Wolfe vs. Rappaport: A Standoff Between FDA and One of Its Advisory Committee Members

There was some disharmony at Jazz Pharmaceuticals’ FDA panel review of its drug Rekinla for fibromyalgia.

FDA’s Arthritis Drugs Advisory Committee and Drug Safety & Risk Management Advisory Committee voted 20-2 against recommending Rekinla (sodium oxybate) for a supplemental indication for treatment of fibromyalgia on August 20; sodium oxybate is currently approved for the reduction of daytime sleepiness and cataplexy in patients with narcolepsy under the trade name Xyrem. (See our coverage in "The Pink Sheet" DAILY, here.)

Anyone that has been to an FDA panel meeting knows there are ebbs and flows that contribute to the final outcome.

One of those critical points came in the late morning during the FDA question and answer session, following the agency’s formal presentations.

Enter Drugs Safety & Risk Management committee member and outspoken drug industry critic Sidney Wolfe (director of Public Citizen’s Health Research Group). Wolfe explained that he had obtained publicly available documents that cast negative light on the trustworthiness of the sponsor to responsibly market Rekinla if the panel delivered a positive recommendation and FDA approved the drug.

To resolve parallel criminal and civil allegations of off-label marketing for Xyrem by their Orphan Medical division, Jazz entered a guilty plea and paid $20 million in monetary penalties as part of a settlement with the US Attorney’s Office for the Eastern District of New York. (To view the press release, click here).

Committee Chair Kathleen O’Neill (University of Oklahoma College of Medicine) tried to cut Wolfe off, saying the session was only for questions to FDA and could only address the material in front of the panel on that day.

Wolfe continued to read a summary of the off-label marketing settlement and said he eventually would have a question.

With Wolfe unwilling to stop reading, FDA took the seemingly unprecedented action of cutting off Wolfe’s microphone. That step has become routine during the open public hearing where there is a time limit but this was one of their own advisory committee members.

Wolfe turned the microphone back on and finally got to his question: Why, he asked, did FDA not mention the Xyrem off-label settlement in its presentations to the committee? After all, he argued, it was relevant to the decision at hand: could the sponsor be trusted to market Xyrem—also known as gamma-hydroxybutyrate (GHB)—to a much broader indication than it was already approved for?

FDA Division of Anesthesia & Analgesia Products Bob Rappaport stepped in and first instructed Wolfe to stop talking when the panel chair requests that he stop talking, explaining that it was her prerogative.

Rappaport continued that Wolfe’s reading of the documents were the first time he had ever heard of the off-label case and that it was not relevant to the Rekinla review despite the fact that both Xyrem and Rekinla are the same drug (sodium oxybate). Rappaport then admonished Wolfe for not providing the documents to FDA earlier, noting that he had called FDA's advisory committee management staff earlier in the week to raise an issue, but not provided the information he was reading at the meeting.

[UPDATE: Wolfe tells us "I had never previously told FDA officials that I had obtained these documents since I assumed, as it turned out incorrectly, that they were aware of them because FDA's Office of Criminal Investigation had been involved in the criminal prosecution. Why they were unaware, as Rappaport said, is another issue."]

The drama appeared to have come to a close with Rappaport’s comments; however, the FDA official returned after the lunch break and the open public hearing with a prepared statement:

“The issue that Dr. Wolfe raised this morning is a matter related to compliance and is not related to the topic under discussion today, unless there has been an accusation of data integrity problems with this application – and I’m not aware of any data integrity concerns. The only other way that the case referred to by Dr. Wolfe could be pertinent to this application would be if it was brought up to impugn the sponsor in the hopes that the committee would be punitive towards them in your deliberations and recommendations regarding this application. However it is important for you to recognize that that would not really be punitive to the sponsor but would really be punitive to the patients.”

At that point, Jazz Pharmaceuticals' Chief Compliance Officer Janne Wissel added a few remarks.

"We do have a corporate integrity agreement because we assumed responsibility for the acts of Orphan Medical at the time we purchased the company. The Department of Justice, as well as the OIG concluded at the end of their investigation that the behaviors of Jazz Pharmaceutical were not the same as those of Orphan Medical. However, we assumed responsibility for those actions.

"We have completed three years under our corporate integrity agreement where we have reports that are based on information and an audit conducted by an independent review organization with respect to our compliance for promoting our product within our labeling. All of those reports have concluded that we are promoting our product within labeling and that we are compliant with respect to the aspects of our corporate integrity agreement."

Wolfe was not given an opportunity to respond at the meeting, so we asked him if he would care to after the fact. He emailed us the following statement:

The previous RiskMap program and the Xyrem Success Program, that were agreed upon in 2002 by Orphan as a condition of approval of Xyrem for narcolepsy, included extremely restricted distribution through one pharmacy, education of doctors and patients and a registry of patients getting the drug.

One of the questions our advisory committee was being asked to respond to was the adequacy of the new REMS program for the expanded use of oxybate for treating fibromyalgia .

Xyrem’s manufacturer, Orphan, violated the above mentioned restrictions on distribution by illegal, criminal off-label marketing and was successfully prosecuted for this. When I discovered this, a week before the hearing, I assumed that the reason why it was not included in the Advisory Committee’s briefing materials was that for some reason the FDA did not want us to know about it. This seemed peculiar, since the prosecution of the company seemed quite relevant to our evaluation of whether the new REMS program could be expected to be effective.

As I asked in my question to FDA, following the material I read from the US Attorney’s prosecution of Orphan, Why didn’t the agency provide the material to us?

Dr. Rappaport’s surprising answer was that they were not aware of the criminal prosecution. He later added that this was really a matter involving FDA compliance and that it was not “related” to the issues being discussed by the committee because it did not involve data integrity.

Although it is the compliance part of FDA that was involved in investigating this (the FDA Office of Criminal investigation was also involved), the idea that the details of this criminal prosecution involving violations of the agreed-upon restricted marketing of this dangerous drug were not relevant to our deliberations seems irrational.

Dr. Rappaport went on to say that since it was not relevant to our discussion, the only reason I brought it up was to “impugn the sponsor” and thereby turn the vote against them. This would, he said, “not really be punitive to the sponsor but would
really be punitive to the patients.”

Following Dr. Rappaport’s after-lunch statement, Jazz Pharmaceutical, the owner of Orphan since June, 2005—including, according to the US Attorney, for at least seven months while the illegal activities were occurring--stated to the Advisory committee that the company had been essentially exonerated by the US Attorney’s office and was under a corporate integrity agreement with the HHS Inspector General. This statement, like Dr. Rappaport’s, is also incorrect since, in its non-prosecution agreement with Jazz, the US attorney stated on July 13, 2007:

“Based on the evidence gathered during this investigation, the government maintains that it would be able to prove that JPI [Jazz Pharmaceutical Incorporated], as a consequence of the criminal conduct committed by its subsidiary Orphan ("the Unlawful Conduct"), is likewise guilty of introducing and causing the introduction of a misbranded drug into interstate commerce, in violation of 21 U.S.C. 331(a) and 333(a)(2).”

It’s unclear how much of an impact the Wolfe-Rappaport discussion had on the final 20-2 negative vote for Jazz. But it’s clear the public disagreement was a notable turning point in the panel deliberations.

The agency later said “the issue raised this morning by Dr. Sidney Wolfe related to Jazz Pharmaceuticals marketing practices and compliance activities for sodium oxybate is not related to the topic (that was) under discussion. The FDA weighs all of the comments made by committee members equally but will only be considering the safety and efficacy information discussed today as it evaluates sodium oxybate to treat patients with fibromyalgia.”

--Ramsey Baghdadi

FDA Pronounces Rotavirus Vaccine Safe After All: Will FDA Leadership be More Cautious Next Time?

It’s official: FDA has given the all clear to resume use of GlaxoSmithKline’s Rotarix despite evidence of contamination with porcine circovirus. (Read the official announcement here.)

That outcome was something of a foregone conclusion after an advisory committee discussion of the issues last week—and especially after the discovery that Merck’s RotaTeq may be similarly contaminated. After all, it is one thing to suspend use of a vaccine when there is a readily available alternative; it is another to suspend vaccination for a disease altogether. (Read our coverage in “The Pink Sheet” here.)

There are interesting and important implications for manufacturers here, especially as you think about standards for cell-culture based flu vaccines in the future. More generally, any biological product is vulnerable to advances in analytic technology that make possible detection of the previously undetectable.

But we wonder what if any implications this will have on FDA’s newly installed leadership team. We doubt there will be much call to revisit this episode from Congress—as there would have been, if, say, Andrew von Eschenbach were still the commissioner and this were 2007. As you may recall, that was a time when seemingly every decision made by FDA came in for scrutiny on the Hill.

Now, FDA’s leadership has some breathing room: a Democratically controlled Congress has no reason to undercut a Democratically appointed FDA commissioner.

Still, there may be some internal lessons learned that will have implications for how the Hamburg team operates from here on out. There is an old maxim routinely cited by career staff at FDA: “absence of evidence is not evidence of absence.” The leadership team’s response to the circovirus contamination issue appears to be open to some significant second-guessing on that score.

Here is how FDA Commissioner Margaret Hamburg explained the suspension during an address at the Food & Drug Law Institute annual meeting April 22. She cited Rotarix as a classic public health dilemma facing the agency. On the one hand, there was an unexpected contaminant in a vaccine, one that is not known to pose safety risk but still clearly not an acceptable finding. On the other hand, the vaccine is for a disease that is generally mild in the US, but a significant public health threat globally.

Hamburg cited FDA’s actions as an example of “creativity” in applying legal tools in the context of emerging issues where there is no black-and-white answer.

“Our decision was based in part on the fact that an alternative rotavirus vaccine without the extraneous viral material is widely available in this country. But we did not recall the Rotarix vaccine or state that it is unsafe. We also made it clear that other countries could and should make different judgments based on their local assessment of benefit versus risk. Our recommendation was based on an effort to balance science and data with a certain level of uncertainty and also a recognition that this was really the first example of an application of new technologies that allowed us to learn more about a vaccine product.”

Sounds reasonable enough. But read that first part again: “Our decision was based in part on the fact that an alternative rotavirus vaccine without the extraneous viral material is widely available in this country.”

That turns out not to be a “fact” after all, since Merck’s product ultimately showed signs of viral DNA (albeit apparently not the virus itself.) It is one thing to “suspend” use of a product due to an uncertain risk and encourage patients to choose a product free of that risk. But it turns out that FDA, in effect, encouraged doctors and parents to use Merck’s product even though it has a similar risk.

It isn’t just Hamburg who highlighted Rotarix as emblematic of the agency’s new “public health approach to the law.” Chief Counsel Ralph Tyler cited Rotarix as an example of how the Chief Counsel can and should enable FDA’s leadership to meet its public health objective (as we noted here).

Tyler took on New York Times reporter Gardiner Harris, quoting his March 23 article on Rotarix and taking issue with the assertion that FDA’s action “demonstrates that lawyers have lost considerable power at the FDA” since “neither statutes nor agency rules allow the commissioner to ask doctors to pause in their use of a medical product because the agency does not regulate the practice of medicine.”

“This breathtakingly incorrect view of the proper role of the agency’s lawyers is exactly backwards,” Tyler declared. “Contrary to the view expressed by Mr. Harris, empowering a client to act empowers, rather than diminishes, the lawyer.”

“The frequency with which a lawyer says ‘no’ is most assuredly not the measure of a lawyer’s power,” Tyler concluded.

Those remarks were addressed rhetorically to Harris, but the real target was the past approach of the Chief Counsel’s office under the Bush Administration, and most notably under former Chief Counsel Dan Troy. Troy was the first official appointed at FDA during the Bush Presidency, and set a tone of limiting FDA’s actions to those he viewed as soundly based in explicit legal authority. Troy argued that FDA was in danger of losing credibility with the courts, which would potentially eliminate its ability to protect the public health altogether.

Troy, incidentally, happens to be chief counsel for GSK.

So did FDA try a little too hard to find an opportunity to declare a new doctrine for protecting the public health? Should the agency have waited for more data before, in effect, giving the rotavirus vaccine market to Merck?

Those questions are all too easy to answer with the benefit of hindsight. As Hamburg said at FDLI: “We had to operate within shades of gray and I think managed to do so. And the law supported us.”

The real question is whether Hamburg may decide to be more cautious next time …

image from flickr user ~K~ used under a creative commons license