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

Asclera: A REMS By Any Other Name…

Quick quiz. There’s a new molecular entity pending at FDA, intended for a cosmetic use. There is a clear signal of a risk of anaphylactic reactions, most likely associated with off-label use at high doses. The review team is in agreement: there needs to be some form of communication plan and special monitoring to assure that physicians don’t casually use higher doses.

Will the product have a Risk Evaluation & Mitigation Strategy as a condition of approval?

We don’t know about you, but our guess would certainly have been yes. After all, FDA seems to be using REMS more and more, right?

Well, not this time.

Here is how Cardio-Renal Drug Products Division Director Norman Stockbridge explained the decision, in the summary review of the March 30 approval of BioForm Medical’s varicose vein treatment Asclera (polidocanol):

“All team members concur on approvability.

An issue to be resolved is how to address the risk of anaphylaxis. There are no such cases in the controlled experience, but there are other allergic reactions—urticaria, hives, sneezing, and what sounds like angioedema. Similar cases to these appear in post-marketing use [overseas]. Post-marketing, there appears to be one reasonably clear anaphylaxis case following low-volume administration to treat a leg varicosity….

Overall, the team has the impression that the risk of anaphylaxis may increase with dose, and that seems plausible. A goal of labeling and any additional post-marketing safety-related activities ought to be discourage off-label use for larger varicosities where the volume of drug necessary will be much higher than it is for the indicated uses.

Dr. Southworth recommends a bolded warning, similar to the one sotradecol has. I concur with this. She recommends a communications plan for healthcare providers for the first few years, and annual review of hypersensitivity reactions. (These can be done outside of a REMS.) I concur with these, too.

She is equivocal on a medication guide, citing the closely monitored setting of administration. I do not favor a medication guide; there is ample opportunity for the patient and physician to discuss treatment options, and practitioners are generally familiar with the risks from use of sotradecol. While I agree with Dr. Southworth that the cosmetic use creates a low threshold for taking conservative measures, I do not think the bar should be quite this low.”

Final decision: approval with no REMS.

So is this a sign that REMS mania has crested? Should sponsors celebrate the return of a standard where REMS are the exception rather than the rule?

Well, not so fast.

First, Stockbridge has already voiced his displeasure with some of the accoutrements of the “Safety First” era, declaring in his memo on Effient that “no one associated with this review should feel good about this.” He meant the endless deliberations about the potential safety issues with Lilly/Daichii’s clot-dissolving drug. Stockbridge was clearly ready to approve the drug long before he wrote those words in April 2009. But Effient itself wasn’t approved for another three months after.

In other words, Stockbridge can’t change anything on his own, and its clear that other FDA review managers have different levels of enthusiasm for the new safety tools. For example, FDA’s Endocrine & Metabolic Drugs Division management, for example, seems to have a very different view of the value of REMS tools. (We’ll have more on that in an upcoming issue of The RPM Report.)

And, while Stockbridge’s rejection of a REMS did avoid a last minute delay for Asclera, it didn’t exactly make this a lightning fast approval. Asclera was first submitted in 1999, and got a “complete response” in 2004. Meanwhile, it continued to be marketed overseas, building the safety database that helped reassure FDA that the risk of anaphylaxis is very rare. That puts Asclera in a venerable class of NMEs that always have an easier time at FDA: those with long marketing histories overseas.

More importantly, while there isn’t technically a REMS on Asclera, there might as well be. FDA and the sponsor agreed to a Dear Doctor letter at launch outlining the risk of anaphylaxis. It isn’t required, so it isn’t a REMS—but it was agreed to prior to approval, and we bet the sponsor doesn’t see much difference there.

And then there is a mandatory post-marketing study—a pretty unusual one at that:
The sponsor will provide “a yearly report (containing both interval-based and comprehensive data) analyzing spontaneous adverse event reports received that describes anaphylaxis or death.” Reports are due annually until 2016.

So BioForm doesn’t have to comply with a REMS. But it does have to send a “Dear Doctor” letter warning of a very rare potential adverse event with off-label use, and submit annual analyses of post-marketing reports.

A REMS by any other name still smells as sweet…

Can a Biomarker Salvage Novartis' Joicela (AKA Prexige?)

In the "History of Troubled Drugs" playbook, lumiracoxib (Prexige, now called Joicela) is only a footnote, hardly a Vioxx or Avandia.

Prexige, however, may make a mark after all in pharma annals, far beyond its missed revenue opportunity or beneficial impact on patients. The drug, which is made by Novartis, is a selective COX-2 inhibitor, indicated for symptomatic relief of pain from osteoarthritis. COX-2s --as in the infamous Vioxx--are all but off the market in the US because of their cardiovascular side effects, but lumiracoxib binds to a different site on the COX-2 receptor, which may give it advantages that lift it from under the Vioxx shadow: minimal CV side effects, high selectivity, rapid cleansing from the blood and absorption into the inflamed joint.

The drug received European marketing authorization in November 2006 and launched in parts of Europe the following year. It has its own demons, however – rare but potentially fatal risk of liver failure at higher doses, and the FDA never approved it. In 2007, Novartis began under pressure from regulators to withdraw it from the market in the EU and elsewhere.

Now, as Joicela, lumiracoxib linked to a lab test may make a comeback. Novartis scientists have come up with a genetic marker, which they say can identify patients who are potentially at risk for lumiracoxib-associated hepatotoxicity. In essence, Novartis argues, patients who test negative for the marker aren't at high risk of liver side effects and can take the drug. Those who test positive for the marker should not get the drug.

It's an interesting case study in the murky, fragile world of companion diagnostics, which is starting to show up as more than a blip on pharma's radar. One indicator: Roughly a dozen or so diagnostic-drug companies deals with the aim of bringing a diagnostic and drug that are linked through to commercialization, were signed in 2009 --compared to seven in 2008. Novartis itself started a Novartis Molecular Diagnostics business unit--which is developing the diagnostic for Joicela and has 10 projects in the works --only little more than a year ago.

If Joicela makes it back on the market, pharma is likely to take note. For pharma, a biomarker strategy for rescuing flawed drugs holds tremendous appeal (think Exanta, Galvus, etc.), even if the ultimate market is nowhere near the original projections--especially if regulators accept data based on analysis of archived samples from previously completed studies. That's the approach Novartis has taken in Europe, where it submitted an application for marketing authorization in December 2009.

Novartis' next step in the US is less clear cut because the FDA has yet to propose a regulatory pathway for companion diagnostics --and the agency's paralysis has been a hurdle to say the least. Yet some good news happened on Feb. 25: Commissioner Margaret Hamburg for the first time publicly stated a timeframe: She expects the agency will propose companion diagnostics guidance this year.

FDA To Increase Criminal Prosecutions Of Execs

The pharmaceutical industry spends plenty on lawyers for all sorts of things - patent challenges, product-liability litigation, employment matters. The list is long, but it may be time to add another reason - criminal defense of executives.

Sure, there have been some big fines paid of late for such things as off-label promotions, but the FDA is now saying it will increase prosecutions of executives as part of an effort to bolster its Office of Criminal Investigations. It's not the first time FDA has made noises intended to get drug execs thinking about doing hard time.

So why the renewed vigor now? The agency is responding to a report issued today by the Government Accountability Office, which found there is little oversight of the OCI. This is the office that's responsible for probing counterfeit drugs and other criminal activities, as well as misconduct by FDA employees. But oversight is so lax that the GAO concluded the FDA "has relied largely on the OCI director to determine which aspects of OCI's operations and investigations are made known to FDA's top management." So who's in charge? Apparently not the FDA commissioner.

For instance, the OCI has six field offices across the U.S., and each office is supposed to undergo evaluation at least every three years. But the GAO found that only seven evaluations, or roughly 30 percent of those required, took place between 1996 and last August. One office has not been reviewed in more than a decade, according to the GAO report, which was undertaken at the request of Charles Grassley, the Iowa Republican on the US Senate Finance Committee who has regularly investigated drug safety issues.

The FDA is sent a more detailed response today to Grassley (see this), although the agency already agreed with the GAO findings (there is a letter at the end of the GAO report that you can read). For those looking to connect dots, the recent Senate Finance report on Avandia made a point of noting that several big drugmakers have paid huge fines for criminal violations, such as off-label promotion, and that more diligent oversight is needed to ensure consumer safety. In other words, Grassley was leaning on the FDA to get tough. But will anyone get convicted?

The FDA response (read here) says the agency will "increase the appropriate use of misdemeanor prosecutions, which allows responsible corporate officials to be held accountable and is a valuable enforcement tool." So maybe it is time to find a full-service law firm.

photo from flickr creative commons sbaker

XenoPort Experiences Restless Investor Syndrome

File this one under Regulatory Setback Syndrome. The FDA decision to issue a complete response letter to XenoPort and GlaxoSmithKline for their Horizant drug to treat Restless Leg Syndrome appears to have stunned the drugmakers. In a conference call this morning with analysts, XenoPort chief executive Ron Barrett confessed he didn't see it coming until the FDA missive arrived yesterday.

"It certainly did surprise us," he told the listeners, insisting the issue was never raised in any discussions with the agency during the entire pre-approval processs. "Many of the activities that you would expect to happen going into a PDUFA date had and were happening, including the REMS, and this one came out of left field."

What went wrong? The FDA bounced the drug because a trial showed a cancer risk in rats, specifically a prevalence of pancreatic acinar cell tumors in male rats. Interestingly, a similar finding showed up in Pfizer's Neurontin (gabapentin), which is approved to treat refractory epilepsy, and Barrett said the strength of the signal was no worse than what was seen with the Pfizer drug.

The FDA acknowledged that findings in lab animals don't necessarily translate into risk in humans, Barrett continued, adding that the agency "noted that gabapentin products have been available for over 15 years, and they do not appear to be associated with a clinical signal for pancreatic cancer based on analysis of spontaneous reports in the adverse event reporting system."

The issue for the FDA, though, is that treating epilepsy is a more serious matter than Restless Leg Syndrome, a line of thinking that may bolster those who have criticized the marketing surrounding the condition, even though it is deemed to be kosher by the National Institute of Neurological Disorders and Stroke (take a look).

For now, the implications for XenoPort are more immediate and severe than any marketing debate. Glaxo already announced plans to exit research into pain, and Barrett concedes their deal for the drug may be up in the air, possibly threatening further development of Horizant to treat neurothropic pain, where a Phase II trial failed last year, and migraines. Barrett, however, refused to offer any definitive insights on this particular topic. "The question of risk-benefit is something that is going to have to be probed for each indication."

In response to a question about Glaxo's ability to end the deal based on development setbacks, Bennett offered this sobering reply: "I think it's fair to say that any license agreement of this type is going to have termination provisions. And without speaking to language that might be redacted, I think it is reasonable to expect that this agreement is no different than that GSK would have the ability to terminate for reasons that include what you have articulated, among others. So I think people should understand that a termination by GSK is possible in the wake of this news, as well as in the wake of other developments."

Consequently, XenoPort is now suffering from Restless Investor Syndrome - its shares are down a whopping 67% in midday trading to about $6.54 on nearly 10 times normal trading volume. Given these events, Bennett has to be sorry Horizant isn't already available to treat migraines.

arrow thx to austinsdkeys on Flickr Creative Commons

ESA Safety and the New, Transparent FDA

If you are interested in knowing what FDA thinks about important regulatory issues, including specific product reviews, it is time to renew your subscription to the New England Journal of Medicine.
A team of FDA officials, including Office of Drug Evaluation I Deputy Director Ellis Unger and Center for Drug Evaluation & Research Deputy Director for Clinical Science Robert Temple, used NEJM as a vehicle to announce a formal reassessment of the safety profile of erythropoeitin stimulating agents in chronic kidney disease, including an advisory committee review to consider (most likely) whether use should be limited to the minimum amount necessary to avoid the need for a blood transfusion.

The advisory committee isn't surprising; as we reported in The RPM Report last month, FDA was looking carefully at new clinical data suggesting that use of ESAs (Amgen's Aranesp, J&J's Procrit) may increase the risk of strokes in chronic kidney disease patients. And, given all the issues around safety of ESAs in oncology, an advisory committee was probably inevitable.

What is surprising is the forum to announce the plan.

But not too surprising. Unger previously used NEJM to publish a summary of the basis for approving Lilly/Daiichi Sankyo's Effient, after a long and controversial review. Former Merck drug safety head Peter Honig cited Unger's Effient editorial during an Institute of Medicine meeting on drug safety in September as a good way for the agency to explain its thinking about safety issues.

And Commissioner Margaret Hamburg and Deputy Commissioner Joshua Sharfstein announced their agenda at FDA in an editorial published by NEJM on the day Hamburg took office.

We expect a lot more pharma execs will be scanning those headlines in weeks to come.

Is There a Drug Lag? We Still Don't Know

Is there a difference in the pace of approvals between the US and Europe? We asked, and you answered, with a clear, unambiguous "maybe."

The results of our poll are below, and glance at the responses makes it clear: about half of you think that yes, FDA has become too conservative and therefore drugs are more likely to make it to market first in Europe. And about half of you think there is really no difference.

There isn't much support for the idea that maybe the problem is that Europe hasn't learned to be appropriately cautious. We, however, feel compelled to point out that many in FDA might feel that way, raising the distinct possibility that if there is a drug lag, it will only close if Europe starts to slow down.

Thanks to all who commented, including a few who proposed "other" responses. Our favorite: "Both yeses are correct."

"Lagging Indicators:" Does Europe Approve Drugs Faster Than The US?

We heard a phrase we haven't heard in a long time this week: "Drug Lag."

Merck EVP Worldwide Regulatory Affairs & Product Safety Peter Honig used the phrase during his introductory remarks to an Institute of Medicine workshop on drug safety, intended as part of a series of updates on IoM's past review of the US Food & Drug Administration's safety regulation.

Drug lag is a term straight out of the 1980s, when the pharmaceutical industry argued that excessive conservatism by FDA meant plenty of lifesaving drugs came to market first in Europe, while US patients suffered or died waiting for the agency to act. We've since seen analyses claiming the whole notion of a "drug lag" was hooey, but that didn't matter: the perception, as Honig noted, was a key motivating factor in helping push through the Prescription Drug User Fee Act, which undeniably led to a rapid increase in the number of new drugs first marketed in the US.

Indeed, a generation of pharmaceutical industry managers grew up in a world where the industry's largest market (the US) was also its fastest growing market, and the one most likely to grant market entry first. Quite a trifecta.

Well, the US is still the largest pharmaceutical market in the world, but it sure isn't the fastest growing. And Honig, at least, thinks it is also showing signs of lagging behind Europe in market entry. The Merck exec didn't press his case hard, but he did prompt a response from FDA's top new drug review manager, John Jenkins (pictured above).

There are really "two issues people are raising" about new drug reviews, Jenkins noted. One is the undeniable fact that there are some delays associated with new processes and procedures, like the Risk Evaluation & Mitigation Strategies or "safety first" initiative. Jenkins acknowledges that FDA has "taken on a huge process burden" and "the money has not followed at the same pace as the new responsibilities." So some "lag" may be inevitable, at least until resources and habits catch up with the new workflow.

But, Jenkins continued, that isn't really what people worry about. They worry about whether "FDA is becoming more conservative."

And that, Jenkins said, is very hard to quantify, because "we have lagging indicators." Economists, he noted, prefer to focus on leading indicators, but the only was to tell what is happening with approvals is to look at statistics for various application cohorts, and the data inevitably trail months or even years behind the calendar.

So "the most recent data we have is from fiscal 2008, and you really can't see any kind of fall-off or change that is dramatic for first cycle approvals of new molecular entities."

But, to Jenkins' credit, he doesn't just drop the issue there. "It is hard to quantify if my division directors or my office directors are affected by the drug safety debate that has been raging in this country for the last five or six years." The issue "has calmed down a bit recently," Jenkins said, but "have they been impacted?" Are "they less likely to approve a drug today with the same data package that they might have been five years ago?"

"It is impossible to make that assessment because you just can't answer those questions," Jenkins says. "What you have to look at is the data over time to see if you see any trends."

Jenkins noted that he presented an analysis of recent drug approvals last year (at, we might add, our very own FDA/CMS Summit for Biopharma Executives in Washington DC). That data showed seven drugs approved in Europe at that time, but not in the US, and only two in the US but not Europe. (Read our coverage here.) But that data is "now close to a year old. We've been looking at it again, but we haven't reported any more recent analyses." (We hope that will change this Dec. 3, when Jenkins opens the fifth annual FDA/CMS Summit.)

But even a clear indication that there are more drugs approved in Europe first may not be persuasive. "There are a handful of drugs approved in Europe that we haven't approved," Jenkins said. "We'd be happy to argue in public why we didn't approve them, but we can't always do that."

One of those drugs, Sanofi Aventis' weight loss agent Accomplia, was ultimately withdrawn in Europe for safety reasons. So, Jenkins said, "Only time will tell: are we being too conservative and depriving patients of needed drugs, or are they being too aggressive and going to run into the same safey buzz saw that we blew through in the 2000 decade."

Time will tell indeed, but we are impatient here, so why don't you all tell us instead: respond to our poll and let us know what you think. Is there a drug lag? And if there is, is it because FDA is too conservative or EMEA is too reckless? Look for the results next week. (If you are reading via email, click here to take the poll.)

The IN VIVO Blog Poll Results: Bye Bye Avandia

The people have spoken, and they expect a long year ahead for GlaxoSmithKline. That’s because Avandia was the run-away winner in our poll based on our purely speculative if not insanely irresponsible notion that the US Food & Drug Administration might just pull a drug to demonstrate that it is taking Congressional concerns about drug safety seriously.

It ain’t scientific, but 42% think Avandia is most likely to be pulled. And, for its worth, that’s twice as many people as think we are crazy to think this way. (See full results below.)

Frankly, we were temped to vote “crazy” ourselves, so we consider this result a bit of surprise.

We also got lots of comments—a few of the “you are crazy” variety (keep it clean, people!), but also some suggesting candidates we didn’t include in the poll. Two votes for Avelox, one for Oxycontin, and one for midrodine. Oh, and one pointing out that we should have listed Accutane for a different side effect.

So folks clearly think there is a risk here.

One final note: the polls closed before readers could digest our two most recent posts, based on our conversation with gadfly and advisory committee member Sid Wolfe. In the first, he--quite unprompted by us--predicted that Celebrex will eventually be withdrawn. In the second, he discussed his relationship with incoming deputy commissioner Joshua Sharfstein.

Celebrex only got 6% of the vote in our poll. Wonder if people feel differently today?

Following Up With Sid Wolfe (Part 2)

Washington is full of interesting connections.

Given how much people jump from job to job in DC, it’s only a bit of an overstatement to say that everybody has worked with everybody at some point in their careers.

So it should come as no surprise, perhaps, that Joshua Sharfstein, the incoming principal deputy commissioner of the Food & Drug Administration, used to work with a prominent policy figure in Washington who happens to be a staunch critic of the pharmaceutical industry.

No, we’re not talking about Rep. Henry Waxman, for whom Sharfstein worked early in his career. This is someone perhaps even less favorable to Big Pharma (if that could be possible): Public Citizen’s Health Research Group director Sidney Wolfe.

Sharfstein worked at Public Citizen as a researcher between April-August 1992—after completing his undergraduate degree from Harvard University and starting medical school. During his five months at Public Citizen, he contributed to a report on the capacity of the U.S. correction system’s ability to care for mentally ill. (One finding: states without adequate inpatient mental health facilities jailed mentally ill patients rather than providing appropriate treatment.)

In an interview, Wolfe recalled Sharfstein's stint at Public Citizen, but was careful not to give him too much praise. When asked of his impressions of the incoming FDA official, Wolfe spoke generally of the “extreme public health experience” of both Sharfstein and FDA commissioner-designate Margaret Hamburg. “I can’t remember the last commissioner with solid public health experience,” Wolfe said. (He discounted David Kessler, who as the former head of a hospital, Wolfe says, did not rise to the same level as health commissioner of a big city.)

After Public Citizen, Sharfstein went into his first year of medical school, and promptly did something rather Wolfeish: he led a student campaign urging his classmates to return free textbooks donated by pharmaceutical companies.

According to a story in the Harvard Crimson, Sharfstein set up a drop-box for students to return two textbooks donated by Sandoz, and wrote a letter to president Timothy Rothwell protesting their distribution. The protest didn’t seem to attract much support: few books were returned, and a few that were returned were stolen from the drop-box.

Wolfe and Sharfstein kept in touch, collaborating on a 1999 petition to then-HHS secretary Donna Shalala against Pfizer’s marketing practices for the antibiotic Zithromax. Wolfe and Sharfstein, who at the time was a pediatrics fellow at Boston Medical Center, accused Pfizer of launching a campaign to convince physicians to prescribe Zithromax over the “effective and inexpensive” antibiotic amoxicillin—against CDC guidelines.

They also testified at the same FDA public hearing in 2008 over the safety of cough and cold medicines; Sharfstein petitioned FDA to relabel the products as not safe and effective for children under six years. At the public meeting, Sharfstein was the opening presenter, and Wolfe spoke during the open public hearing portion of the meeting.

We're not saying that makes them bosom buddies, but it does make for an interesting Washington connection.

Following Up With Sid Wolfe (Part One)

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.

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.

If FDA Pulls a Drug, Which One Will It Be?

This podcasting stuff is fun, but sometimes we even surprise ourselves.

During our most recent IN VIVO Blog podcast, we (meaning my fellow podcaster Ramsey Baghdadi) made a bold prediction: that there will be a high profile drug safety withdrawal this year, in effect to make the point that it is no longer business as usual at FDA.

We (meaning me) were very surprised to hear that prediction, and frankly disagreed. Its not that we don't think the new FDA leadership will take steps to show its independence from industry, its just that it seems inconceivable that they would go to the extreme of pulling an FDA-approved drug to make that point. More Warning Letters, sure. Tough regulatory responses to manufacturing problems, yes. A clampdown on direct-to-consumer advertising, okay. Heck, maybe even putting a CEO in jail the next time sloppy manufacturing or unethical marketing causes patient harm.

But pulling a drug? That's crazy.

Then we started thinking about it a bit. If you had told us in 1990 that David Kessler would, as commissioner, pull a perfectly harmless national brand of orange juice from the shelves nationwide simply to make a point about truth in labeling, we would have called you crazy. But he did. (Remember Citrus Hill "Fresh" OJ? P&G does.) And he did as part of a frankly anti-regulatory Republican administration, no less.

So, given all the attention that the Democratic leadership in Congress has focused on drug safety--and especially on a few prominent examples where they view FDA as having failed in its public health mission--maybe it isn't so inconceivable that the new commissioner will end up pulling one to demonstrate unequivocally that the "old" FDA is gone forever.

Now, bearing in mind that this is pure speculation on our part, we then got to thinking: if FDA decided to go that route, which drug would they pull?

It isn't too hard to come up with candidates. To our mind, the criteria would be relatively simple: what are the drugs where Congress has raised the most concern, where the impact of a withdrawal would do the most to enhance FDA's credibility as a regulator (in the eyes of those who equate being tough on industry with credibility), and where the commissioner could make the case most convincingly that the drug would never have been approved if the agency knew everything it now knows about the risk/benefit profile.

Here is our top five, but we want to know what you think too. And, to repeat: this to get you thinking about the "what ifs," not a prediction of (or call for) any product withdrawal.

Avandia -- As the poster child for drug safety in 2007, GlaxoSmithKline's diabetes medicine would obviously be vulnerable if the new FDA leadership wants to signal a break with the past. Recall that FDA itself was publicly split on whether Avandia should stay on the market, and that it was the subject of a review by the agency's Drug Safety Oversight Board, which voted 9-8 in favor of continued marketing. The new leadership at FDA could simply reconvene that board--with its new membership in the new Administration, and perhaps convene it in public to embrace the Administration's commitment to "transparency"--and we bet the outcome could easily go the other way. That would certainly make Rep. Henry Waxman happy.

Ketek -- FDA took a grilling for the review of Sanofi-Aventis' antibiotic because of a severe case of clinical investigator misconduct in the pivotal trials. The agency ultimately decided that the dataset in support of Ketek is strong enough without the suspect results to continue marketing. However, the new leadership could easily take the position that there is no way to trust any of the data in the Ketek NDA and therefore that the approval is rescinded. That would make Sen. Chuck Grassley happy.

Celebrex -- Pfizer's celecoxib is the only cox-2 inhibitor left on the market. Pulling it would certainly tell the world that the Vioxx era is over once and for all. To be fair, Celebrex is probably one of the most thoroughly studies medicines ever marketed at this point--but that wasn't good enough for Merck's Arcoxia.And with a big settlement soon to be announced regarding Pfizer's marketing of its cox-2 brands, a withdrawal could play as just desserts.

Accutane -- Roche's off-patent acne drug has been marketed for years under a series of risk management programs intended to minimize the potential for birth defects associated with the drug. Ironically, it is only in the past few years that the agency finally thinks it has a program in place that works. But the risk/benefit ratio for the drug has also been a tough case, given that the drug is for cosmetic use, and that only got tougher when questions were raised about potential risk of suicidality with the drug. And those questions have been one of the toughest issues for FDA politically, since Rep. Bart Stupak's son is among those who committed suicide while on therapy with the drug. If FDA is looking to please its Congressional critics above all else, that step may do more than any other to achieve that goal.

OTC cough/cold remedies -- Incoming deputy commissioner Josh Sharfstein led the charge on relabeling over-the-counter cough/cold products to restrict pediatric use. But is he satisfied that FDA went far enough? He can make the call himself soon enough.

Alright, so what do you think? Take our poll below and we'll post the results next week.

Prasugrel Backlash Doesn't Deter Kaul

Sanjay Kaul doesn’t get discouraged easily.

The very public debacle over Kaul’s potential intellectual conflict of interest with Lilly/Daiichi Sankyo’s anti-clotting agent prasugrel has not deterred the cardiologist from fulfilling his obligation as a member of the Cardiovascular-Renal Drugs Advisory Committee.

According to information posted on FDA website, Kaul will participate in the committee review of Sanofi-Aventis’ antiarrhythmic dronedarone (Multaq). Dronedarone will be his first meeting as a permanent member of the Cardio-Renal advisory committee after being “disinvited” from the February 3 prasugrel panel due to a potential intellectual bias.

At the time, Office of New Drugs director John Jenkins expressed hope that Kaul, a well-known cardiologist at the Cedars-Sinai Heart Institute, would remain a member of the advisory committee, despite that fact that his disinvitation sparked a very public—and at times nasty—post-meeting debate over the integrity of FDA’s advisory committee process. (We’ll have more on that in the next issue of The RPM Report.)

“Dr. Kaul is a new standing member of the Cardio-Renal advisory committee. This would have been his first meeting as a standing member,” Jenkins said in a post-prasugrel interview. “We hope that he will continue to serve and will be a productive member of the committee going forward.”

Jenkins was careful to clarify that Kaul was not to blame for the incident. “He did everything he was supposed to do,” he said. “There’s been some suggestion out there—and maybe it’s even from the FDA press statement—that in some way he did not provide us with the information. That’s not correct.”

“He submitted all the paperwork that was required to be on the committee and to be screened for the committee. And when questions were raised about the abstracts, he responded very promptly.”

Kaul is also expected to participate in the second day of the meeting, which will consider the approvability of Johnson & Johnson’s novel factor Xa rivaroxaban (Xarelto) for use in prophylaxis of deep vein thrombosis. Like prasugrel, rivaroxaban is an antithrombotic, and like prasugrel, it may unseat the standard of care, in this case warfarin/heparinoid therapy.

And if all that isn’t enough reason to tune in this week, here’s one more. Pharmaceutical industry critic and Public Citizen Health Research Group director Sidney Wolfe will be at the conference table, representing the Drug Safety & Risk Management Advisory Committee.

FDA's "Secret" Opioid REMS Meeting

Who doesn’t love to find out about secret meetings? Especially secret meetings between FDA and your top competitors?

Well, if you have any interest in FDA’s implementation of Risk Evaluation & Mitigation Strategies—especially if you market opioids—then you’re in luck. Because we’ve got the scoop on what happened at the closed-door meeting FDA held last week about requiring a class REMS for extended-release pain killers.

FDA holds closed-door sessions with industry all the time. But as we reported in “The Pink Sheet,” this meeting was especially significant: the first in a series of discussions to develop a risk management plan that will be, in the words of one FDA official, “orders of magnitide” greater than anything industry has ever seen.

For the opioids under that umbrella—and those that are not—the REMS will change the commerical landscape for prescription painkillers.

To be fair, it wasn't really a “secret” meeting: FDA announced when was taking place (March 3), and disclosed who was invited (16 opioid manufacturers, listed here). But it also wasn't open to the public, and any information about what happened at the meeting had to be gathered after it took place.

Since we published our story, FDA has released a bit more information, posting the agenda and the slide decks from the three agency presentations on its website. Division of Analgesics, Anesthetics, and Rheumatology Products Director Bob Rappaport gave a history of the risk management of the opioid class; Associate Director for Policy Jane Axelrad reviewed FDA’s REMS authorities under the Amendments Act; and deputy division director Sharon Hertz outlined FDA’s initial thoughts on the proposed REMS.

Right now, FDA wants to see a class Medication Guide; elements to assure safe use (certification of health care providers, physician training on proper use, and patient-physician agreements); and an implementation system (database of all enrolled health care providers and a system to monitor and evaluate the REMS). That could all change, of course, but that is FDA's current thinking.

None of those elements are surprising; they have all been used in past REMS. And as scheduled drugs, opioids already carry some restrictions on their use. But given the sheer size of the market involved, the development and implementation of this REMS should be watched closely.

(Image by flicker user Anna C. used with permission through a creative commons license.)

ISMP Draws Attention to Drug Safety Issues In New Report

Once again, a noisy non-profit group is drawing attention to drug-safety issues. The Institute for Safety Medication Practices, which last year caused a ruckus over a laundry list of side effects associated with Pfizer's Chantix anti-smoking tablet, has just issued its latest quarterly report and maintains there are two shortcomings in the system for protecting patient safety and minimizing risks.

To illustrate its point, the non-profit cites issues with two drugs. The first is the Actavis Digitek heart pill, which was recalled last April and subsequently prompted reports of 650 patient deaths, and Merck's Singulair asthma medication, which was tagged in an FDA communication last March over psychiatric side effects and also later generated a substantial hike in adverse event reports. In its report, ISMP argues that "modest" FDA notices triggered an "outpouring" of AE reports, suggesting that patient injuries associated with prescription drug use is "routinely underreported.'

In the Digitek case, the FDA sent repeated warning letters in recent years to Actavis and, last fall, the Department of Justice filed suit to prevent manufacturing at three plants until quality-control procedures were instituted. After analyzing 2,403 adverse event reports received since January 2006, ISMP believes that 1,979, or 82 percent, were definitely or positively associated with the recall, including 630, or 89 percent of patient deaths.

To read the full report, click here.

At the same time, ISMP acknowledges it can't determine whether defective Digitek pills lets to the large number of patient deaths due to overstrength tables, because overdose toxicity is a known risk. However, ISMP complains the FDA "allowed the company to manage public notification" and that the CDER communication was "a reproduction of a brief company statement. The company stated that it had no evidence that any defective tablets had, in fact, entered commercial distribution," and recalled nearly 1 billion tablets and closed plants. An Actavis spokeswoman didn't respond to requests for comment. An FDA spokeswoman wrote us that the increase in AE reports, including deaths, occurred "exclusively" after the recall was announced publicly.

As for Singulair, ISMP identified 918 adverse event reports since 2006, including 644, or 71 percent, since the March notice. Earlier this week, the FDA issued an updated safety review indicating data so far reviewed doesn't suggest an association with suicide or suicidal behavior, however the Singulair trials reviewed "weren't designed specifically to examine neuropsychiatric events. As a result, some events may not have been reported." see this link - http://www.fda.gov/cder/drug/early_comm/montelukast_200901.htm

The drugmaker also issued a statement maintaining Singulair is safe, suicide wasn't an issue in its clinical trials and that adverse event reports have slackened compared with the period immediately following the FDA notice last spring. "The number of reports is almost non-informative. You can't base true risk on the number of reports," says Scott Korn, vp of clinical risk management and safety surveillance, tells us. "You really have to look at individual reports…It's really been a US phenomenon. We haven't seen similar trends in reports received overseas." Merck statement - http://www.merck.com/newsroom/press_releases/product/2009_0113.html

Nonetheless, Tom Moore, ISMP's senior scientist for drug safety and policy, wrote us that "the massive (Digitek) recall, together the the recalls of other important drugs, raises questions about what might be wrong with the system for ensuring the manufacturing quality of generic drugs. And the signal for Singulair - combined with new statements from the FDA and Merck - shows that even after an exhaustive review of clinical trials data, a serious possibility remains that the drug may cause psychiatric side effects."

- Ed Silverman

Next Steps For Prasugrel: The Anatomy of an Advisory Committee

Eli Lilly and Daiichi Sankyo used the morning of New Years Eve (‘tis the season for hiding news) to announce that the delayed anti-clotting drug prasugrel will be considered by the Cardiovascular-Renal Advisory Committee February 3. (Shameless self-promotion alert: We predicted that February meeting in October.)

Now that a date has been offically set, let the next round of speculation begin.

That news can be viewed in two ways: optimists (like Lilly and Daiichi investors) will argue that the meeting is a signal that the review is wrapping up and a decision is close at hand. Pessimists will argue that the meeting is an indication of the internal strife at FDA over prasugrel’s benefit-risk profile—and that products that go before an advisory committee are less likely to be approved on the first cycle.

Here's our take. First, we should note that the confirmation of the advisory committee meeting is a milestone in prasugrel’s development. It’s the first word to come out of FDA on the drug since June, when the agency extended the review by three months. FDA then let the revised September 26 review deadline pass without an approvability decision.

Another positive indicator for Lilly and Daiichi is that FDA is only convening the Cardio-Renal committee—and is not asking for a joint review with the Drug Safety & Risk Management Advisory Committee. A joint meeting would indicate significant concerns at FDA regarding prasugrel’s safety profile, which we have delved into in this earlier post.

Of course, that certainly doesn’t preclude FDA from drawing from members of the Drug Safety & Risk Management Advisory Committee as needed—including its newest member, Public Citizen’s Sidney Wolfe, who is unlikely to look kindly upon the prasugrel NDA.

Wolfe is just one extra member that could be asked to show up on February 3, given the current vacancies on the Cardio-Renal advisory committee. There are just eight permanent Cardio-Renal members, including a consumer rep (Consumers Union’s Stephen Findlay) and a non-voting industry rep (AstraZeneca’s Jonathan Fox).

That can make for a lot of last-minute additions. At the committee’s last meeting, FDA added 13 temporary members, including two regulars: University of Washington statistician Thomas Fleming and Duke University human cognition expert Ruth Day.

So who might be asked to serve? With a product like prasugrel, one obvious choice for a temporary member is Steven Nissen, the head of cardiology at the Cleveland Clinic—an expert on cardiovascular drug safety and a former chair of the Cardio-Renal advisory committee.

Nissen’s participation on the committee would be a positive development for Lilly and Daiichi, given that he has come out in favor of prasugrel—first giving the drug a thumbs up for approval and then criticizing FDA for not delivering an on-time approvability decision. Nissen isn’t exactly a shrinking violet, so if he still favors a prasugrel approval, he stands a good chance of getting the committee to see things his way.

But those statements may prevent Nissen from serving—especially given FDA’s tougher line on conflicts of interest. Indeed, Nissen himself has questioned whether he is qualified to serve on an advisory committee under the new CoI guidelines. The meeting roster will be out in the next month. Lilly and Daiichi should hope Nissen's name is on it.

Human brain image courtsey of flickr user hduhadaway.

FDA Drug Safety Official Seligman Set to Depart

FDA's top drug safety communication official--Center for Drug Evaluation & Research Associate Director of Safety Policy and Communication Paul Seligman--will apparently be moving to a new position focusing on food supply integrity issues.

Seligman is understood to be departing CDER to focus on food quality being imported from Latin America.

Seligman’s departure will leave a void in the safety communication area at FDA’s Center for Drug Evaluation & Research at a critical time for the agency.

FDA is just beginning to get its arms around implementing the many postmarket surveillance provisions of the FDA Amendments Act, including the Risk Evaluation & Mitigation Strategies (REMS), a new requirement for quarterly web postings of emerging drug safety signals and the evolving Sentinel active surveillance system (See “Communication Conundrum,” The RPM Report, October 2008).

Seligman was named associate director of safety policy and communication in April 2006, a newly created position at the time that reported directly to the CDER director. He was previously director of the Office of Pharmacoepidemiology & Surveillance, which was eliminated.

The associate director position was an important organizational change for CDER when first announced because it demonstrated the center’s focus on safety.

Seligman’s primary role was to develop drug safety policies across CDER and oversee the MedWatch voluntary adverse event reporting system, the Drug Safety Oversight Board, the “early communication” program, the drug safety newsletter, and the quarterly safety signal web postings mandated by FDAAA.

The Lesser Of Two Evils?

When Steve Nissen is not qualified to serve on an FDA advisory committee under the agency’s new conflict of interest guidelines, you know things are bad. Really bad.

According to Nissen, and as reported in "The Pink Sheet" DAILY, his position as chair of the cardiology department at the Cleveland Clinic likely bars him from serving another term on an FDA expert panel.

Nissen may not be exactly beloved by the pharmaceutical industry, but no one can argue that the man knows drug development, and is a global expert on cardiovascular drug safety. And when it comes to conflicts, Nissen prides himself in not only disclosing all the companies he has worked for, but also donating all his fees directly to charities so that he can't claim the tax benefit.

Plus, he has served as an advisory committee member before: Nissen was a permanent member of the Cardiovascular & Renal Advisory Committee from 2001 to 2005, that last year as chairman. Since then, he has served as a temporary member as duty calls, like the July meeting on type 2 diabetes clinical trial endpoints. So if he can't serve, then who can?

“The current rules are pretty bizarre,” Nissen told attendees at the recent FDC-Windhover FDA/CMS Summit. “The imputation of conflict of interest guidelines based on institutional contracts eliminates a lot of desirable people.”

In Nissen’s case, the trouble is with a section of the new CoI guidelines that bars the “head of a department” that is conducting or will conduct studies on a product (or its competitors) “that is the focus of a meeting and receives personnel or salary support, designs or advises on any aspect of clinical trials, or reviews data or reports from the trials.”

We emailed Nissen to clarify, and he pointed out that the cardiology department has more than 100 faculty members. So “for most advisory committees, it is highly likely that someone within our department is involved with the company in some fashion.” And given the size of the Cleveland Clinic, Nissen said, “the likelihood that someone...receives funding from the sponsor or its competitors is 100%.”

Of course, Nissen’s inability to serve on an advisory committee is most likely be welcome news for drug sponsors, who see him as, frankly, a pain in the derriere. Granted, this is the man who prevented Bristol/Merck’s Pargluva (muraglitazar) from ever seeing the light of day, and crippled the commercial future for GlaxoSmithKline’s Avandia. So you can understand that angst.

But industry should not be breaking out the champagne quite yet. If it is true that Nissen is no longer eligible to serve on an advisory committee, it underlines a disturbing trend at the agency: FDA’s continued inability to fully staff its expert panels with individuals that qualify under—and are willing to serve despite of—more stringent conflict of interest guidelines.

When we last looked at the staffing problems in the advisory committee system in The RPM Report, there were 83 vacant seats, and three-quarters of the panels did not have permanent chairs. That was despite a major recruitment effort at the agency. Things haven’t improved much since.

And when drug sponsors start to see who is qualified to serve as permanent advisory committee members under FDA’s conflict of interest rules, they may be wishing for Nissen. You tell us. As a sponsor, who would you rather have: Nissen, or Public Citizen’s Sidney Wolfe and Center for Science in the Public Interest’s Merrill Goozner?