An FDA advisory committee gave Pfizer Inc.'s tofacitinib passing grades as an arthritis treatment Wednesday, but it piled on the homework.

The Arthritis Advisory Committee (AAC) voted 8-2 to recommend approval for tofacitinib as a second-line treatment in rheumatoid arthritis (RA). If the FDA goes along with that recommendation, tofacitinib would become the first JAK inhibitor in the RA space and the first new disease modifying anti-rheumatic drug (DMARD) in 10 years. The compound has an August PDUFA date.

However, judging by comments made by rheumatologists on the panel, first-in-class won't guarantee tofacitinib a spot at the front of the class.

Safer drugs are available, said AAC Chairwoman Lenore Buckley, a professor of internal medicine at the Virginia Commonwealth University School of Medicine.

Where tofacitinib is a new drug, there's not a lot of experience with it, and its safety profile isn't fully known, Buckley said. As a clinician, she would want a large safety registry that she could follow for some time before she would be comfortable moving it to the front of the line when another DMARD fails.

Buckley, who voted against approval, said she would have passed tofacitinib had the indication been more restricted. Even those who voted for approval echoed her sentiments.

Pfizer has proposed an indication to treat moderately to severely active RA in adults who have had inadequate response to one or more DMARDs. It also is seeking approval of two doses: 5 mg and 10 mg.

That's a broad indication that would allow tofacitinib to be used in patients who failed on an anti-malarial, said Sherine Gabriel, a professor of medicine and epidemiology at the Mayo Medical School. She cast the other no vote.

While the committee unanimously voted for tofacitinib's efficacy, it had reservations when it came to the safety profile. Many of those reservations revolved around the limited data associated with tofacitinib's first-in-class status.

"I would struggle with this drug," Buckley said. She noted that Pfizer provided more data than she has seen with other products, including biologics, but as a clinician, she would need to see more – especially since this a first-in-class drug.

David Blumenthal, assistant professor of medicine at Case Western Reserve University, agreed, saying New York-based Pfizer made a good-faith effort to assess the risks. The data are as good as possible at this stage, he added.

To provide those data and protect patients from unknown risks, the panel suggested large safety registries, large extended postmarket trials and a systematic, patient-centered pharmacovigilance program. It also recommended starting with the lower dose and only using 10 mg when absolutely necessary.

Pfizer outlined plans for what it called a robust postmarket program and risk evaluation and mitigation strategy.

FDA Concerns

In its briefing documents for the meeting, the FDA raised safety concerns and questions about efficacy, specifically in radiographic outcomes of structural damage progression. Although not required for earlier RA drugs, the agency now wants one radiographic study with a large treatment effect. (See BioWorld Today, May 8, 2012.)

Pfizer conducted the study, but the agency said the treatment effect was too small to establish efficacy. The committee didn't seem overly concerned about the radiographic results. Such studies are the most difficult to do and the hardest standard for new RA treatments to meet, Blumenthal said.

Since a number of other outcome measures are available to assess efficacy, he said a radiographic study can be done postmarket.

Leslie Crofford, division chief for rheumatology at the University of Kentucky College of Medicine, questioned whether the FDA is raising the bar too high with its radiographic outcomes requirement. "My major concern would be, from a clinician's point of view, . . . that using radiographic outcomes as the end-all and be-all" of RA efficacy endpoints will become more difficult over time, she said.

Another concern is the FDA's commitment to placebo-controlled trials, an issue that came up Tuesday when the AAC considered Regeneron Pharmaceuticals Inc.'s Arcalyst (rilonacept) as a gout prophylactic. In that instance, the agency raised its hand over a possible risk of malignancies, citing an "imbalance" of malignancies between the treatment and placebo arms. The concern seemed to ignore the 3:1 randomization imbalance built into the trials. Only about a fourth of the subjects were in the placebo arms. (See BioWorld Today, May 9, 2012.)

With tofacitinib, the agency again bemoaned limited placebo data. In the Pfizer trials, patients randomized to the placebo arm in the various trials were moved to treatment arms after three months.

That is a difficult situation that sponsors will continue to face in the future when they need to limit patient exposure to placebo treatment, Crofford said.

Pfizer wasn't the only one getting homework assignments Wednesday. During the public comment period, Janet Wyatt, of the Arthritis Foundation, suggested an assignment or two for the FDA. She encouraged the agency to use its review of tofacitinib to strengthen its transparency policies and to create a standardized process to establish what it considers an adequate response, as well as a treatment failure.

The FDA also needs to develop a systematic way to engage patients in the long-term monitoring of drug safety, she added.