On May 9, a Food and Drug Administration (FDA) voted 8-2 to recommend the approval of tofacitinib, the first oral drug of its kind to treat rheumatoid arthritis. The 10-member panel reviewed the application made by the drug’s manufacturer Pfizer Inc. for the treatment of adult patients with moderate to severe rheumatoid arthritis who experienced an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). The committee was requested to consider four questions.
The first question was “Do the data provide substantial evidence of the efficacy of tofacitinib for radiographic [X-ray] outcomes?" Two panel members voted yes and eight voted no. Leslie Crofford, MD, from the University of Kentucky School of Medicine in Lexington, voted yes. She noted that the evidence of radiographic efficacy was substantial and that she did not interpret substantial to mean "definitive." A panel member who voted no on the question, Elizabeth Smith, a patient representative from Burke, Virginia, noted that she did not consider the evidence of radiographic efficacy to be substantial. However, she agreed with other panel members that a better answer might not be available.
The second question was "Overall, do the data provide substantial evidence of the efficacy of tofacitinib for the treatment of moderately to severely active rheumatoid arthritis in patients who have had inadequate response to one or more [DMARDs]?" All 10 committee members voted yes. They noted that the data were consistent across studies.
The third question was "Is the safety profile of tofacitinib adequate to support approval of tofacitinib for the treatment of moderately to severely active rheumatoid arthritis in patients who have had inadequate response to one or more DMARDs?" Seven panel members voted yes, two voted no, and one abstained.
On the basis of preclinical and clinical research, Pfizer proposed that 5 mg and 10 mg doses of tofacitinib to be taken twice a day on the basis of its preclinical and clinical research. The FDA noted that the medication was associated with dose- and/or treatment duration-dependent increases in malignancy rates, lipid and cholesterol levels, and serious infection rates. The abstaining panel member, James Ware, PhD, from the Harvard School of Public Health in Boston, Massachusetts, noted that he understood the value of the drug; however, he was concerned about its safety profile. The majority of the panel members who voted yes expressed a preference for the 5 mg dose because it appeared to be comparable in effectiveness to the 10 mg dose. Furthermore, several committee members expressed concern that the indication for the drug was too broad. Lenore Buckley, MD, MPH, from the Virginia Commonwealth University School of Medicine in Richmond, voted no. She noted that she would have voted yes for this question if the indications were limited to high-risk patients.
The fourth question was "Do the efficacy and safety data provide substantial evidence to support approval of tofacitinib for the treatment of moderately to severely active rheumatoid arthritis in patients who have had inadequate response to one or more DMARDs?" Eight panel members voted yes and two voted no. Many of the panel members echoed their preference for the 5 mg dose over the 10 mg dose as well as the need for longer-term safety data. Sherine Gabriel, MD, from Mayo Medical School in Rochester, Minnesota, who voted no, agreed with Dr. Buckley that the indication was too broad and said that she would have supported approval with a more limited indication.
During the open public hearing session of the meeting, David Mandel, MD, a rheumatologist from Ohio, supported the approval of the drug. He noted, "As an oral medication, tofacitinib offers some very promising advantages to patients of ours who do not have access to infusion, who are 'needle-phobic,' or who [have difficulty in traveling to the clinic for infusions]," Dr. Mandel stated during the meeting. "This medication will improve the care of our patients with rheumatoid arthritis."
Take home message:
I find the side-effects of increases in malignancy rates, lipid and cholesterol levels, and serious infection rates to be disturbing. Although individuals suffering from rheumatoid arthritis are anxious to try a new medication, which might provide them with relief, they might be trading the possible improvement of their arthritis with another, possibly serious problem. Just a few days ago, the Institute of Medicine noted that the type, frequency, and severity of side-effects may be higher in the general population than a study group. It also noted that side-effects often do not appear months or even years after a drug receives FDA approval and released on the marketplace.