Fighting Like a Wolfe Against Johnson & Johnson

There are certain codes of conduct during advisory committee meetings. Come prepared having thoroughly read the briefing documents. Speak in turn. Don’t discuss the merits of the application over lunch.

Sidney Wolfe isn’t one to stand on protocol.

During the March 19 Cardiovascular-Renal Drugs Advisory Committee review of Johnson & Johnson’s anticoagulant rivaroxaban, Wolfe, the acting consumer representative, took the unusual step of calling out to an FDA drug safety reviewer—Office of Surveillance & Epidemiology associate director for science John Senior, who was sitting in the audience—to ask him point-blank the very question the committee was being asked to deliberate: whether rivaroxaban should be approved based on the available data.

It was clear from the start that Wolfe wasn't keen on a rivaroxaban approval, and he set up Senior to issue a negative opinion. Wolfe noted the divergent conclusions drawn by J&J and FDA on rivaroxaban’s liver toxicity profile, and the expectation that the drug could be used extensively off-label. Then he asked Senior: “You’ve been involved in this for some time … Do you think it is a good idea to approve now without waiting to see the results of much more data from much longer duration trials?”

The question was significant for a couple reasons. First, it demonstrated that Wolfe isn’t afraid to step outside the typical bounds of advisory committee meetings to make his point. As we’ve blogged before, Wolfe is not your average committee member, and he’s certainly no shrinking violet. And while there is no hard and fast rule against asking an FDA reviewer his or her opinion about an application, to put Senior on the spot was a bit unusual—especially since he was not part of the FDA team at the conference table.

Calling on Senior served another purpose: it was Wolfe's way of getting another public FDA opinion against the approvability of rivaroxaban. OSE was well-represented at the meeting: director Gerald Dal Pan was at the committee table, and medical officer Kate Gelperin delivered a compelling critique of rivaroxaban’s safety profile. But Senior’s reasoned evaluation of the NDA only fueled Wolfe's arguments.

Senior said that while he was “impressed” with J&J's early look of longer-term safety trials (known as the ATLAS study), “I'd like to see more.”

Senior then evoked AstraZeneca's failed anticoagulant ximelagatran (Exanta). FDA should “learn the lessons from ximelagatran,” Senior said. Exanta's heptotoxicity signal did not surface until longer-term studies were analyzed, he reminded the advisory committee. With Exanta, FDA issued a “not approvable” letter, and AstraZeneca's eventually discontinued development. Without reading much between the lines: FDA should take its time with rivaroxaban.

Senior added that only under one circumstance should rivaroxaban be approved without longer-term data: “If it can be shown that the drug is saving more lives than it is risking, then I would think reduction in mortality would trump the risk of liver injury. But I haven’t been convinced that those data are real. I think we need to see that.”

Those statements seem to sum up how FDA—or at least the drug safety office—is thinking about the NDA. As reported in “The Pink Sheet” this week, the good news for J&J is that those longer-term data are available: the six-month ATLAS study has concluded. But time is likely to run out: it is unlikely that J&J can submit the final report and FDA can review it before the late May user fee deadline.

In the end, Wolfe cast only one of two votes against approval. Sanjay Kaul, perhaps best known as the disinvited prasugrel committee member, also actively argued against rivaroxaban. Neither managed to convince the rest of the advisory committee to see things their way. But the Wolfe-Senior exchange still illustrated Wolfe's tenacity in making his point—and his savvy in understanding FDA politics. Like we said before, Wolfe is not your typical advisory committee member.