Bowel Cleansing for 
Colonoscopy: Efficacy and 
Safety Considerations for 
Developing New Products 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Andrew Kelleher at 301-796-9330.  
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2021 
Clinical/Medical 
37295516dft.docx 
11/30/21  Bowel Cleansing for 
Colonoscopy: Efficacy and 
Safety Considerations for 
Developing New Products 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD  20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
December 2021 
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Draft  Not for Implementation 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 ........................................................................................................................ 2 
C.  Efficacy Considerations .................................................................................................... 3 
1. Efficacy Assessments ........................................................................................................... 3 
2. Statistical Considerations .................................................................................................... 5 
D.  Safety Considerations ........................................................................................................ 6 
E.  Additional Considerations ................................................................................................ 7 
REFERENCES ...................................................................................................................8 
APPENDIX .........................................................................................................................9 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Bowel Cleansing for Colonoscopy: Efficacy and Safety 
2  Considerations for Developing New Products 
3  Guidance for Industry1 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION 
18   
19  The purpose of this guidance is to help sponsors in the clinical development of products2 for 
20  bowel cleansing in preparation for a colonoscopy3.  Specifically, this guidance describes the 
21  Food and Drug Administrations (FDAs) current thinking about the necessary attributes of 
22  clinical trials for drugs being developed under Section 505 of the Food, Drug, and Cosmetic Act 
23  (21 U.S.C 355) and 21 CFR Parts 312 and 314 for use as bowel cleansing agents before 
24  colonoscopy, including trial population, trial designs, efficacy considerations, and safety 
25  assessments.4 
26   
27  The contents of this document do not have the force and effect of law and are not meant to bind 
28  the public in any way, unless specifically incorporated into a contract.  This document is 
29  intended only to provide clarity to the public regarding existing requirements under the law.  
30  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
31  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
32  Agency guidances means that something is suggested or recommended, but not required. 
33   
34   
 
1 This guidance has been prepared by the Division of Gastroenterology and Inborn Errors Products in the Center for 
Drug Evaluation and Research at the U.S. Food and Drug Administration. 
 
2 For the purposes of this guidance, product refers to either a new drug with a single active pharmaceutical 
ingredient, or a fixed-dose combination drug product. 
 
3 This draft guidance is being issued consistent with FDAs good guidance practices regulation (21 CFR 10.115). 
When finalized, it will represent FDAs current thinking on this topic.  
 
4 In addition to consulting guidances, sponsors are encouraged to contact the Division to discuss specific issues that 
arise during the development of products. 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
35  II.  BACKGROUND 
36   
37  Colorectal cancer is a leading cause of cancer death in U.S. adults (Siegel et al. 2017).  A 
38  colonoscopy is recommended as the preferred modality for colorectal cancer screening (Rex et 
39  al. 2017). 
40   
41  The success of a colonoscopy is closely linked to the adequacy of preprocedure bowel cleansing, 
42  and up to 25 percent of all colonoscopies are reported to have inadequate bowel preparation.  
43  Inadequate bowel preparation results in lower adenoma detection rate, longer procedural time, 
44  lower cecal intubation rate, increased electrocautery risk, and shorter intervals between 
45  examinations (Johnson et al. 2014).  Adequate bowel preparation is also important for 
46  diagnosing, surveilling, and treating other gastrointestinal conditions. 
47   
48  The goal of bowel cleansing is to remove fecal matter and fluids from the colon to permit 
49  adequate visualization of colonic mucosa (Wexner et al. 2006; Mamula et al. 2009).  An optimal 
50  bowel cleansing product is safe, efficacious, and well tolerated, and results in high rates of 
51  patient compliance with the prescribed regimen. 
52   
53   
54  III.  DEVELOPMENT PROGRAM 
55   
56  A.  Trial Population 
57   
58  Sponsors developing products for bowel cleansing for colonoscopy should consider the 
59  following: 
60   
61    Include patients undergoing routine colonoscopy either for screening or diagnostic 
62  purposes. 
63   
64    Enroll a population that is sufficiently broad and inclusive to assess safety and efficacy 
65  across all relevant subgroups likely to use the product.  For example, enroll adequate 
66  numbers of patients older than 65 years of age, as well as adequate representation of 
67  ethnic and racial minorities. 
68   
69    Include patients with stable chronic kidney disease when available nonclinical and 
70  clinical data indicate that exposing patients with reduced kidney function to a bowel-
71  cleansing product would not place patients at unreasonable risk and/or adequate steps can 
72  be taken to mitigate potential risks.  Sponsors should provide adequate justification for 
73  including/excluding patients with different levels of kidney function based on the stage of 
74  product development, safety profile of the product, and understanding of the effect of 
75  kidney function on elimination of the product, if absorbed. 
76   
77  B.  Trial Design 
78   
79  Sponsors developing products for bowel cleansing for colonoscopy should consider the 
80  following: 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
81   
82    We recommend a randomized, investigator/colonoscopist-blinded, parallel group trial 
83  design. 
84   
85    Typically, trials to demonstrate efficacy of new bowel-cleansing products are designed as 
86  noninferiority trials with comparison to one or more approved bowel-cleansing products. 
87   
88    Sponsors should select an appropriate active comparator that demonstrates an efficacy 
89  profile that is relevant to the current standard of care.  The active comparator should be 
90  agreed upon with the Division before trial initiation.  
91   
92    An appropriate comparator is a U.S.-approved product, is widely used in U.S. clinical 
93  practice at the time of the trial, and has demonstrated efficacy using split-dose 
94  administration.  Choice of active control is further discussed in the guidance for 
95  industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016).5  
96   
97    In general, we recommend that both the active comparator and the new product be 
98  administered in a split-dose administration schedule, consistent with current 
99  recommendations to optimize efficacy.  Sponsors intending to study the new product 
100  as a single-day dose should discuss the plan and justification (e.g., safety in a specific 
101  subpopulation, etc.) with the Division before trial initiation.  
102   
103    We recommend that a different active comparator be used across the two phase 3 
104  trials (e.g., large volume versus low volume, or two products with different active 
105  ingredients) to best characterize the efficacy and safety profile of the new product.  
106   
107  C.  Efficacy Considerations 
108   
109  1.  Efficacy Assessments 
110   
111  Sponsors developing products for bowel cleansing for colonoscopy should consider the 
112  following: 
113   
114    Efficacy should be assessed during insertion of the colonoscope (i.e., before washing and 
115  suctioning) to ensure that the effect measured is attributable to the bowel-cleansing 
116  product, not to intraprocedural cleansing efforts of the colonoscopist.6 
117   
118    All colonoscopy readings should be video recorded. 
119   
 
5 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
6 For studies that were initiated before publication of this guidance and are assessing efficacy during withdrawal of 
the colonoscope, sponsors should discuss with the Division the additional analyses that will be requested to support 
the efficacy assessment (e.g., volume of water used to clean, time spent washing, etc.). 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
120    We recommend that each endoscopy video be reviewed and scored by at least one 
121  independent central reader who is blinded to treatment assignment.  However, alternative 
122  proposals (e.g., adjudicating a random subset for quality control) may be discussed with 
123  the Division. 
124   
125    The quality of the bowel preparation on insertion should be assessed primarily using air 
126  insufflation, and colonoscopists should be instructed to minimize use of water flushing to 
127  permit assessment of the effects of the bowel-cleansing product.  
128   
129    We recommend the following regarding selection of a bowel cleansing scale to assess 
130  efficacy: 
131   
132    Efficacy scales used to define the categories of excellent, good, fair, and poor should 
133  be based on nonoverlapping criteria.  Previously used scales7 have some limitations 
134  (such as overlapping criteria between grades) but may be modified to improve clarity 
135  of definition or criteria.  A recommended four-point scale that could be used is shown 
136  in Table 1 (see Appendix).  Sponsors wishing to develop an alternative scale should 
137  meet with the Division early in development to ensure agreement is reached on the 
138  adequacy of the proposed scale. 
139   
140    Each colon segment should be scored individually.8 
141   
142    We recommend the following primary endpoint: 
143   
144    Proportion of patients achieving successful bowel cleansing (defined as a score of 
145  excellent or good in every colon segment). 
146   
147    Because adequate visualization of the entire colon is important, particularly in 
148  screening colonoscopy to avoid missed lesions, a score of fair or poor in any segment 
149  will result in the patient being considered a failure for the primary efficacy analysis. 
150   
151    We recommend the following secondary endpoints: 
152   
153    Cecal/ileal intubation rate 
154    Proportion of patients achieving excellent grade in all segments 
155    Time to reach cecum 
156    Adenoma detection rate 
157    Nonpolypoid adenoma detection rate9 
 
7 Examples of scales used in the past include Aronchick, Boston, and Harefield cleansing scales. 
 
8 Colon segments should be defined as follows: right colon (to include cecum and ascending colon); transverse colon 
(to include splenic flexure, transverse colon, and hepatic flexure); and left colon (to include descending colon, 
sigmoid colon, and rectum). 
 
9 Defined as the proportion of subjects with at least one nonpolypoid adenoma detected. 
 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
158   
159  2.  Statistical Considerations 
160   
161  Sponsors developing products for bowel cleansing for colonoscopy should consider the 
162  following: 
163   
164    Sponsors should prespecify a primary estimand of interest for each endpoint and justify 
165  that it is meaningful and that it can be estimated with minimal and plausible assumptions 
166  with the proposed analysis.10   
167   
168    Sponsors should conduct the primary efficacy analysis in the population of all 
169  randomized patients who received at least a partial dose (initiated the first dose), 
170  excluding patients who did not undergo a colonoscopy for reasons other than safety or 
171  lack of efficacy (e.g., procedure cancelled for scheduling reason, study colonoscopist 
172  unavailable because of emergency).  The reason should be clearly documented.  
173  Excluding a large number of patients for these types of reasons would be evidence of 
174  poor study conduct and may raise a review issue. 
175   
176    Sponsors should prespecify methods to handle missing values for the primary and 
177  secondary endpoints in the statistical analyses and should align them with the targeted 
178  estimand of interest. 
179   
180    Patients unable to complete preparation because of adverse events or patients whose 
181  physician opted not to conduct the colonoscopy because of inadequate preparation should 
182  be considered nonresponders. 
183   
184    Supplementary analyses should evaluate the probability of successful bowel cleansing 
185  in the subset of patients who completed the full dose of study medication. 
186   
187    Strategies for handling other types of missing data, including missing segmental data, 
188  should be discussed with the Division and clearly specified in the SAP. 
189   
190    The noninferiority (NI) margin should be prespecified and informed by the maximal 
191  degree of inferiority of the test product to the active control that can be considered 
192  acceptable to support approval.11  Sponsors should submit a detailed justification of the 
193  proposed NI margin to FDA and reach agreement with FDA on this margin before 
194  initiating a trial. 
195   
 
10 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. 
 
11 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness. 
 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
196    The choice of active comparator should be justified and relevant to current practice 
197  standards to avoid biocreep12 (refer to section III. B., Trial Design).  
198   
199  D.  Safety Considerations 
200   
201  Sponsors developing products for bowel cleansing for colonoscopy should consider the 
202  following: 
203   
204    In-person study visits should occur at randomization, day of colonoscopy (before 
205  procedure), and 48 to 72 hours after colonoscopy for all patients to assess vital signs and 
206  blood chemistry. 
207   
208    For patients with clinically significant abnormal laboratory tests at 48 to 72 hours post-
209  colonoscopy, sponsors should conduct an additional study site visit for laboratory testing 
210  7 days post-colonoscopy. 
211   
212    Thresholds to define clinically significant abnormal laboratory parameters that would 
213  mandate repeat visits, even in the absence of symptoms, should be specified in the 
214  protocol and agreed upon with FDA before trial initiation. 
215   
216    Patients with ongoing adverse events should be followed until resolution or stabilization 
217  of symptoms.  If the adverse event was a laboratory test abnormality, sponsors should 
218  conduct repeat testing to document return to baseline or, if not resolving, until stable. 
219   
220    Sponsors should prospectively plan for safety analyses to compare treatment groups with 
221  respect to risk (e.g., with a risk difference, relative risk, rate ratio, or hazard ratio) along 
222  with a confidence interval for the chosen metric to help quantify the uncertainty in the 
223  treatment comparison.  Sponsors should stratify by study any analyses of integrated data 
224  from multiple studies. 
225   
226    We recommend the following laboratory shift analyses: 
227   
228    Proportion of patients with a normal baseline laboratory value who had a post-
229  baseline value outside the normal limit at the 48 to 72 hours post-colonoscopy visit. 
230   
231    Sponsors should further summarize these results by severity grade of the 
232  electrolyte abnormality, using a standard rating scale such as the Common 
233  Terminology Criteria for Adverse Events. 
234   
235    Proportion of patients with possible acute kidney injury, defined as those patients 
236  who experienced an increase in serum creatinine from baseline of more than 0.3 
237  mg/dL within 48 to 72 hours. 
 
12 Biocreep phenomenon may occur when an investigational treatment is noninferior but slightly worse compared 
with its active control; later on, the same treatment is used as an active control for another NI trial.  If this pattern 
repeats several times in a sequence of NI trials, then it may result in a suboptimal standard for achieving efficacy 
and allow inferior treatments to be marketed. 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
238   
239    Sponsors should summarize additional details on the clinical course of these 
240  patients in the submission, with documentation of outcome as resolved, resolving 
241  or persistent increase above baseline. 
242   
243    Sponsors should also conduct this analysis separately in the subgroup of patients 
244  with abnormal baseline renal function to determine whether patients with 
245  preexisting renal impairment are more susceptible to acute kidney injury. 
246   
247  E.  Additional Considerations 
248   
249  If the proposed study product contains two or more active ingredients, it would most likely be 
250  considered a fixed-dose combination product as defined in 21 CFR 300.50.  Sponsors should 
251  meet with the Division regarding fixed-dose combination considerations early in the 
252  development process.
7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
253  REFERENCES 
254   
255  Literature 
256   
257  Johnson DA, Barkun AN, Cohen LB, Dominitz JA, Kaltenbach T, Martel M, Robertson DJ, 
258  Boland RC, Giardello FM, Lieberman DA, Levin TR, and Rex DK, 2014, Optimizing Adequacy 
259  of Bowel Cleansing for Colonoscopy: Recommendations From the US Multi-Society Task Force 
260  on Colorectal Cancer, Am J Gastroenterol, 109(10):15281545. 
261   
262  Mamula P, Adler DG, Conway JD, Diehl DL, Farraye FA, Kantsevoy SV, Kaul V, Kethu SR, 
263  Kwon RS, Rodriguez SA, Tierney WM, 2009, Colonoscopy Preparation. Gastrointest Endosc,  
264  69(7):12011209. 
265   
266  Rex DK, Boland RC, Dominitz JA, Giardiello FM, Johnson DA, Kaltenbach T, Levin TR, 
267  Lieberman D, and Robertson DJ, 2017, Colorectal Cancer Screening: Recommendations for 
268  Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal Cancer, Am J 
269  Gastroenterol, 112(7):10161030. 
270   
271  Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, and Jemal A, 2017, 
272  Colorectal Cancer Statistics. CA Cancer J Clin, 67(3):177193. 
273   
274  Wexner SD, Beck DE, Baron TH, Fanelli RD, Hyman N, Shen B, and Wasco KE, 2006, A 
275  Consensus Document on Bowel Preparation Before Colonoscopy: Prepared by the Task Force 
276  From the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for 
277  Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and 
278  Endoscopic Surgeons (SAGES), Gastrointest Endosc, 63(7):894909. 
279   
280   
281  Guidances1 
282   
283  Guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 
284  2016) 
285   
286  International Council for Harmonisation harmonized guideline E9(R1) Addendum on Estimands 
287  and Sensitivity Analysis in Clinical Trials to the guideline on Statistical Principles for Clinical 
288  Trials (November 2019)2 
289   
 
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 Available at https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf. 
8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
290  APPENDIX 
291   
292  An acceptable four-point efficacy scale (see Table 1) that could be used to define the categories 
293  of excellent, good, fair, and poor is shown below. 
294   
295   
296  Table 1 Elements That Should Be Included in the Grading Criteria of the Bowel Cleansing 
297  Assessment Scale 
Grading  Criteria 
Excellent  No more than small bits of fecal residue or fluid that requires no washing 
and no/minimal suctioning, resulting in clear visualization of the entire 
colonic mucosa. 
Good  Small amounts of fecal residue or fluid that can be easily washed and 
suctioned but still results in clear visualization of the entire colonic 
mucosa. 
Fair  Enough feces to require extensive washing and suctioning, which may 
prevent clear visualization of the entire colonic mucosa. 
Poor  Large amount of fecal residue; clear visualization of entire colonic mucosa 
is not possible. 
298   
9