End points in irritable bowel syndrome

Keywords::

• bowel function
• end point
• irritable bowel syndrome
• patient-reported outcomes
• urgency

The success of a clinical trial rests on achieving clinical and statistical significance on the primary end point of the study. Therefore, proper selection of primary and key secondary end points is of the utmost importance for obtaining regulatory approval of a drug, as well as for identifying the proper therapeutic profile of the agent. If there is an inappropriate selection of study end points, an efficacious drug could appear as nonefficacious or the specifics related to a drug’s profile may not be correctly described.

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders. Hallmark features of IBS are abdominal pain and altered bowel functions, and these symptoms present in an episodic manner [1,2]. The alterations in bowel patterns in IBS can be manifested as predominantly diarrhea, predominantly constipation or an alternation between diarrhea and constipation. These bowel patterns define the three IBS subtypes of diarrhea-predominant IBS (D-IBS), constipation-predominant IBS (C-IBS) and mixed or alternating IBS [1,2]. The most bothersome symptoms that patients with D-IBS experience include abdominal pain, bowel urgency, increased stool frequency and loose stool consistency [3]. Patients with C-IBS experience abdominal pain, straining, decreased stool frequency, hard stool consistency and bloating. Given the nature of these symptoms, primary and secondary end points need to be based on patient-reported outcome (PRO) measures that address the symptoms appropriate for the IBS subtype.

Over the past two decades, only three drugs – alosetron, lubiprostone and tegaserod – have achieved regulatory approval for the treatment of IBS. Alosetron shows benefit in the treatment of D-IBS, whereas tegaserod and lubiprostone are efficacious in the treatment of C-IBS [3–7]. Although alosetron and tegaserod encountered safety-related difficulties following approval, alosetron remains on the market in the USA.

The primary end points used in the clinical development programs of these three drugs are not considered acceptable primary end points by the US FDA [101]. However, the adequate relief end point that was used in the alosetron program shows many properties of a validated end point: responsive, reproducible and moving in the direction of other meaningful measures [8–12]. The FDA has expressed concern with the adequate relief end point [101] as it is binary and, therefore, worsening cannot be shown. Although worsening is not shown on a binary end point, all other relevant IBS end points (pain, urgency, frequency, consistency and straining) can be collected using instruments or scales, with graded scores and worsening of symptoms during treatment measured.

FDA PRO guidance document

In recent years, the FDA has become more critical of instruments used to measure PROs in clinical trials. Specifically, the agency now requires a higher degree of scientific rigor in the development and psychometric evaluation of these measures, as well as the documentation of these processes, particularly for PRO measures intended to support drug approval or labeling claims.

To facilitate decisions related to the approval of drugs, labels and promotional claims based on PROs, the FDA created the Study End Points and Label Development (SEALD) group. Members of SEALD are often included in pivotal meetings with study sponsors to provide feedback regarding proposed PRO end points. In addition, SEALD serves as an advisory group to review divisions of the FDA and has developed both a draft and final version of a guidance related to the use of PRO measures used to support drug approvals and label claims [102].

The draft version of the ‘Guidance for industry patient-reported outcome measures: use in medical product development to support labeling claims’, released in February 2006, focused on describing both the recommended development of a PRO measure and the psychometric properties for which evidence must be presented if the measure is to support regulatory approval or promotional claims. The final version of the PRO guidance, released in December 2009 [102], focuses less on the development of PRO measures and describes in detail how the FDA reviews and evaluates existing, modified or newly developed PRO instruments to support drug approvals and product labeling. Both the draft and final versions of the PRO guidance clearly stipulate that any PRO measure used to support drug approval or label claims must be developed with extensive input from patients and thoroughly evaluated in the population involved in the clinical trials [102].

FDA IBS guidance document

Since the release of the draft PRO Guidance, the FDA has been extremely cautious in their acceptance of PRO measures used by sponsors to support requested labeling claims. In an area such as IBS, which depends on the use of PROs for drug approval, the current regulatory environment with respect to PROs has the potential to both delay the availability of new therapies, but also to discourage sponsors from investing in the development of promising compounds.

In 2010, the FDA released the draft guidance ‘Irritable bowel syndrome – clinical evaluation of products for treatment’ [101]. This document recommends specific PRO end points, measures and responder definitions for use in IBS clinical trials, pending the development and qualification of an integrated symptom measure. The FDA’s IBS Guidance recommends co-primary end points of changes in stool frequency or consistency, and abdominal pain intensity for trials in D-IBS, and changes in stool frequency and abdominal pain for C-IBS trials. All are to be measured (reported by patients) on a daily basis and weekly averages are to be computed during analysis.

Expert viewpoint on end points in IBS

From a clinical standpoint, what are the important properties of a primary end point in IBS clinical trials? The primary end point must be able to reflect the benefit of a drug over placebo when there is superior benefit of a drug. Likewise, if a drug is not more efficacious than placebo, the end point should reflect no meaningful difference from placebo. Furthermore, the end point must be a reflection of symptoms that are most significant to a patient population. Finally, the end point must be constructed such that even though there is a therapeutic effect, ‘false benefit’ is not observed.

The concept of false benefit can be readily explained by examining the FDA IBS guidance. The intent of the IBS guidance is to evaluate end points that reflect the most meaningful symptoms to patients, using both a subjective (pain) and an objective end point (stool consistency or frequency of stool). Pain is an unambiguous end point from the standpoint that pain is always ‘bad’ and the absence of pain is always ‘good’. Thus, there is no ambiguity in directionality of improvement [13].

By contrast, the parameters of stool consistency and frequency have a flaw associated with the current analysis methods [13]. Imagine a patient with D-IBS with an average stool consistency on the Bristol Stool Form Scale of 6.4. If an efficacious agent is administered and the average stool consistency improves to 4.5, the patient is ‘normalized’ and a difference score of 2.1 is recorded. If the stool continues to harden with continued use of the medication, and now the average consistency score is 2.2, the difference from baseline is 4.2. Both the magnitude of the treatment effect and statistical significance would be recorded as greater improvement in the latter scenario. However, in this case, the patient may now be constipated. Thus, measures of stool consistency and frequency allow for the false appearance of greater therapeutic benefit as patients move from a state of diarrhea to normal to constipation.

The end point of urgency, similar to pain, shows a lack of ambiguity in directionality. Urgency reflects changes in bowel frequency and consistency, is meaningful to patients and understood by patients [14]. In two separate surveys of patients with D-IBS [3], urgency was considered to be the second most bothersome symptom to patients – only abdominal pain was rated as more bothersome. These findings were recently replicated in interviews with patients with D-IBS [14].

The choice of end points in a clinical trial is of utmost importance. We believe that a combination of pain and urgency would uniquely reflect the most important symptoms to patients with D-IBS, and urgency does not have potentially flawed analysis methods. For C-IBS, a similar co-primary end point with abdominal pain, such as straining or sense of constipation, should be explored.

Financial & competing interests disclosure

All funding for this project was provided by RTI Health Solutions, a division of RTI International. RTI is a not-for-profit research institute. The authors are currently collaborating on a project with the IBS Working Group within the Critical Path Institute’s PRO Consortium on the development of a PRO instrument intended to be used to assess primary end points in IBS clinical trials. The views and opinions expressed in this editorial are those of the authors and should not be attributed to the Critical Path Institute or its IBS Working Group. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.