Celiac Disease: Developing Drugs 
for Adjunctive Treatment to a 
Gluten-Free Diet 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 http://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 Richard Whitehead at 301-796-4945. 
 
 
 
 
 
 
 
 
 
 
 
 
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 
44761827dft.docx 
04/18/22   
Celiac Disease: Developing Drugs 
for Adjunctive Treatment to a 
Gluten-Free Diet 
Guidance for Industry 
 
Additional copies are available from: 
 
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Food and Drug Administration 
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or  
 
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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Draft  Not for Implementation 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 .................................................................................................................................... 4 
C.  Efficacy Considerations ................................................................................................................. 5 
1. Efficacy Assessments ........................................................................................................................ 5 
2. Clinical Outcome Assessments ........................................................................................................ 6 
3. Statistical Considerations ................................................................................................................ 7 
D.  Safety Considerations .................................................................................................................... 8 
REFERENCES ............................................................................................................................ 10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Celiac Disease: Developing Drugs for Adjunctive Treatment to a 
2  Gluten-Free Diet  
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  The purpose of this guidance is to help sponsors in the clinical development of drugs2 for the 
18  treatment of celiac disease (CeD) as an adjunct to a gluten-free diet in adults. Specifically, this 
19  guidance addresses the Food and Drug Administrations (FDAs) current recommendations on 
20  clinical trials for drugs being developed under section 505 of the Federal Food, Drug, and 
21  Cosmetic Act (21 U.S.C. 355) and 21 CFR parts 312 and 314 and/or for biologics being 
22  developed under section 351 of the Public Health Service Act and 21 CFR part 601 for the 
23  treatment of CeD as an adjunct to a gluten-free diet in adults. This guidance also addresses 
24  considerations for eligibility criteria, trial design features, efficacy evaluations, clinical outcome 
25  assessments, and safety assessments.  
26   
27  This guidance does not address the clinical development of drugs intended to prevent signs and 
28  symptoms of CeD or treatment of CeD as monotherapy (i.e., treatment replacing a gluten-free 
29  diet). In addition, this guidance does not address the clinical development of drugs to treat CeD 
30  in asymptomatic patients or patients with minimal to no histologic inflammation who continue to 
31  experience symptoms. 
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  guidance means that something is suggested or recommended, but not required. 
39   
 
1 This guidance has been prepared by the Division of Gastroenterology (the Division) in the Center for Drug 
Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) in the Food and 
Drug Administration. 
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
40   
41  II.  BACKGROUND 
42   
43  CeD is an autoimmune condition in which dietary gluten triggers small bowel inflammation and 
44  villous atrophy, causing malabsorption and gastrointestinal symptoms. The only treatment for 
45  CeD is a strict, lifelong gluten-free diet (Green 2007). CeD affects about 1% of the U.S. 
46  population with a female preponderance (Rubio-Tapia 2012). 
47   
48  Malabsorption results in gastrointestinal signs and symptoms, including diarrhea, abdominal 
49  pain, bloating, vomiting, weight loss, anemia, and micronutrient deficiencies. Patients with CeD 
50  may also have extraintestinal symptoms such as fatigue, headaches, depression, difficulty 
51  concentrating, skin rashes, and arthralgias. Some patients with CeD are asymptomatic (Green 
52  2007). 
53   
54  CeD is diagnosed based on a patients medical history, physical examination, serologies (e.g., 
55  serum tissue transglutaminase IgA), and histologic findings on small bowel biopsies. Proper 
56  biopsy technique is important to confirm the diagnosis. Multiple histologic scoring systems have 
57  been developed that incorporate assessments of villous atrophy, crypt hyperplasia, and 
58  intraepithelial lymphocytes to identify and classify severity of small bowel inflammation. 
59   
60  The goals of treatment in patients with CeD include resolution of intestinal inflammation and 
61  associated clinical signs and symptoms. For many adults, strict adherence to a gluten-free diet 
62  will result in improvement in both histologic findings and signs and symptoms; however, some 
63  adults may not be able to achieve normalization of the mucosa (Wahab 2002; Rubio-Tapia 
64  2010). In addition, intentional and inadvertent dietary digressions can lead to disease 
65  exacerbation. Complications of CeD include poor growth, osteoporosis, tooth enamel defects, 
66  neuropathy, and vitamin deficiencies. Although rare, serious complications such as small 
67  intestinal lymphoma and adenocarcinoma can occur in patients with CeD (Green 2007; Catassi 
68  2005). 
69   
70   
71  III.  DEVELOPMENT PROGRAM 
72   
73  A.  Trial Population 
74   
75  Sponsors developing drugs to treat CeD as an adjunct to a gluten-free diet should consider the 
76  following: 
77   
78    A diagnostic esophagogastroduodenoscopy with multiple biopsies of the duodenum is 
79  needed to establish a diagnosis of CeD. One or two biopsies of the duodenal bulb and at 
80  least four biopsies of the distal duodenum should be obtained to confirm diagnosis 
81  (Rubio-Tapia 2013). The diagnostic endoscopy can be provided by historical record or 
82  performed during the screening period. 
83   
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
84    A screening esophagogastroduodenoscopy with biopsy should be performed to ensure 
85  patients meet histologic eligibility criteria at time of enrollment. We encourage sponsors 
86  to use a central reader to ensure consistent histologic evaluations. 
87   
88    Relying solely on symptomatic assessment without histologic evidence of active CeD 

89  at baseline may result in inclusion of patients whose symptoms are not caused by 
90  CeD (e.g., functional gastrointestinal disorders) (Drossman 2016), given that signs 
91  and symptoms of CeD are heterogeneous and can overlap with those of other 
92  gastrointestinal disorders.  
93   
94    We recommend that sponsors assess the mucosa with a clinically accepted histologic 

95  scale, which incorporates evaluation of villous atrophy, crypt hyperplasia, and 
96  intraepithelial lymphocytic infiltration (e.g., modified Marsh-Oberhuber 
97  classification) (Oberhuber 2000). Sponsors should reach agreement on the approach 
98  to the histologic assessment before trial initiation.   
99   
100    Patients should be sufficiently symptomatic at baseline, based on prespecified enrollment 
101  criteria, to allow for observation of improvement caused by treatment during the trial.  
102   
103    Investigators should document in a standardized case report form the type and 

104  severity/frequency of signs and symptoms to support eligibility.   
105   
106    The celiac serologies (e.g., anti-tissue transglutaminase or antigliadin antibodies) can be 
107  used in conjunction with clinical and histologic findings to aid in the diagnosis of CeD; 
108  however, celiac serology assays have not been cleared by the Center for Devices and 
109  Radiological Health to monitor disease progression or indicate disease stability or 
110  remission.3   
111   
112    Because strict adherence to a gluten-free diet is a known effective treatment for CeD, 
113  patients should maintain a stable gluten-free diet preceding enrollment for a prespecified 
114  duration (e.g., 1 year) and throughout the duration of the trial. Dietitians experienced in 
115  CeD management should evaluate patients during the screening period to assess for 
116  adherence to the gluten-free diet. 
117   
118    Sponsors should enroll patients who reflect the characteristics of clinically relevant 
119  populations, including with regard to race and ethnicity, and should consider clinical trial 
120  sites that include geographic locations with higher proportions of racial and ethnic 
121  minorities to recruit a diverse study population.4 
122   
 
3 Available at https://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm. 
 
4 For additional recommendations, see the guidance for industry Enhancing the Diversity of Clinical Trial 
Populations  Eligibility Criteria, Enrollment Practices, and Trial Designs (November 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.  
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
123  B.  Trial Design 
124   
125  Sponsors developing drugs to treat CeD as an adjunct to a gluten-free diet should consider the 
126  following: 
127   
128    We recommend a randomized, double-blind, placebo-controlled trial design. 
129   
130    We recommend that sponsors include a screening period before randomization of the 
131  patients to confirm histologic eligibility criteria, document persistence of clinical signs 
132  and symptoms, and train patients and/or care providers to collect the clinical outcome 
133  assessment (COA) data appropriately. 
134   
135    The trial duration and timing of efficacy assessments should be guided by the goal of 
136  therapy, mechanism of action of the drug and its expected onset of action, and the time 
137  frame in which a clinical benefit is expected to be observed.   
138   
139    For drugs intended to be administered chronically as adjunctive treatment to a gluten-free 
140  diet, we recommend a placebo-controlled treatment period of at least 52 weeks duration 
141  to allow for characterization of the safety profile and durability of response. Patients 
142  should continue the gluten-free diet throughout the 52-week duration. 
143   
144    The primary efficacy assessment on both clinical and histologic endpoints may be 

145  evaluated at week 24. 
146   
147    An esophagogastroduodenoscopy with biopsy should be performed at week 52 to 

148  assess for durability of response. Durability of response is especially important for 
149  diseases, such as CeD, that may result in serious clinical sequelae if untreated or 
150  inadequately treated over time. Persistent and/or worsening underlying histologic 
151  inflammation at week 52 would be inconsistent with the expected clinical benefit and 
152  will be taken into account when evaluating the benefit and risk.    
153   
154    Data from the entire controlled period (i.e., 52 weeks total) should be included at time 

155  of submission of an application for registration.   
156   
157    Sponsors should discuss with the appropriate review division the number of patients 

158  exposed to the to-be-marketed dosing regimen for a minimum of 1 year that should be 
159  available at the time of application submission.    
160   
161    Sponsors should include an assessment of patient adherence to the gluten-free diet during 
162  the treatment period.  
163   
164    We acknowledge the limitations of incorporating daily diet logs, as patients may 

165  modify behavior by adhering more or less strictly to the gluten-free diet in the setting 
166  of a clinical trial. At a minimum, we recommend that patients record any intentional 
167  or suspected inadvertent gluten exposure during the trial. 
168   
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
169    We recommend that dietitians experienced in CeD management be involved in 

170  evaluating patients for the adherence to the gluten-free diet during the treatment 
171  period.  
172   
173    The following considerations are relevant for trial designs that incorporate a gluten 
174  challenge: 
175   
176    Sponsors should justify the need for gluten challenge in the proposed trial. 

177    
178    The amount and duration of gluten exposure during a gluten challenge should be 

179  justified. 
180   
181    Patients with known history of severe hypersensitivity reactions or anaphylaxis to 

182  gluten should be excluded from participation in gluten challenges. 
183   
184    Histologic evaluations should be incorporated both before and after a gluten 

185  challenge to evaluate the response to gluten exposure. 
186   
187  C.  Efficacy Considerations 
188   
189  Sponsors developing drugs to treat CeD as an adjunct to a gluten-free diet should consider the 
190  following: 
191   
192  1.  Efficacy Assessments 
193   
194    Trials intended to support marketing approval should evaluate a drugs effect on both 
195  signs and symptoms and the related underlying mucosal inflammation. Therefore, 
196  sponsors should include coprimary endpoints5 in phase 3 trials that assess improvement 
197  or resolution from baseline in the following: 
198   
199    Clinically important signs and symptoms, using a well-defined and reliable COA 

200  instrument. 
201   
202    Histology using a clinically accepted scale (e.g., Marsh-Oberhuber classification). 

203   
204    The primary endpoint to assess symptomatic improvement should be based on 
205  prespecified core signs and symptoms of CeD and not be limited to a single sign or 
206  symptom. 
207   
208    We recommend a prespecified secondary endpoint to assess the proportion of patients 
209  who achieve improvement in both signs and symptoms and mucosal inflammation. 
210   
 
5 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. 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
211    We acknowledge that improvement of signs and symptoms and mucosal inflammation 
212  may not occur simultaneously. To inform timing of the endpoint assessments, sponsors 
213  should consider the duration of time in which improvement or resolution of signs and 
214  symptoms and mucosal inflammation are expected to occur based on the mechanism of 
215  action of the drug and the patient population. 
216   
217  2.  Clinical Outcome Assessments  
218   
219  Sponsors developing drugs to treat CeD as an adjunct to a gluten-free diet should consider the 
220  following: 
221   
222    FDA encourages sponsors to seek FDA input as early as possible and at important 
223  milestones throughout the drug development process to meet the challenges of COA 
224  development in this patient population.6 We also encourage sponsors to obtain patient 
225  input early in the drug development process to identify what matters most to patients 
226  regarding burden of disease and burden of treatment.7,8 
227   
228    Until a well-defined and reliable patient-reported outcome (PRO) instrument that 
229  measures the clinically important signs and symptoms of CeD is available and accepted 
230  for regulatory use, we recommend modifying an existing instrument or developing a new 
231  instrument based on patient input regarding the relevant and important signs and 
232  symptoms of CeD.7,8 For measurement of core signs and symptoms, sponsors should use 
233  instruments with daily assessments (e.g., past 24-hour recall period, event log) in which 
234  patients complete the instruments at the same time each day (e.g., evening before bedtime) 
235  or at the time of event.  
236   
237    Items assessing symptom severity (e.g., abdominal pain) should ask patients to rate their 
238  worst experience of a specific symptom over the past 24 hours. For example, item 
239  response options can be based on either a verbal rating scale (e.g., ratings are none, mild, 
240  moderate, severe, and very severe scored 0-4) or an 11-point (i.e., 0 to 10) numeric rating 
241  scale, where 0 reflects the absence of the symptom and 10 reflects the worst possible 
242  symptom experience. 
243   
244    Items assessing event-related signs and symptoms (e.g., diarrhea, vomiting) should ask 
245  patients to report each occurrence of a specific sign or symptom. Frequency should be 
246  reported as the exact number of episodes over a 24-hour period, and a clear definition of 
247  what is considered one episode should be provided to patients to ensure consistency both 
 
6 For general recommendations regarding PRO assessments (as well as information relevant for other COAs) and the 
documents to be provided to FDA for review, see the guidance for industry Patient-Reported Outcome Measures: 
Use in Medical Product Development to Support Labeling Claims (December 2009). 
 
7 For additional recommendations, see the guidance for industry, Food and Drug Administration staff, and other 
stakeholders Patient-Focused Drug Development: Collecting Comprehensive and Representative Input (June 2020).  
 
8 For additional recommendations, see the draft guidance for industry, Food and Drug Administration staff, and 
other stakeholders Patient-Focused Drug Development: Methods to Identify What Is Important to Patients (October 
2019). When final, this guidance will represent the FDAs current thinking on this topic. 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
248  within and between patients in reporting the number of episodes a sign or symptom has 
249  occurred. 
250   
251    Sponsors also can assess as secondary or exploratory endpoints, once identified, the 
252  important and common impacts of CeD signs or symptoms on patients daily lives using 
253  a separate score from the core signs and symptoms.  
254   
255    We recommend that sponsors, when modifying an existing PRO instrument or 
256  developing a new PRO instrument, use data obtained in phase 2 trials to help inform 
257  finalization of scoring algorithms and endpoint definitions. Piloting the proposed PRO 
258  instrument in phase 2 trials can provide the sponsor an opportunity to evaluate the 
259  instruments psychometric properties and performance (reliability, validity, and ability to 
260  detect change) as well as provide guidelines for interpretation of clinically meaningful 
261  within-patient change in scores and confirm the endpoint definition. Pilot results can 
262  further inform plans for implementation of the proposed instrument in phase 3 trials.  
263   
264  3.  Statistical Considerations 
265   
266  Sponsors developing drugs to treat CeD as an adjunct to a gluten-free diet should consider the 
267  following: 
268   
269    Efficacy analyses should include all randomized patients. 
270   
271    To support efficacy, the trial results should demonstrate statistical significance for both 
272  primary endpoints (clinical endpoint and histologic endpoint).  
273   
274  To gain precision in the evaluation of overall treatment effects, we recommend statistical 
275  analyses adjust for patient characteristics at baseline that may impact efficacy outcomes, such as 
276  age, duration of disease, disease severity, duration of prior adherence to gluten-free diet, etc.  
277   
278    Given that adherence to a gluten-free diet could impact efficacy outcome, sponsors 
279  should conduct analyses of adherence to a gluten-free diet. 
280   
281    Sponsors should prespecify a primary estimand of interest for each endpoint and justify 
282  that it is meaningful and that it can be estimated with minimal and plausible assumptions 
283  with the proposed analysis.9 All clinically important intercurrent events, such as 
284  treatment discontinuation, should be considered when defining an estimand. Potential 
285  strategies for handling intercurrent events include the following: 
286   
287    A treatment policy strategy in which outcomes are collected after the intercurrent 

288  event and used in analyses. 
289   
 
9 For additional recommendations, see the International Council for Harmonisation harmonized guideline E9(R1) 
Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the guideline on Statistical Principles for 
Clinical Trials, available at https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf. 
 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
290    A composite strategy in which patients who experience the intercurrent event are 

291  considered to have an unfavorable outcome (e.g., to have not achieved clinical or 
292  histologic improvement). 
293   
294    Sponsors should continue to follow patients after the occurrence of all intercurrent 
295  events, regardless of the strategy used in the primary analysis, to facilitate important 
296  analyses using a treatment policy strategy. The protocol should distinguish between 
297  reasons for treatment discontinuation and reasons for study withdrawal and should 
298  include plans to follow patients for collection of relevant data after treatment 
299  discontinuation and use of rescue therapies. 
300   
301    Sponsors should prespecify sensitivity analyses to evaluate whether the results from the 
302  primary and secondary analyses are robust to the missing data assumptions. These 
303  sensitivity analyses should comprehensively explore the space of plausible assumptions. 
304   
305  We recommend sponsors analyze COA endpoints as continuous or ordinal variables using 
306  baseline values as covariates. For COA endpoints, FDA does not recommend a percentage 
307  change from baseline endpoint. 
308   
309    Small but statistically significant group-level mean differences in the COA endpoint may 
310  not establish whether the effect is clinically meaningful. 
311   
312    To aid in the interpretation of the COA endpoint results, sponsors should propose an 

313  appropriate range of within-patient score change that patients consider to be clinically 
314  meaningful using anchor-based methods (e.g., patient global impression scales as 
315  anchors) supplemented with empirical cumulative distribution function curves using 
316  data pooled across trial arms. 
317   
318    Additionally, sponsors should submit for review empirical cumulative distribution 

319  function curves by treatment arm and supportive descriptive analyses of within-
320  patient changes from baseline. 
321   
322  D.  Safety Considerations 
323   
324  Sponsors developing drugs to treat CeD as an adjunct to a gluten-free diet should consider the 
325  following: 
326   
327    Given that the therapeutic benefit of an investigational drug is unknown during conduct 
328  of clinical trials, it is critical that patients understand the importance of adhering to the 
329  gluten-free diet, and risks of nonadherence should be communicated in the informed 
330  consent form.   
331   
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
332    For drugs intended for long-term treatment, such as for CeD, a sufficient number of 
333  patients should be exposed to the to-be-marketed dosing regimen for at least 52 weeks to 
334  characterize the safety profile of the drug.10 
335   
336    For trials of therapeutic protein products, such as monoclonal antibodies, sponsors should 
337  consider recommendations in the guidance for industry Immunogenicity Assessment for 
338  Therapeutic Protein Products (August 2014).  Sponsors should evaluate neutralizing 
339  capabilities of antidrug antibodies and their impact on clinical efficacy and safety. 
340   
341    Sponsors should prospectively plan for safety analyses to compare treatment groups with 
342  respect to risk (e.g., with a risk difference, relative risk, rate ratio, or hazard ratio) along 
343  with a confidence interval for the chosen metric to help quantify the uncertainty in the 
344  treatment comparison. Sponsors should stratify by study any analyses of integrated data 
345  from multiple studies.
 
10 For recommendations regarding 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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Draft  Not for Implementation 
346  REFERENCES 
347   
348  Literature 
349   
350  Catassi C, Bearzi I, and Holmes GKT, 2005, Association of Celiac Disease and Intestinal 
351  Lymphomas and Other Cancers, Gastroenterology, 128(4 Suppl 1):S79S86. 
352   
353  Drossman DA, 2016, Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical 
354  Features, and Rome IV, Gastroenterology, 150(6):12621279. 
355   
356  Green PHR and Cellier C, 2007, Celiac Disease, N Engl J Med, 357(17):17311743. 
357   
358  Oberhuber G, Histopathology of Celiac Disease, 2000, Biomed Pharmacother, 54(7):368372. 
359   
360  Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, and Murray JA, 2013, ACG Clinical 
361  Guidelines: Diagnosis and Management of Celiac Disease, Am J Gastroenterol, 108(5):656676.  
362   
363  Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, and Everhart JE, 2012, The Prevalence 
364  of Celiac Disease in the United States, Am J Gastroenterol, 107(10):15381544. 
365   
366  Rubio-Tapia A, Rahim MW, See JA, Lahr BD, Wu TT, and Murray JA, 2010, Mucosal 
367  Recovery and Mortality in Adults with Celiac Disease after Treatment with a Gluten-Free Diet, 
368  Am J Gastroenterol, 105(6):14121420. 
369   
370  Wahab PJ, Meijer JWR, and Mulder CJJ, Histologic Follow-Up of People with Celiac Disease 
371  on a Gluten-Free Diet: Slow and Incomplete Recovery, 2002, Am J Clin Pathol, 118(3):459463. 
372   
373  Guidances1 
374   
375  Draft guidance for industry, Food and Drug Administration staff, and other stakeholders Patient-
376  Focused Drug Development: Methods to Identify What Is Important to Patients (October 2019)2 
377   
378  Draft guidance for industry Multiple Endpoints in Clinical Trials (January 2017)3 
379   
380  Guidance for industry, Food and Drug Administration staff, and other stakeholders Patient-
381  Focused Drug Development: Collecting Comprehensive and Representative Input (June 2020) 
382   
 
1 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. 
 
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. 
 
3 When final, this guidance will represent the FDAs current thinking on this topic. 
 
  10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
383  Guidance for industry Immunogenicity Assessment for Therapeutic Protein Products (August 
384  2014) 
385   
386  Guidance for industry Patient-Reported Outcome Measures: Use in Medical Product 
387  Development to Support Labeling Claims (December 2009) 
388   
389  Guidance for industry Premarketing Risk Assessment (March 2005) 
390   
391  International Council for Harmonisation harmonized guideline E9(R1) Addendum on Estimands 
392  and Sensitivity Analysis in Clinical Trials to the guideline on Statistical Principles for Clinical 
393  Trials (November 2019)4 
394   
 
4 Available at https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf. 
  11