On the strength of an eight to two vote, on May 9, 2012, an arthritis advisory committee recommended the U.S. Food and Drug Administration (FDA) approve Pfizer Inc.'s (PFE) pill, tofacitinib, for the treatment of moderate to severe rheumatoid arthritis (RA) in adults.
Heading into the meeting the FDA reviewers expressed concerns about the drug's safety and asked the panel to discuss the potential effect "missing data" had on the panelist's interpretation of the drug's effectiveness. There was little doubt about efficacy as they voted 10 to 0 that, overall, the drug was effective. Safety was not as clear-cut.
Is It Safe?
In the briefing documents the agency said it felt Pfizer's data suggested tofacitinib was associated with an increased risk of malignancy. During the meeting, the FDA stated it felt this risk was not specific to the JAK-inhibitor class, which tofacitinib belongs to, but rather to tofacitinib itself. That is certainly good news for other companies like Incyte (INCY), Eli Lilly (LLY) and Vertex (VRTX) which are developing their own JAK-inhibitors for RA. (Drugs by Chelsea (CHTP) and Rigel (RIGL) do not belong to this class).
The increased malignancy risk was especially worrisome in the 10mg dose. So much so that when it came time to vote on the basis of safety, members insisted the FDA change the question or provide guidance. Panelists were instructed to vote yes if they felt either of the 5mg or 10mg doses were safe enough to grant approval. If neither dose was safe then vote no. Seven voted yes, two no, and one abstained. It was clear if the question had been clarified to "vote yes only if both doses are safe enough" the vote would be split at best. The final overall eight to two vote played out in similar fashion.
Committee members wondered if the efficacy benefit in the 10mg dose over the 5mg dose was enough to justify the increased safety risk. Especially considering patients could be on the drug for five to 10 years, there was little long-term safety data for the 10mg dose, and that Pfizer's submission is for widespread use with patients eligible after having failed only one previous DMARD (disease-modifying antirheumatic drug). The FDA also mentioned more than once that a 3mg dose, which was not submitted for approval, was safer and demonstrated efficacy similar to Abbott Laboratories' (ABT) Humira in one study.
Can It Stop Disease Progression?
The FDA reanalyzed Pfizer's radiographic outcomes data and asked the panel to discuss the impact the reanalysis had on their opinion of the drug's effectiveness. Comments from various panelists included:
- Insisting on definitive scans of patient's joints might be "setting the bar a little bit too high"
- "This gold standard outcome" becomes "tougher to evaluate"
- "Failure to show progression is not a strong negative"
- I'm "comfortable making decisions without radiographic data"
Despite the progressive, forward-thinking nature of the panelists, perhaps the shortcoming of Pfizer's radiographic outcomes data won't be dismissed by the FDA as readily. In oncology, surrogate endpoints like response rate and progression-free survival do not always translate into survival benefits. This is why overall survival remains the FDA's gold standard metric for many cancer indications. While the ACR20 and DAS-28 are not surrogate endpoints there is a good reason why radiographic outcomes remain a gold standard measure for the FDA in RA. This excerpt is from the FDA briefing documents for tofacitinib (page 4):
Radiographic progression may occur in people who have very low apparent disease activity and patients with clinical disease activity may have no evidence of radiographic progression. Thus, documentation of a benefit of treatment on structural damage progression has been an important goal of clinical development programs for new products proposed for RA, particularly if the product has a novel target. This has become an increasingly important aspect of the risk-benefit assessment for new RA treatments in light of the many approved treatments that have documented beneficial effects in inhibiting structural damage progression.
The panel actually felt, in an eight to two vote, the radiographic data was insufficient to support a claim. The data was suggestive the drug is effective in stopping disease progression, but not definitive. Many felt a second trial assessing this endpoint should be performed. The FDA informed panelists it historically only asks for one radiographic trial (Pfizer only conducted one) but was quick to note usually the outcomes from a lone trial are more definitive than what was witnessed with tofacitinib.
8 to 2 But …
On the surface, eight votes out of 10 for approval sure sounds convincing. But closer examination of the issues underlines this may not be as clear-cut as headlines make out. Will the FDA approve both doses, just the 5mg dose, neither? The doctors on the panel would clearly like to have tofacitinib as a treatment option for patients. Is the FDA willing to leave the decision up to them? Dick Van Patton would be the first to tell you eight is enough. But is eight enough for Pfizer?