IBS Trials Should Gauge Efficacy In Maintenance And Retreatment, FDA Says

Agency’s final guidance on clinical evaluation of irritable bowel syndrome drugs says sponsors should assess benefits of maintenance therapy and repeated courses of treatment in addition to short-term efficacy. The recommendations on clinical endpoints are “provisional” pending development of new patient-reported outcome measures.

Clinical trials for irritable bowel syndrome treatments should be designed to demonstrate not just short-term benefit but also efficacy in maintenance and retreatment, FDA said in a recently finalized guidance on IBS drug development.

The recommendation for evaluation of longer-term effects marks a change from a 2010 draft guidance, which focused on efficacy over a two- to three-month period and a two-week post-treatment period.

The final guidance appears to reflect the agency’s recent regulatory approach to Salix Pharmaceuticals Ltd.’s gut selective antibiotic treatment Xifaxan (rifaximin), which has been slowed in its bid to add an IBS indication due to the need to conduct a new study on treatment of symptom recurrence.

The guidance emphasizes the provisional nature of the endpoint recommendations pending development and validation of an acceptable patient-reported outcomes instrument.

The final guidance, “Irritable Bowel Syndrome – Clinical Evaluation of Drugs for Treatment,” contains several other changes from its draft predecessor, including an explicit recognition that a drug can be developed to treat only one of the two major symptoms of IBS.

Although issued in final form, the guidance emphasizes that the endpoint recommendations contained within are provisional, pending development and validation of an adequate patient-reported outcomes instrument for evaluating IBS drugs.

Few Approved Treatments

IBS is a challenging therapeutic area in which efficacy hurdles and safety concerns have resulted in few approved treatment options (Also see "IBS-D Lead May Go To Tioga With Salix Required To Run Another Trial" - Pink Sheet, 22 Aug, 2011.).

Prometheus Laboratories Inc.’s Lotronex (alosetron) is the only product approved for diarrhea- predominant IBS (IBS-D). However, its availability is limited under a Risk Evaluation and Mitigation Strategy due to the risk of serious gastrointestinal adverse events, including ischemic colitis.

Drugs in late-stage development for IBS-D include Salix’s rifaximin, an antibacterial agent that was the subject of an FDA “complete response” letter last year. The drug is already approved for travelers’ diarrhea and reducing the risk of overt hepatic encephalopathy recurrence. Tioga Pharmaceuticals Inc.’s asimadoline, a selective kappa opioid receptor agonist, is being studied for IBS-D in a Phase III trial conducted under a Special Protocol Assessment. The trial is expected to complete by the end of 2012.

The different mechanisms of action of the Salix and Tioga drugs reflect the disagreement within the medical community as to whether IBS-D is caused by infection or should be treated as a chronic condition.

Sucampo Pharmaceuticals Inc.’s chloride channel activator Amitiza (lubiprostone) is the only approved and widely available drug for the constipation-predominant form of the condition (IBS-C). Amitiza may soon have company on the market, however. Ironwood Pharmaceuticals Inc. and Forest Laboratories Inc.’s GC-C agonist linaclotide is under FDA review for IBS-C and chronic constipation, with a September user fee deadline (Also see "Business News, In Brief" - Pink Sheet, 7 May, 2012.).

Novartis AG’s Zelnorm (tegaserod), 5-HT4 partial agonist, was approved for women with IBS-C in 2002 but its marketing was suspended in 2007 after a pooled analysis of clinical trials showed a higher rate of ischemic CV events in patients taking the drug. It is currently available by IND only for emergency situations (Also see "FDA May Ease Up On CV Safety Requirements For GI Motility Drugs Compared To Diabetes, Obesity" - Pink Sheet, 5 Dec, 2011.).

Evolving Guidelines

FDA issued a draft guidance on clinical evaluation of IBS drugs in March 2010. That document focused on the regulatory evolution of PRO measures in IBS clinical trials, with FDA concluding that general items asking patients to rate overall change in IBS symptoms as primary endpoints are no longer adequate to support efficacy claims.

The guidance discussed the process necessary for developing a new, validated multi-item PRO instrument that captures all of the clinically important signs and symptoms of IBS. Pending development of such an instrument, the draft offered recommendations on co-primary endpoints and trial designs. It suggested a randomized, placebo-controlled design with a 1-2 week screening period, 8-12 week treatment period and 2-week post-treatment period.

The trial design recommendations in the final guidance retain the screening period with a minimum 8-week treatment period for therapies that will be administered on a chronic and continuous basis. However, FDA now says this treatment period should be followed by a randomized withdrawal design to address the need for maintenance treatment to prevent recurrence of signs or symptoms. “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.”

The need for clinical data on response with repeat treatment cycles was at the heart of FDA’s “complete response” letter to Salix (Also see "Salix Tumbles With Expected "Complete Response" Letter On Xifaxan In IBS" - Pink Sheet, 24 Feb, 2011.). The agency convened its Gastrointestinal Drugs Advisory Committee in November 2011 to discuss design of a new study to assess efficacy, safety and durability of rifaximin with retreatment.

The panel endorsed Salix’s proposed trial design for assessing short-term treatment of symptomatic recurrence but said the sponsor also should collect data on the duration of symptom relief (Also see "Data On Length Of Symptom Relief Could Improve Xifaxan Trial, Panel Members Suggest" - Pink Sheet, 28 Nov, 2011.).

Targeting Only One Symptom

The final guidance retains the draft’s recommendation for a primary endpoint that measures the treatment effect on the two major signs and symptoms of IBS: abnormal defecation and abdominal pain. The defecation component should be evaluated by assessing stool frequency in IBS-C studies and stool consistency in IBS-D studies. Abdominal pain intensity should be evaluated using an 11-point numeric rating scale, and abdominal discomfort is recommended as a secondary endpoint.

In a departure from the draft guidance, the final document clarifies that a drug can be developed specifically to treat only one of the major signs or symptoms of IBS, and this should be identified as the primary endpoint in a clinical trial.

Demonstration of a significant, clinically meaningful effect on a targeted single endpoint could serve as a basis for drug approval, as long as other important symptoms have not worsened on treatment.

“The identification of a single sign or symptom of interest should be based on the mechanism of action of the drug,” the guidance states. “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.”

For IBS-D trials, entry criteria were broadened in the final guidance to allow more patients to participate in clinical studies.

While the draft guidance included definitions of weekly responders for IBS-C and IBS-D, the final guidance adds a new category for daily responders in IBS-D. It also includes new responder definitions for abdominal pain, constipation (IBS-C) and diarrhea (IBS-D) for drugs intended to target only one symptom.

The final guidance contains an unusual caveat in which FDA acknowledges the uncertain evidentiary base upon which the responder definitions were developed.

“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,” FDA said.

“The abdominal pain responder definition of a greater than or equal to 30% reduction in abdominal pain intensity compared with baseline is primarily based on published literature concerning other chronic pain conditions. 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% 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%, 40%, 50%) as well as particular reductions (e.g., 100% pain intensity reduction) as secondary endpoints.”

“Provisional” Endpoints

The guidance stresses that FDA views the recommended trial endpoints as provisional until PRO measures of the signs and symptoms of IBS-C and IBS-D are qualified for use. An October 2010 draft guidance laid out the process for FDA qualification of drug development tools, such as PRO instruments, to support regulatory decision-making (Also see "FDA Drug Development Tool Guidance Leaves Door Open For Advisory Committee Reviews" - Pink Sheet, 15 Nov, 2010.).

The agency said it is actively working with the PRO Consortium, a public-private partnership formed in 2008 at the Critical Path Institute, and others in the consultation and advice stage of the qualification process for development of IBS-C and IBS-D PRO instruments.

“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,” the final guidance states. “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.”