Guidance for Industry 

Irritable Bowel Syndrome  

Clinical Evaluation of Drugs 

for Treatment 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
May 2012 

Clinical/Medical 

 
   
Guidance for Industry 

Irritable Bowel Syndrome  

Clinical Evaluation of Drugs 

for Treatment
  
 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 
 
Center for Drug Evaluation  and Research 
 
Food and  Drug Administration 

10903 New Hampshire Ave., Bldg. 51, rm. 2201 
 
Silver Spring, MD   20993-0002 
 
Tel:  301-796-3400; Fax: 301-847-8714; E-mail:  druginfo@fda.hhs.gov 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
May 2012 

Clinical/Medical 

   
TABLE OF CONTENTS 

 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 2 
 
III.   EVOLUTION OF PRO MEASURES IN IBS CLINICAL TRIALS ........................... 2  

IV.   PROVISIONAL ENDPOINTS AND TRIAL DESIGN FOR IBS CLINICAL TRIALS. 4 
 
1.  Trial Design .....................................................................................................................................4
  
2.  Trial Endpoints ................................................................................................................................5
  
3.  Trial Populations .............................................................................................................................6
  
4.  Efficacy Measures............................................................................................................................7
  
5.  Definition of a Responder................................................................................................................7
  
V.   FUTURE DEVELOPMENT OF IBS PRO INSTRUMENTS.................................... 11 
 
VI.   CONCLUSION ............................................................................................................... 11
  
REFERENCES............................................................................................................................ 12 
 
  Contains Nonbinding Recommendations 
1
 
Guidance for Industry  
Irritable Bowel Syndrome  

Clinical Evaluation of Drugs for Treatment 

 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance. 
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to assist the pharmaceutical industry and investigators who are 
developing drugs2 for the treatment of irritable bowel syndrome (IBS).  IBS diagnosis and 
assessment of clinical status depend mainly on an evaluation of IBS signs and symptoms that are 
known to the patient. Capturing all of the clinically important signs and symptoms associated 
with IBS in a reliable measure of treatment benefit can be challenging.  The guidance for 
industry Patient-Reported Outcome Measures:  Use in Medical Product Development to Support 
Labeling Claims (PRO guidance)3 defines the term  treatment benefit as [t]he effect of treatment 
on how a patient survives, feels, or functions. 
 
This guidance addresses two main topics.  Section III discusses the evolution of patient-reported 
outcome (PRO) measures as primary endpoints for IBS clinical trials; and section IV provides a 
set of provisional endpoints and trial design recommendations that sponsors may apply to IBS 
clinical trials as PRO measurements continue to evolve.  The guidance also discusses, in section 
V, the future development of IBS PRO instruments through the FDA qualification process and 
the FDAs collaboration with the Critical Path Institute.  The recommendations provided in this 
guidance are consistent with good measurement science as reflected in other FDA guidance.   
 
                                                 
1 This  guidance has been  prepared by the Division of  Gastroenterology and Inborn Errors Products and the Study  
Endpoints and Labeling Development Team  in the Center for Drug  Evaluation and Research (CDER) at 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. 
 
3  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
  1
  Contains Nonbinding Recommendations 
The goal for efficacy endpoints in IBS clinical trials is to assess the treatment effect on the core 
disease-defining signs and symptoms of IBS in a well-defined and reliable way.  Until such 
endpoints are available, the provisional endpoint assessments suggested in this guidance can be 
used in the evaluation of treatment benefit in IBS clinical trials. 
 
This guidance applies to the IBS indications for IBS with diarrhea (IBS-D) and IBS with 
constipation (IBS-C). Sponsors should contact the Division of Gastroenterology and Inborn 
Errors Products to discuss endpoint assessments and trial design proposals for other IBS 
populations not discussed in this guidance (i.e., mixed irritable bowel syndrome and unsubtyped 
irritable bowel syndrome). 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
 
II.  BACKGROUND  
 
IBS is a complex condition that is not well-linked to any readily measured physiological 
abnormality.  Despite advances in our understanding of basic neuroenteric mechanisms and the 
role of effectors and transmitters in the brain-gut axis, a reliable biologic marker of IBS has yet 
to be indentified.4  PRO measures of the signs and symptoms of the condition are the only 
currently available measures that can adequately define a treatment effect in a clinical trial.  
 
 
III.   EVOLUTION OF PRO MEASURES IN IBS CLINICAL TRIALS 
 
An adequate measure of treatment benefit should capture the most significant signs and 
symptoms of IBS.  The primary challenge in designing clinical trials to evaluate the efficacy of 
drugs for this condition has been to define the critical signs and symptoms that are most relevant 
to patients, and then select or develop adequate assessment tools that measure improvement and 
decrements in these important signs and symptoms.   
 
In the past, IBS clinical trials commonly used a single-item patient-reported rating of overall 
change in condition as the primary efficacy endpoint.5  When the single-item patient-reported 
rating of change was used as the primary endpoint, specific IBS signs and symptoms were often 
included as separate secondary endpoints.  As detailed in Table 1, examples of single-item  
patient-reported ratings of change have included questions posed to patients about adequate 
relief or satisfactory relief and the single item  Subject Global Assessment of Relief of IBS 
symptoms. Usually, the patient-reported ratings of change required patients to average either 
specific symptoms (e.g., abdominal pain or discomfort) or all signs and symptoms of IBS over a 
                                                 
4 See reference  numbers 1-8 in the References section at the end of the guidance. 
 
5 See reference  numbers 9-23 in the References section at the end of the guidance. 
  2
  Contains Nonbinding Recommendations 
weeks time, and then compare this average to a period in the past, typically before trial entry.  
Table 1 describes primary endpoints that have been used in several IBS clinical trials.  Although 
these endpoints may well have captured the direction of change (trials were controlled and 
blinded), they could not provide useful information on the effect of treatment on the severity of a 
specific sign or symptom. 
 
Table 1. Primary Endpoints Used in IBS Clinical Trials 
Drug and  Primary  Questions (Single-Item) Used to Assess Efficacy   Responses 
Indication  Endpoint 
Alosetron   Adequate relief  In the past 7 days, have you  had  adequate relief of   Binary (Yes/No) 
IBS-D1     your IBS pain or  discomfort?    
       
Tegaserod   Satisfactory  Did you have satisfactory relief of your overall IBS  Binary (Yes/No) 
IBS-C2   relief  symptoms  during the last week?    
       
    Did you have satisfactory relief of your abdominal   Binary (Yes/No) 
    discomfort or pain during the last week?    
       
  Subject Global   Please consider how you felt during the past   5-Point Likert scale  
  Assessment of  treatment period in  regard to your  IBS, in  particular    
  Relief (SGA)  your overall well-being, and symptoms of  abdominal    
    pain/discomfort and altered bowel habit. Compared    
    to the way you  usually felt before entering the trial,   
    how would you rate your relief of symptoms  during   
    the past week?   
       
Lubiprostone   Modified   How would you rate your relief of IBS symptoms   7-Point Likert scale  
 IBS-C3  version of the  (abdominal discomfort/pain, bowel habits, and  other 
  SGA  IBS symptoms) over the past  week compared with how 
you felt before you entered the trial?  
1 See reference numbers 9-14 in the References section at the end of the guidance.  
2 See reference numbers 15-22 in the References section at the end of the guidance.  
3 See reference number 23 in the References section at the end of the guidance. 
 
As noted above, the PRO guidance defines treatment benefit as the effect of treatment on how a 
patient survives, feels, or functions. PRO instruments define and capture the patients 
perspective with respect to the disease or condition of interest and can be appropriate for 
measuring the effect of treatment in a clinical trial, particularly when the desired effect of the 
treatment is on signs and symptoms known only to the patient.  Consistent with FDA regulations 
for drug approval, the effectiveness of a treatment must be based on substantial evidence 
including evidence that the method of assessment of subjects responses are well-defined and 
reliable (21 CFR 314.126(b)(6)).  The PRO guidance sets forth the FDAs review principles for 
determining whether assessments are well-defined (i.e., valid) and adequately developed (i.e., 
reliable, sensitive, and interpretable) to measure what they are intended to measure.  
 
As reflected in the PRO guidance, the type of PRO instruments we consider appropriate for data 
collection to support labeling claims has evolved from what was considered appropriate in the 
past. For example, we no longer recommend a single general item asking patients to rate change 
in their overall IBS symptoms as a primary endpoint to support an efficacy claim.  A single 
general item cannot adequately capture whether benefit is achieved in all, or only some, of the 
important signs and symptoms.  For example, a single item that queries a patient about his or her 
  3
  Contains Nonbinding Recommendations 
overall IBS experience will likely not capture a situation where the patients stool frequency has 
improved, but abdominal pain has not improved or even worsened.   
 
In recognition of the limitations of using a single-item patient-reported rating of overall change 
as a primary endpoint and based on the principles explained in the PRO guidance, we now 
recommend the development of a multi-item PRO instrument.  The PRO measure(s) should 
capture all of the clinically important signs and symptoms of the IBS target population (e.g., 
IBS-C or IBS-D). Changes from previous scores can then be calculated.  If a drug is developed 
specifically to improve only one of the major signs or symptoms of IBS (e.g., abdominal pain), 
based on the drugs mechanism of action, it is still important to assess the other important signs 
and symptoms to document that the drug has not negatively affected those components.  
Ultimately, the drugs indication should reflect the findings from the clinical trials.   
 
 
IV. 	 PROVISIONAL ENDPOINTS AND TRIAL DESIGN FOR IBS CLINICAL 
TRIALS 
 
A well-defined and reliable PRO instrument that measures the clinically important signs and 
symptoms associated with each IBS subtype would be the ideal primary efficacy assessment tool 
in clinical trials used to support labeling claims, but at this time such an instrument is not 
available. We recognize that it will take some time to develop adequate instruments and that in 
the meantime there is a great need to develop effective therapies for patients with IBS.  
Therefore, until the appropriate PRO instruments  have been developed, sponsors should consider 
the strategies discussed in the following sections when designing IBS clinical trials.  These 
sections set forth provisional standards with regard to:  (1) trial design; (2) trial endpoints; (3) 
trial populations; (4) efficacy measures; and (5) definition of a responder.    
 
Following this discussion is Table 2, which summarizes the provisional standards for IBS-C and 
IBS-D trial designs, including primary endpoints, patient entry criteria, and responder 
definitions.  Table 2 is intended as a summary of the discussion in this guidance.  Sponsors 
should refer to the text of the guidance for full detail.    
 
1.  T	 rial Design 
 
Because the clinical signs and symptoms associated with IBS-C and IBS-D can be significantly 
different, the two conditions ordinarily should be studied in separate clinical trials.  
 
A randomized, placebo-controlled trial design should include a 1- to 2-week single-blind or 
open-label screening period. The 1- to 2-week screening period can be used to establish the 
presence and persistence of trial entry criteria and train patients in the mode of PRO data 
collection selected for the trial.  The screening period can also be used to select patients with 
specified levels of severity of signs and symptoms.  For therapies that will be administered on a 
chronic and continuous basis, we recommend a treatment period of at least 8 weeks duration, 
followed by a randomized withdrawal design to address the need for maintenance treatment to 
prevent sign or symptom recurrence.   
 
  4
  Contains Nonbinding Recommendations 
For therapies with an intermittent administration schedule, sponsors should provide repeated 
courses of therapy to demonstrate sustained efficacy over time, and to characterize the safety of 
intermittent and repeated administration.   
 
2.  Trial Endpoints 
 
To support an indication of treatment of IBS, we recommend a primary endpoint that measures 
the effect of treatment on two major IBS signs and symptoms:  abnormal defecation and 
abdominal pain.6  The primary efficacy analysis should be a comparison of the response rates 
between investigational drug and placebo. 
 
For IBS-C, the defecation component of the proposed primary endpoint can be evaluated by 
assessing stool frequency. Stool frequency, as measured by the number of complete spontaneous 
bowel movements (CSBMs) per week, is readily defined, has been useful in defining a treatment 
response in chronic constipation clinical trials, and is clinically relevant for IBS-C patients.  
 
For IBS-D, the defecation component of the proposed primary endpoint can be evaluated by 
assessing stool consistency.7  The Bristol Stool Form Scale, which is reproduced in Figure 1, 
provides a pictorial and verbal description of stool consistency and form and is an appropriate 
instrument for capturing stool consistency in IBS trials.8    
 
Figure 1. Bristol Stool Form Scale  
 
                                                 
6 See reference  number 24 in the References section at the end of the guidance. 
 
7 See reference  numbers 25 and 26 in the References section at the end of the guidance.  
 
8 See reference  number 27 in the References section at the end of the guidance. 
  5
  Contains Nonbinding Recommendations 
 
Stool frequency should be evaluated as a key secondary endpoint, using the weekly number of 
CSBMs. Stool consistency, rather than stool frequency, is the recommended primary endpoint 
for IBS-D because it is more clinically relevant and better correlated with signs and symptoms of 
diarrhea.  Currently, there are insufficient data to adequately quantify and qualify the concept of 
urgency based on the patients perspective and thus to support its use as a component of the 
primary endpoint definition of treatment response.  Until an adequate urgency assessment tool is 
developed, stool urgency should be assessed as an exploratory endpoint in IBS-D trials. 
 
The second component of the primary endpoint in both IBS-C and IBS-D trials is abdominal 
pain. Although previous IBS clinical trials have used an item that assesses abdominal pain or 
discomfort, it is not clear whether the abdominal pain and abdominal discomfort experienced by 
patients with IBS are synonymous or two different symptoms.  Although adequate qualitative 
trials have not fully addressed these questions, clinical data provided to and reviewed by the 
FDA suggest that abdominal pain and discomfort may be different symptoms that should be 
assessed by different questions. Because frank pain seems to be a symptom that is experienced 
with more significant intensity than discomfort and because the chronic pain literature suggests 
that pain intensity may be a more clinically relevant assessment than pain frequency,9 we 
recommend abdominal pain intensity as the primary pain assessment in IBS trials.  Abdominal 
discomfort can be evaluated as a secondary endpoint. 
 
We recommend evaluating abdominal pain intensity by using an 11-point (i.e., 0 to 10) numeric 
rating scale that asks patients daily to rate their worst abdominal pain over the past 24-hours.10    
 
This type of pain assessment has been used to assess pain in somatic, visceral, and neuropathic 
chronic pain conditions.11    
 
A drug can be specifically developed to treat only one of the major signs or symptoms of IBS, 
which should be identified as the primary endpoint in the clinical trial.  The identification of a 
single sign or symptom of interest should be based on the mechanism of action of the drug.  The 
other key efficacy endpoints should be assessed in the clinical trial as secondary endpoints.  
Demonstration of significant and clinically meaningful changes in the targeted single endpoint 
could serve as a basis for approval, as long as the other important symptoms or signs have not 
worsened on treatment.    
 
3.  Trial Populations 
 
Based upon the evolution of the IBS diagnostic criteria, prospective IBS clinical trials should 
enroll patients who meet the subtype-specific Rome III IBS diagnostic criteria.12  In addition, 
patients who enter the trial should have the clinical manifestations of IBS that will be assessed in 
                                                 
9 See reference  number 28 in the References section at the end of the guidance. 
 
10 See reference  numbers 28 and 29 in the References section at the end of the guidance.  
 
11 See reference  number 30 in the References section at the end of the guidance. 
 
12 See reference  number 25 in the References section at the end of the guidance. 
  6
  Contains Nonbinding Recommendations 
the trial to define treatment response, and the manifestations should be present with sufficient 
intensity to make demonstration of a clinically meaningful improvement possible.  In light of the 
components of the primary endpoints for IBS-C and IBS-D previously described, we recommend 
that trial entry criteria include the following:   
 
IBS-C 
   Abdominal Pain Intensity:  weekly average of worst daily (in past 24 hours) abdominal 
pain score of > 3.0 on a 0 to 10 point scale  
 
and 
 
	   Stool Frequency:  fewer than three CSBMs per week 
 
IBS-D 
   Abdominal Pain Intensity:  weekly average of worst daily (in past 24 hours) abdominal 
pain score of > 3.0 on a 0 to 10 point scale 
 
and 
 
	   Stool Consistency:  at least one stool with a consistency of Type 6 or Type 7 Bristol 
stool score (BSS) on at least 2 days per week 
 
4.  Efficacy Measures 
 
Sponsors should choose a format for daily sign or symptom assessment (e.g., interactive voice 
response or personal digital assistant) so that patients can evaluate their IBS signs or symptoms  
on a daily basis throughout the trial.  When assessing responses, sponsors should consider two 
distinct approaches:  (1) examining the difference in average score (or average change from  
baseline score) between the treated and untreated groups; or (2) examining the difference in 
response rate in the treated and untreated groups, where the response is prospectively defined 
and represents an effect considered clinically meaningful.  In many instances, an effective drug 
will have an effect on both measures.   
 
5.  Definition of a Responder 
 
Definitions of a responder for use in analyses of the primary endpoint should be prospectively 
described in the protocol and statistical analysis plan.  A patient should be categorized as an 
overall responder if the patient achieved the prespecified improvement in weekly or daily 
response for at least 50 percent of the weeks or days of treatment (e.g., 6/12 weeks or 42/84 
days). 
 
Our recommendations for how to define a weekly or daily response in each IBS setting is as 
follows: 
 
  7
  Contains Nonbinding Recommendations 
IBS-C13  
A patient is categorized as a weekly responder if the patient is a weekly responder in both  
pain intensity and stool frequency. 
 
 	  An Abdominal Pain Intensity Weekly Responder is defined as a patient who experiences 
a decrease in the weekly average of worst abdominal pain in the past 24 hours score 
(measured daily) of at least 30 percent compared with baseline weekly average  
 
 	  A Stool Frequency Weekly Responder is defined as a patient who experiences an 

increase of at least one CSBM per week from baseline 

 
IBS-D 
A patient is categorized as a weekly responder if the patient is a weekly responder in both  
pain intensity and stool consistency. 
 
 	  An Abdominal Pain Intensity Weekly Responder is defined as a patient who experiences 
a decrease in the weekly average of worst abdominal pain in the past 24 hours score of at 
least 30 percent compared with baseline  
 
 	  A Stool Consistency Weekly Responder is defined as a patient who experiences a 50 
percent or greater reduction in the number of days per week with at least one stool that 
has a consistency of Type 6 or 7 compared with baseline 
 
A patient is categorized as a daily responder if the patient is a responder in both pain 
intensity and stool consistency. 
 
	   An Abdominal Pain Intensity Daily Responder is defined as a patient who experiences a 
decrease in worst abdominal pain in the past 24 hours score of at least 30 percent 
compared with baseline  
 
	   A Stool Consistency Daily Responder is defined as a patient whose stool consistency 
(i.e., BSS) is less than 5 for all bowel movements on that day or no bowel movement  
 
For IBS-D, either the weekly responder or daily responder definition may be acceptable.  For 
drugs intended to target only one major IBS sign or symptom, based on their mechanism of 
action, we recommend the following responder definitions: 
 
Abdominal pain in IBS-C 
   An Abdominal Pain Intensity Weekly Responder is defined as a patient who experiences 
a decrease in the weekly average of worst abdominal pain in the past 24 hours score of at 
least 30 percent compared with baseline.  Stool Frequency (for IBS-C) is unchanged or 
improved compared with baseline.   
 
                                                 
13 Because IBS-C patients do not have daily bowel movements, even though abdominal pain may occur more  
frequently, daily response criteria are not relevant to this patient population.  
  8
  Contains Nonbinding Recommendations 
Abdominal pain in IBS-D 
 	  An Abdominal Pain Intensity Weekly Responder is defined as a patient who experiences 
a decrease in the weekly average of worst abdominal pain in the past 24 hours score of at 
least 30 percent compared with baseline and the number of days per week with at least 
one stool with consistency of Type 6 or 7 that is the same as baseline or decreased and 
the number of stools of Type 6 or 7 on those days remains unchanged or decreased  
 
or 
 
	   An Abdominal Pain Intensity Daily Responder is defined as a patient who experiences a 
decrease in worst abdominal pain in the past 24 hours score of at least 30 percent 
compared with baseline and whose stool consistencies during the day are less than 5 for 
all bowel movements or no bowel movement  
 
Constipation in IBS-C 
	   A Stool Frequency Responder is defined as a patient who experiences an increase of at 
least one CSBM per week from baseline, and abdominal pain is unchanged or improved 
compared with baseline 
 
Diarrhea in IBS-D 
 	  A Stool Consistency Responder is defined as a patient who experiences a 50 percent or 
greater reduction in the number of days with at least one stool that has a consistency of 
Type 6 or 7 compared with baseline, and abdominal pain is unchanged or improved in 
comparison with baseline 
 
Because the responder definitions described in this guidance are not supported by adequate 
content validation, it is unclear if they represent clinically meaningful changes in abdominal pain 
and abnormal defecation for patients with IBS.  The abdominal pain responder definition of a 
greater than or equal to 30 percent reduction in abdominal pain intensity compared with baseline 
is primarily based on published literature concerning other chronic pain conditions.14  Therefore, 
we recommend conducting additional responder analyses that evaluate greater reductions in 
abdominal pain intensity with treatment (i.e., greater than or equal to 40 and/or 50 percent 
reduction in abdominal pain intensity compared with baseline).  In addition, it would be useful to 
examine the cumulative distribution of several magnitudes of abdominal pain intensity reduction 
associated with treatment (e.g., 30 percent, 40 percent, 50 percent) as well as particular 
reductions (e.g., 100 percent pain intensity reduction) as secondary endpoints.  
 
Although we do not recommend a patient rating of change as a primary endpoint, because a 
single general item cannot adequately capture the treatment effect on all of the clinically 
important signs and symptoms of IBS, it can be useful in defining a clinically meaningful change 
in another measure through an anchor-based approach (relating changes in scores to a measure 
that is different from the specific measure itself).  Therefore, we recommend including patient 
ratings of change anchors as exploratory endpoints in conjunction with the endpoints included in 
this guidance.  The global assessment should ask patients to evaluate only their current IBS 
                                                 
14 See reference  number 31 in the References section at the end of the guidance. 
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  Contains Nonbinding Recommendations 
status and not compare their current IBS signs and symptoms to another point in time, such as 
baseline status. Examples of such assessments include the following questions, which could be 
asked of patients on a weekly basis: 
 
 	  How would you rate your abdominal pain overall over the past 7 days? 
 
 	  How would you rate your constipation (for IBS-C) or diarrhea (for IBS-D) overall over 
the past 7 days? 
 
 	  How would you rate your IBS signs or symptoms overall over the past 7 days?   
 
Sponsors can consider Likert scale response options, such as:  2 = Significantly Relieved, 1 = 
Moderately Relieved, 0 = Unchanged, -1 = Moderately Worse, and -2 = Significantly Worse.  
 
Table 2. Summary of Recommended Provisional Primary Endpoints,* Entry Criteria, and 
Responder Definition 
Indication  Primary   Entry Criteria  Responder Definition  
Endpoints    
  Abdominal Pain Intensity   Abdominal Pain Intensity  
     
Abdominal Pain  Weekly average of worst abdominal pain   Decrease in weekly average of  worst abdominal 
Intensity  in past 24 hours  score of >  3.0 on a 0 to 10  pain in the past 24 hours score of at least 30%  
  point scale  compared with baseline  
     
IBS-C  AND  AND  AND 
     
Stool Frequency  Stool Frequency   Stool Frequency  
   
< 3 CSBMs per  week  Increase of 1 or  more CSBM per week compared  
with baseline 
  Abdominal Pain Intensity   Abdominal Pain Intensity  
     
Abdominal Pain  Weekly average of worst abdominal pain   Weekly responder defined as:  decrease in weekly  
Intensity  in past 24 hours  score of >  3.0 on a 0 to 10  average of  worst abdominal pain in past 24 hours  
  point scale  score of at least 30% compared  with baseline 
     
AND  AND  Daily responder defined as:  decrease in worst 
    abdominal pain  in the past 24 hours score of at 
Stool  Stool Consistency   least 30% compared with baseline  
Consistency      
At least 2 days per week with at least one  AND 
IBS-D 
stool that has a consistency of Type 6 or    
Type 7 BSS (see Figure 1 for details)   Stool Consistency  
 
Weekly responder defined as:  decrease at least 
50% in the number of days per week with at least 
one stool that has a consistency  of Type 6 or 7 
compared with baseline 
 
Daily responder defined as:  a patient whose stool 
consistency is less than 5  for all bowel movements 
on that day or no bowel movement 
* Drugs may be designed to improve  only one of the major signs or symptoms of IBS.   For further detail, please refer to the discussion in Section 
IV of this guidance.    
 
 
  10  Contains Nonbinding Recommendations 
V.  FUTURE DEVELOPMENT OF IBS PRO INSTRUMENTS  

 
In October 2010, we published the draft guidance for industry Qualification Process for Drug 
Development Tools.15  Drug development tools (DDTs) intended for potential use, over time, in 
multiple drug development programs include, but are not limited to, biomarkers and clinical  
outcome assessments including PRO instruments.  FDA qualification is a conclusion that within 
the stated context of use, the results of assessment with a DDT can be relied upon to have a 
specific interpretation and application in drug development and regulatory decision-making. 
 
The qualification process provides an efficient means for DDT development.  Because 
qualification requires significant work, the formation of collaborative groups may lessen the 
resource burden upon any individual or company.  One such collaborative group, the PRO 
Consortium, formed in 2008 at the Critical Path Institute, is a public-private partnership.  The 
PRO Consortium is charged with the task of efficiently and collaboratively developing reliable, 
interpretable instruments that will be available in the public domain for all sponsors to use in 
medical product clinical trials.  The collaboration includes members from the FDA, industry, 
academia, professional organizations, patient advocacy groups, and other governmental agencies.  
Additional information about the PRO Consortium can be found at http://www.c-path.org. 
 
We are actively participating with the PRO Consortium and others in the consultation and advice 
stage of qualification for the development of PRO measures of the signs and symptoms of IBS-C 
and IBS-D. Once qualified, these IBS subtype-specific PRO measures will replace the 
provisional endpoints described in this guidance as the FDAs recommended measures of 
treatment benefit for use in IBS-C and IBS-D clinical trials.  
 
 
VI.  CONCLUSION 
 
The provisional endpoints and trial design recommendations in this guidance are currently 
acceptable for use in the evaluation of drugs for the treatment of IBS-D and IBS-C.  These 
recommendations will assist drug developers in developing treatments to address the needs of 
patients with IBS while the important work of developing well-defined and reliable PRO 
instruments for FDA qualification continues.   
 
                                                 
15  When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent version of a 
guidance, check the FDA Drugs guidance Web page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.   
  11
  Contains Nonbinding Recommendations 
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Complexes and Therapeutic Targets, Neurogastroenterol Motil, 16:135-142. 
 
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Type 3 Antagonists on Symptom Relief and Constipation in Nonconstipated Irritable Bowel 
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4. Heaton, KW, J Radvan, H Cripps et al., 1992, Defecation Frequency and Timing, and Stool 
Form in the General Population:  A Prospective Study, Gut, 33:818-824. 
 
5. Horikawa, Y, H Mieno, M Inoue et al., 1999, Gastrointestinal Motility in Patients With 
Irritable Bowel Syndrome Studied by Using Radiopaque Markers, Scand J Gastroenterol, 
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6. Sadik, R, PO Stotzer, M Simren et al., 2008, Gastrointestinal Transit Abnormalities Are 
Frequently Detected in Patients With Unexplained GI Symptoms at a Tertiary Centre, 
Neurogastroenterol Motil, 20:197-205. 
 
7. Gorard, DA, GW Libby, MJ Farthing, 1995, Effect of a Tricyclic Antidepressant on Small 
Intestinal Motility in Health and Diarrhea Predominant Irritable Bowel Syndrome, Dig Dis Sci, 
40:86-95. 
 
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