FDA Panel to Review Humira Colitis Data

FDA Panel to Review Humira Colitis Data

August 24th, 2012 // 11:11 pm @

Further studies may be needed to demonstrate clear benefits for the tumor necrosis factor (TNF) inhibitor adalimumab (Humira) in ulcerative colitis, FDA staff suggested.

In briefing documents prepared in advance of a meeting of the Gastrointestinal Advisory Committee on Aug. 28, FDA staff reviewers questioned whether a difference in rates of clinical remission of less than 10% compared with placebo could be considered “clinically meaningful.”

In two randomized trials comparing adalimumab with placebo in patients with moderate to severe ulcerative colitis, these rates of remission were seen:

Study 826, week 8, 18.5% versus 9.2%, difference 9.3% (95% CI 0.8% to 17.9%, P=0.031)
Study 827, week 8, 16.5% versus 9.3%, difference 7.2% (95% CI 1.3 to 13.2, P=0.019)
Study 827, weeks 8 and 52, 8.5% versus 4.1%, difference 4.4% (95% CI 0.1 to 9, P=0.047)

Although these findings were statistically significant, alternative analyses conducted by the reviewers, which adjusted for differences in baseline disease severity scores, showed nonsignificant differences (P=0.085).

The FDA had previously rejected the application by the manufacturer, Abbott Laboratories, for this moderate to severe ulcerative colitis indication, arguing that studies had not conclusively demonstrated efficacy.

In the briefing documents, posted online, agency staff reviewers also questioned whether the proposed 160-mg induction dose used for induction is adequate. Pharmacologic studies suggested that greater remission rates might be achieved with higher doses.

Furthermore, the reviewers wrote, one of the trials excluded patients who had previously been treated with a TNF inhibitor, while in the other study 40% of patients had had previous exposure.

The agency also suggested that an additional useful study might explore the possibility that this treatment could have specific benefits in certain subgroups of patients.

Adalimumab was approved for use in rheumatoid arthritis in 2002, and approval has since been extended to several other conditions such as psoriatic arthritis and Crohn’s disease.

Conventional therapies for ulcerative colitis include immunosuppressive agents and corticosteroids; one other TNF inhibitor, infliximab (Remicade) also has been given approval as being safe and effective in inflammatory bowel disease.

If approved, adalimumab could offer an alternative to infliximab, particularly for patients who lose their response or are unable to tolerate infliximab.

In addition, patients might prefer adalimumab, which can be self-administered subcutaneously, rather than by infusion.

With regard to safety, the current labeling for the drug appears to be adequate, including a boxed warning for malignancies and serious infections, the FDA reviewers noted. Nor, they wrote, are there any new safety concerns.

“The central review issue is whether the applicant has adequately demonstrated and provided evidence of benefit sufficient to conclude that the benefit outweighs the risks of Humira for this indication,” the staff review concluded.

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