FDA's release of Centocor from a Risk Evaluation and Mitigation Strategy for Simponi could signal a reprieve from the REMS regulatory burden for other tumor necrosis factor inhibitors as well.

TNF inhibitors, which include Amgen's Enbrel (etanercept), Centocor's Remicade (infliximab), Abbott's Humira (adalimumab), and UCB's Cimzia (certolizumab), each have a REMS consisting of a Medication Guide and communication plan, similar to that for Simponi (golimumab).

FDA called for REMS for all members of the class in September 2008 to warn about the risk of invasive fungal infections, including histoplasmosis (Also see "TNF Blocker Fungal Infection: FDA Uses REMS For Relabeling, Education" - Pink Sheet, 8 September, 2008.).

The agency also reported safety concerns about an increased risk of malignancies and new-onset psoriasis with TNF-blockers in August 2009 and addressed these issues in the drugs' labeling and Medication Guides. FDA has asked for another round of labeling changes on an increased risk of a rare form of lymphoma (see related story, "Also see "FDA Warns Again Of Rare Cancer Associated With TNF Blockers" - Pink Sheet, 2 May, 2011.").

As a latecomer to the class, the REMS for Simponi was part of the biologics' original approval in April 2009. The sponsor committed to sending a Serious Infection Education Guide, along with a Dear Healthcare Professional Letter, to approximately 400,000 clinicians who might prescribe Simponi for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

As with all REMS, there was a timetable for assessments of the effectiveness of the program.

Based on Centocor's first assessment, FDA concluded that "because the communication plan has been completed and adequately assessed, we have determined that it is no longer necessary to include it in the approved REMS," according to a March 17 BLA supplement approval letter.

In keeping with its recent policy shift, FDA further informed the company that, "It is no longer necessary for the biologics' Medication Guide to be part of a REMS to ensure that the benefits of the drug outweigh its risks." The MedGuide, however, will continue to be part of labeling.

Though FDA initially required all MedGuides to be handled as a REMS, it recently proposed a draft guidance that allows most MedGuides to be removed from the REMS requirements of the Food and Drug Administration Amendments Act when the REMS does not also include elements to assure safe use (Also see "FDA To Sponsors: Say Goodbye To MedGuide-Only REMS" - Pink Sheet, 7 March, 2011.).

"Therefore, a REMS is no longer required for Simponi," FDA's letter states. "We accept the REMS assessment dated January 12, 2011, as the final assessment for this REMS."

Centocor has not released the findings of its assessment, but notes that a focus of its REMS was to communicate the risk of fungal infections.

Determining whether that was accomplished was a key goal for the assessment plan for the Simponi REMS.

Simponi REMS Assessment

Patients' and providers' understanding of the serious risks of the biologic, as measured by surveys
Specification of measures to increase awareness of the fungal infection concerns if surveys indicate provider awareness is inadequate
Periodic summaries of adverse reporting of histoplasmosis and other invasive fungal infections, including analysis of deaths and whether there was prompt administration of appropriate antifungal therapy
Assessment of whether the REMS is meeting its goals or if modifications are needed

FDA also acknowledged in a Dec. 31, 2008, letter approving a communication plan for the Cimzia REMS that communicating the risk of fungal infection would be short-lived. "This element [communications plan] of the REMS is not intended to continue over the lifetime of the product; it will function only to disseminate the new safety information about histoplasmosis and fungal infections."

The key for sponsors of the other TNF-inhibitors is to show FDA that patients and physicians are aware that there is a risk of fungal infection with their individual products and that their MedGuides no longer need be part of a REMS to be effective.

The MedGuides for the five products are similar in calling attention to the increased risk for the fungal infections, as well as tuberculosis, unusual cancers in children and teenagers, and lymphoma. The label for Humira also notes the potential for non-melanoma skin cancer.

Assessments for several of the TNF inhibitors are due to FDA shortly. The first assessment of the Remicade REMS, approved in November 2009, is scheduled for submission to the agency in May, and the first assessment for Humira is due in October.

Because the communication plan was not added to the Enbrel REMS until June 2010, Amgen had little opportunity to evaluate its effectiveness prior to a REMS assessment submitted in September 2010. A three-year assessment of the REMS is due this June.

An initial assessment of the Cimzia REMS was due in November 2009. An FDA letter to UCB Nov. 18, 2009, approved changing the Cimzia REMS goals to reflect information about the malignancies and psoriasis and indicates a communication plan remains in place. The second assessment for the Cimzia REMS would be due in May, according to the original assessment plan for the drug, but a modified plan was approved in May 2009. Details for the revised timetable for assessments are not available.

Simponi is not the first product to escape a REMS requirement, though it is the first to do so because of the change in the handling of MedGuides.

FDA previously released QOL Medical's Sucraid from a REMS that included elements to assure safe use as well as a communication plan (Also see "QOL Medical’s Sucraid Is First To Lose Its REMS" - Pink Sheet, 7 March, 2011.).

By Cathy Dombrowski

Centocor's Simponi Becomes First TNF Blocker To Escape REMS Duties

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