Given the level of interest in our earlier blog post on Sidney Wolfe at the FDA advisory committee review for Johnson & Johnson’s rivaroxaban, we figured we'd call up Sid at his office at Public Citizen and ask the questions that you, dear readers, have posed to us:What was behind Wolfe's decision to ask drug safety official John Senior his opinion of rivaroxaban’s benefit-risk profile during the advisory committee review? Doesn't that go against protocol, and what makes him so damn special?
Here’s what Wolfe had to say:
“John Senior without question, knows more about drug-induced liver toxicity than anyone at FDA.” Senior has organized agency workshops on the topic of hepatotoxicity, and has published numerous papers on the subject. Given that the committee was debating the significance of a liver safety signal, Wolfe said, “I assumed he would be knowledgeable.”
Rivaroxaban's hepatotoxicity signal is good reason by itself to engage thought leaders like Senior, Wolfe said: "FDA has been here before with ximelagatran," the AstraZeneca drug (also known as Exanta) that was rejected by FDA and later discontinued due to liver toxicity.
In the case of rivaroxaban, Wolfe acknowledged, "things are a bit more clouded," because the active comparator, enoxaparin (Sanofi-Aventis' Lovenox) has the potential to raise ALT levels, which may disguise the liver effects with rivaroxaban. In that sense, the rivaroxaban pivotal program reminded Wolfe of Pfizer's cardiovascular safety studies pitting celecoxib (Celebrex) against diclofenac, which he says has a known CV risk.
Wolfe also disputes the contention expressed by The IN VIVO Blog (and some of our readers) that he was stepping out of bounds by addressing Senior during the advisory committee review. FDA often has 15 to 20 different staff members sitting in the audience at advisory committee meetings, Wolfe pointed out, and it is not unusual for them to field questions from the panel.
Fair enough. We'd like to point out, however, that regardless of whether or not the advisory committee staff frown on that sort of exchange, it's not a step many advisory committee members would think to take. Which is precisely why he is not your typical advisory committee member.
And given that this is Sid Wolfe, he had to get one last dig for the pharma industry: Celebrex, he predicted, "will eventually come off the market."
Stay tuned for Part 2 of our chat with Wolfe tomorrow, which will discuss his past history with FDA principal deputy Joshua Sharfstein. Also, look for the tally of our readers' votes on whether Wolfe is right and Celebrex will come off the market.
John Senior does not know more about drug induced liver disease than anyone else at FDA.
ReplyDeleteAnyone who has worked with him at FDA knows that his job is basically to dismiss cases of hepatotoxicity as long as he possibly can.
We know about structure activity relationships and can predict various types of hepatotoxicity. We also know that underlying liver disease and viral hepatitis makes you more susceptable to drug induced liver disease. In spite of this John Senior's job is to always deny that it's due to the drug as unless it's an absolutely pure case without any confounding variables.