct efficacy analyses in all randomized subjects. 
251   
252    Sponsors should prespecify methods to handle intermittent missing data (e.g., lack of at 
253  least 3 consecutive diary days, or 4 nonconsecutive diary days, during the 7 days before a 
254  visit).  
255   
256    Subjects who drop out before the end of treatment should be considered treatment 
257  failures.  
258   
259    Sponsors should prespecify a primary estimand of interest for each endpoint and justify 
260  that it is meaningful and that it can be estimated with minimal and plausible assumptions 
261  with the proposed analysis. The estimand is a precise description of the treatment effect, 
262  reflecting the clinical question posed by a given clinical trial objective. See the 
263  International Council for Harmonisation harmonized guideline E9 R1 Addendum on 
264  Estimands and Sensitivity Analysis in Clinical Trials to the guideline on Statistical 
265  Principles for Clinical Trials.13 The following considerations apply:  
266   
267    The important intercurrent events that should be considered when defining the 

268  estimand include treatment discontinuation attributable to lack of efficacy or adverse 
269  events, use of rescue medication, and CD-related surgery. 
270    
271    Potential strategies for defining and handling intercurrent events include the 

272  following: 
273   
274    A treatment policy strategy in which outcomes are collected after the intercurrent 
275  event and used in analyses. 
276   
277    A composite strategy in which subjects who experience the intercurrent event are 
278  considered to have an unfavorable outcome (e.g., to have not achieved remission). 
279   
280    Sponsors should continue to follow subjects after the occurrence of all intercurrent 

281  events, regardless of the strategy used in the primary analysis, to facilitate important 
 
13 Available at https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf. 
7  Contains Nonbinding Recommendations 
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282  analyses using a treatment policy strategy. The protocol should distinguish between 
283  reasons for treatment discontinuation and reasons for study withdrawal and should 
284  include plans to follow subjects for collection of relevant data after treatment 
285  discontinuation and use of rescue therapies. 
286   
287    Sponsors should prespecify sensitivity analyses to evaluate whether the results from the 
288  primary and secondary analyses are robust to the missing data assumptions. These 
289  sensitivity analyses should comprehensively explore the space of plausible assumptions.  
290   
291  3.  Future Patient-Reported Outcome Instrument Development14,15 
292   
293    Sponsors wishing to develop additional novel PRO instruments (or adapt existing 
294  instruments for use in CD patients) to assess concepts that are relevant to CD patients but 
295  not captured within the CDAI can submit a PRO instrument development proposal for 
296  FDA review. 
297   
298    Sponsors pursuing PRO instrument development may need to collect additional 

299  qualitative information from patients to support the relevance of the selected 
300  symptom(s), and document that patients understand and can use the instruments 
301  proposed items.  
302   
303    To support potential labeling claims, an adequate number of patients should 

304  demonstrate the presence of the additional symptom(s) at baseline, with sufficient 
305  degree of severity in order to be able to measure a clinically meaningful improvement 
306  over the course of treatment. 
307   
308    Additionally, sponsors may need to collect evidence that captures clinically important 

309  improvement at the individual patient level to inform the definition of response using 
310  the PRO instrument, preferably by including anchor-based analyses but also by other 
311  methods. 
312   
313  D.  Safety Considerations 
314   
315  Sponsors developing drugs to treat CD should consider the following: 
316   
317    In general, FDA has recommended a washout period of 5 half-lives for prior therapies or 
318  undetectable serum levels (when available) for trial subjects. To promote timely 
319  enrollment of subjects with active disease and reduce the potential need for escalation of 
 
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.  
 
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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320  corticosteroids as bridging therapy, sponsors may propose shorter washout periods with 
321  appropriate justification. 
322   
323    Sponsors proposing a shorter washout period should acknowledge within the protocol 

324  and informed consent the potential increased risk of adverse events (e.g., serious 
325  infections) in the early portion of the trial, and sponsors should include appropriate 
326  close monitoring and risk mitigation plans. 
327   
328    For drugs intended for long-term treatment, such as for CD, a sufficient number of 
329  subjects should be exposed to the to-be-marketed dosing regimen (selected induction 
330  dose, followed by selected maintenance dose, when applicable) for at least 52 weeks to 
331  characterize the safety profile of the drug.16 
332   
333    Drug-specific considerations may alter the minimum acceptable size of the safety 
334  database, including whether the drug in question is a new molecular entity or has relevant 
335  supportive safety data from other populations, the known and anticipated adverse events 
336  of the drug and drug class, and nonclinical findings. 
337   
338    For trials of therapeutic protein products, such as monoclonal antibodies, sponsors should 
339  consider recommendations in the guidance for industry Immunogenicity Assessment for 
340  Therapeutic Protein Products (August 2014). Sponsors should evaluate neutralizing 
341  capabilities of antidrug antibodies and their impact on clinical efficacy and safety. 
342   
343    Sponsors should prospectively plan for safety analyses to compare treatment groups with 
344  respect to risk (e.g., with a risk difference, relative risk, rate ratio, or hazard ratio) along 
345  with a confidence interval for the chosen metric to help quantify the uncertainty in the 
346  treatment comparison. Sponsors should stratify by study any analyses of integrated data 
347  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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348  REFERENCES 
349   
350  Literature 
351   
352  Levesque, BG, Sandborn WJ, Ruel J, Feagan BG, Sands BE, and Colombel JF, 2015, 
353  Converging Goals of Treatment of Inflammatory Bowel Disease from Clinical Trials and 
354  Practice. Gastroenterology, 148(1):3751.  
355   
356  Peyrin-Biroulet, L, Reinisch W, Colombel JF, Mantzaris GJ, Kornbluth A, Diamond R, 
357  Rutgeerts P, Tang LK, Cornillie FJ, and Sandborn WJ, 2014, Clinical Disease Activity, C-
358  Reactive Protein Normalisation and Mucosal Healing in Crohns Disease in the SONIC Trial, 
359  Gut, 63(1):8895. 
360   
361  Vuitton, L, Marteau P, Sandborn WJ, Levesque BG, Feagan B, Vermeire S, Danese S, DHaens 
362  G, Lowenberg M, Khanna R, Fiorino G, Travis S, Mary JY, and Peyrin-Biroulet L, 2016, IOIBD 
363  Technical Review on Endoscopic Indices for Crohn's Disease Clinical Trials, Gut, 65(9):1447
364  55. 
365   
366   
367  Guidances1 
368   
369  Draft guidance for industry Multiple Endpoints in Clinical Trials (January 2017)2 
370   
371  Guidance for industry and FDA staff Qualification Process for Drug Development Tools 
372  (November 2020) 
373   
374  Guidance for industry, FDA staff, and other stakeholders Patient-Focused Drug Development: 
375  Collecting Comprehensive and Representative Input (June 2020) 
376   
377  Guidance for industry Immunogenicity Assessment for Therapeutic Protein Products (August 
378  2014) 
379   
380  Guidance for industry Patient-Reported Outcome Measures: Use in Medical Product 
381  Development to Support Labeling Claims (December 2009) 
382   
383  Guidance for industry Premarketing Risk Assessment (March 2005)  
384   
 
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 When final, this guidance will represent the FDAs current thinking on this topic. For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents. 
 
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385  International Council for Harmonisation harmonized guideline E9 R1 Addendum on Estimands 
386  and Sensitivity Analysis in Clinical Trials to the guideline on Statistical Principles for Clinical 
387  Trials (November 2019)3 
388   
 
3 Available at https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf. 
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389   
390  APPENDIX 
391   
392  The Crohns Disease Activity Index (CDAI) (see Table 1), a weighted index comprising eight 
393  clinical and laboratory variables that estimate disease activity in Crohns disease (CD), has been 
394  the most commonly used tool in trials intended to support approval of CD treatments. Table 2 
395  outlines the components of the Simple Endoscopic Score for Crohns Disease (SES-CD), a 
396  scoring algorithm that can be used to measure endoscopic features of CD. 
397   
398  Table 1. Crohns Disease Activity Index (CDAI)* 
399   
Variable Description   Multiplier  
Number of liquid or soft stools (each day for 7 days)  X 2 
Abdominal pain, sum of 7 daily ratings (0=none, 1=mild, 2 = moderate,  X 5 
3=severe) 
General well-being, sum of 7 daily rating (0=generally well, 1=slightly  X 7 
under par, 2=poor, 3=very poor, 4=terrible) 
Number of listed complications (arthritis or arthralgia, iritis or uveitis,  X 20 
erythema nodosum or pyoderma gangrenosum or aphthous stomatitis, anal 
fissure or fistula or abscess, other fistula, fever over 37.8oC [100oF]) 
Use of diphenoxylate or loperamide for diarrhea (0=no, 1=yes)  X 30 
Abdominal mass (0=no, 2=questionable, 5=definite)  X 10 
Hematocrit (males, 47-Hct [%], females, 42-Hct [%])  X 6 
Body weight 1-weight/standard weight) x 100 (add or subtract according to  X 1 
sign) 
400  *The total CDAI score is calculated using the sum of each variable times the multiplier. Best WR, Becktel JM, 
401  Singleton JW, Kern F Jr. "Development of a Crohn's disease activity index. National Cooperative Crohn's Disease 
402  Study". Gastroenterology 1976. 70 (3): 439444. 
403   
404   
405   
406  Table 2. Simple Endoscopic Score for Crohns Disease (SES-CD) 
407   
Variable  SES-CD Values 
  0  1  2  3 
Size of ulcers  None  Aphthous ulcers  Large ulcers  Very large ulcers 
(diameter 0.1-0.5  (diameter 0.5-2  (diameter>2 cm) 
cm)  cm) 
Ulcerated surface  None  <10%  10-30%  >30% 
Affected surface   Unaffected  <50%  50-75%  >75% 
segment 
Presence of narrowing   None  Single, can be  Multiple, can be  Cannot be passed 
passed  passed 
408  Adapted from M Daperno, DHaens G, Van Assche G, Baert F, Bulois P, Maunoury V, Sostegni R, Rocca R, Pera 
409  A, Gevers A, Mary J-Y, Colombel J-F, and Rutgeerts P, 2004, Development and Validation of a New, Simplified 
410  Endoscopic Activity Score for Crohns Disease: the SES-CD, Gastrointest Endosc, 60(4):505512. 
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