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Posted 08 August 2016 | By Zachary Brennan 

Ulcerative Colitis Drugs: FDA Offers Draft Guidance on Clinical Development


Pharmaceutical companies looking to understand FDA’s current thinking on efficacy endpoints for clinical trials to develop new ulcerative colitis (UC) treatments will be interested in new draft guidance released Friday.

And though the guidance spells out what primary endpoints should be used, the agency also bemoans the fact that there are not well-defined and reliable clinician-reported, patient-reported and observer-reported outcome instruments for clinical trials.


UC is a chronic, relapsing disease characterized by diffuse mucosal inflammation of the colon, according to FDA, which also notes that the precise etiology of UC is unknown; however, it is thought to be caused by an inappropriate inflammatory response to the gut contents in genetically predisposed individuals.

The estimated US incidence of UC is 9 to 12 cases per 100,000 persons per year, and the estimated prevalence is 205 to 240 cases per 100,000 persons.

Current treatments for UC include anti-inflammatory drugs and immune system suppressors, including Janssen’s blockbuster Remicade (infliximab) and AbbVie’s Humira (adalimumab) for moderate to severe UC for those who do not respond to or cannot tolerate other treatments, according to the Mayo Clinic.

Late last month, Pfizer also reported positive Phase 3 results for a trial testing its already approved Xeljanz (tofacitinib citrate) in UC patients.

Efficacy Assessment

According to FDA, there are three clinical outcome assessment types relevant to the measurement of UC signs and symptoms:

(1) Patient-reported outcome, which is a measurement based on a report coming directly from the patient (i.e., study subject) without amendment or interpretation of the response by a clinician;

(2) Observer-reported outcome, which is a measurement based on a report of observable signs, events or behaviors related to a patient’s health condition by someone other than the patient or a health professional, including a parent, caregiver or someone who observes the patient in daily life;

(3) Clinician-reported outcome, which is based on a report that comes from a trained health professional after observation of a patient’s health condition and usually involves a clinical judgment or interpretation of the observable signs, behaviors or other manifestations related to a disease or condition.

FDA says it believes that the ideal primary efficacy assessment tool used in clinical trials to support marketing approval for a new UC treatment would con

sist of “a signs and symptoms assessment scale, best measured by a patient-reported outcome instrument,” and “an endoscopic and histological assessment scale, best measured by a clinician-reported outcome instrument.”

However, the agency notes that a claim of “mucosal healing” would not be supported by endoscopy findings that provide only an assessment of the visual appearance of the mucosa.

And until well-defined and reliable clinician-reported, patient-reported and observer-reported outcome instruments become available for clinical trials, FDA says sponsors should consider the Mayo Score and Ulcerative Colitis Disease Activity Index (UCDAI), which have been the most commonly used tools to support registration trials in UC.

Both the Mayo Score and the UCDAI incorporate scoring of stool frequency, rectal bleeding, endoscopic findings and a physician’s assessment of disease activity, though both share limitations, including the physician’s assessment of disease activity and the Physician’s Global Assessment (PGA) subscores.

“A single general item cannot adequately capture whether benefit is achieved in all, or only some, of the important signs and symptoms. Additionally, as previously discussed, a signs and symptoms assessment scale is best measured by a patient-reported outcome instrument as opposed to a clinician-reported outcome instrument,” FDA adds, noting an example of standardized instructions for recording a patient’s number of stools and worst rectal bleeding (for the Mayo Score) over a 24-hour period.

Clinical Remission and Response 

In terms of primary endpoints, FDA says both clinical remission (responder definition based on an absolute total Mayo Score and absolute Mayo endoscopy, stool frequency, rectal bleeding and PGA subscores) and clinical response (responder definition based on a reduction in total Mayo Score and reduction in rectal bleeding subscore) have been accepted as primary endpoints in trials.

“We currently recommend a primary endpoint of clinical remission (responder definition based on Stool Frequency, Rectal Bleeding, and Endoscopy scores),” FDA says. “Until a valid patient-reported outcome instrument for UC signs and symptoms and a valid clinician rating scale for mucosal inflammation in UC become available, a modified Mayo or modified UCDAI score omitting the physician’s global or disease activity ratings … can be used as an endpoint measure.

Mucosal healing (based on the Mayo Endoscopy subscore) also has been included as a secondary endpoint in many clinical trials, FDA says.

The guidance also aims to help sponsors with statistical considerations for developing UC treatments, including missing data and pediatric considerations.

Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry


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