An FDA advisory committee has voted 8-2 in favor of recommending approval of the oral JAK inhibitor tofacitinib for the treatment of rheumatoid arthritis.

The agency's Arthritis Advisory Committee voted Wednesday in Silver Spring, Md. that the efficacy and safety data support the use of tofacitinib for adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs.

The panel was unanimous in its assessment of the drug's overall efficacy. "The evidence was compelling and was at least as good as for other biologics," said panelist Maria E. Suarez-Almazor, MD, PhD, of MD Anderson Cancer Center in Houston.

The efficacy was demonstrated in five phase III studies in which the primary endpoint was met.

Less clear was the efficacy as demonstrated on radiographic outcomes, which were assessed in only one study.

Analysis of this outcome was hampered by the fact that very little radiographic progress was seen in the placebo group.

"Radiographic outcome studies are difficult to do with limitations on the duration of placebo controls," said panel member David Blumenthal, MD, of Case Western Reserve University in Cleveland.

"We don't need certainty about radiographic outcomes today. That can be followed during postmarketing," Blumenthal added.

There also was considerable discussion about safety concerns that were raised in the phase III trials.

One area of concern was serious infections, which were seen at a rate of three per 100 patient-years, and most commonly were pneumonia and skin and soft tissue infections.

There also were 12 cases of tuberculosis, mostly in countries where the incidence is high, and 19 cases of serious herpes zoster.

Richard Riese, MD, PhD, of Pfizer noted that the company intends to have an action plan for zoster, in which immunization will be encouraged and follow-up data collected.

The company also presented malignancy data, noting that there had been 66 cancers in tofacitinib-treated patients.

Cancer rates increased over time, rising from an incidence rate of 0.79 per 100 patient-years between baseline and 6 months to an incidence rate of 1.43 per 100 patient-years beyond 24 months.

A total of seven cases of lymphoma also occurred in patients receiving tofacitinib, but none in patients given placebo.

The increases in serious infections and malignancies appeared to be dose related, and several of the panel members expressed a degree of discomfort with the 10 mg dose.

"I have significant concerns about over-immunosuppression with the higher dose, especially when the drug is given in combination with other agents, which is the rule rather than the exception today," said Leslie Crofford, MD, of the University of Kentucky in Lexington.

Despite these concerns, a majority of the panelists agreed that the safety profile was adequate. "There will always be concerns with…but I think the sponsor did as much as could be done at this stage," said Blumenthal.

To provide further long-term safety data, the panelists concurred that ongoing vigilance will be needed, with large registries being established.

The panelists who voted against approval of tofacitinib explained that they felt the indication was too broad, allowing use in patients "who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs."

Even some who voted in favor expressed concerns about the possibility that tofacitinib could be used after failure of a single drug such as sulfasalazine or hydroxychloroquine, suggesting that the indication be limited to use after failure of methotrexate or a biologic.

Blumenthal also called for more flexibility in dosing to alleviate concerns about dose-related safety problems.

"If we could have options of 2.5 mg, 5 mg, 7.5 mg, and 10 mg, that would cover a wide array of potential efficacies and safety risks," he suggested.

The FDA is not required to follow the advice of its advisory committees, but often does so.