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Monday, August 30 2010
There's lots of buzz right now about the potential for FDA to seek jail time for executives involved in quality control problems. This piece on CNN.com, for example.
Readers of the The RPM Report, however, have nothing to worry about. For the past two years, we've been noting the calls for executive accountability, and comments by FDA officials and others about their sweeping ability to hold top executives responsible for failures they may not even have been aware of under the so-called Park doctrine. (Start here or here.)
So all of you can relax, because you made sure that your compliance with FDA standards is beyond question.
Didn't you?
Comments? Email the author at windhover-dc@windhover.com
Tuesday, August 24 2010
We wrote below about an unusual back-and-forth between advisory committee member Sid Wolfe and FDA Division Director Bob Rappaport over the relevance of a criminal case involving the marketing of Jazz Pharmaceuticals’ sodium oxybate to the discussion of a potential new indication.
Wolfe didn’t have the chance to respond to Rappaport during the committee review, so we asked him if he wanted to. Here is his response:
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).”
Wolfe alludes to comments by Jazz Chief Compliance Officer Janne Wissel during the meeting. Here is what she said following Rappaport’s statement:
"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."
Comments? Email the author at windhover-dc@windhover.com
Monday, August 23 2010
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.
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 earlier, noting that he had called FDA’s advisory committee staff earlier in the week to raise an issue, but not shared the documents 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.”
Wolfe continues to defend his position that the settlement and Jazz’ corporate history are key pieces to determining whether Rekinla should be approved. If the issue is the quality of the risk management plan, Wolfe says, how can such a clear failure to limit access not be relevant?
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.”
Comments? Email the author at windhover-dc@windhover.com
Monday, August 23 2010
It is every marketer's dream to have a product that is in a class by itself.
AstraZeneca/MedImmune's respiratory syncytial therapy Synagis (pavilizumab) can claim that distinction in an entirely new way as the Centers for Medicare & Medicaid Services implements new rebate provisions for the Medicaid prescription drug program under the Affordable Care Act: Synagis is the only drug that will benefit from a new, lower mandatory rebate on drugs that are "approved by the Food & Drug Administration exclusively for pediatric indications."
Recall that the health care reform law raised the minimum Medicaid rebate percentage from 15.1% to 23.1% for most brand name drugs. But the law sets a lower rebate amount (17.1%) for two classes of drugs : clotting factors and pediatric-only drugs. (For a complete analysis of the Medicaid rebate changes, see here.)
If that isn't complicated enough, the new rebate amounts were effective retroactively to Jan. 1 (the law was signed at the end of March), but CMS didn't provide any guidance on which products were covered until now.
For clotting factors, the list of covered products was pretty simple, since the new rebate provision specifically cites products that already receive a separate furnishing payment from Medicaid. So that list of affected drugs is no surprise. (Manufacturers who benefit include Bayer, Aventis Behring, CSL Behring, Novo Nordisk, Baxter, Talecris, Grifols and Pfizer/Wyeth).
But it was by no means clear what products were covered by the "pediatric-only" exemption. Now we know: Synagis. (The official "list" is here.)
It turns out that Synagis is the only product approved by FDA all of whose indications are explicitly limited to pediatric use (from birth to age 16). That, at least, is what CMS determined. (The agency does invite anyone who is "aware of other drugs that meet the pediatric definition specified" by CMS to email mdroperations@cms.hhs.gov .)
We note with amusement that CMS' explanation of how it came up with the "list" runs a full page. For that matter, the section of the law that CMS is interpreting [Sec. 1927(c)(1)(B)(iii)(II)(bb) for all you Medicaid rebate wonks] is longer than the list of covered drugs. Wouldn't it have been easier just to say "the minimum rebate on Synagis is 17.1%?"
Okay, that's not how legislation works. And we suspect AstraZeneca is just as happy that the provision flew beneath the radar screen a bit; there is enough controversy about the pharmaceutical industry's "deal" on health care reform--a deal, we might add, negotiated by the Pharmaceutical Research & Manufacturers of America when it was chaired by David Brennan, CEO of AstraZeneca.
But a bit of perspective here. We assume AZ is pleased that the minimum rebate on Synagis is lower than for most brands, but it is not like AZ will reap some kind of windfall as a result.
First, the new minimum rebate is still two percentage points higher than the old 15.1% minimum rebate. According to MedImmune's 2006 10K filing (the last filed by the firm before it was acquired by AZ), every percentage point increase in Medicaid rebate liability translates into roughly an $11 million hit to sales for the brand.
Then there is the separate provision of the health care reform law extending Medicaid rebates to managed care plans. While that affects a relatively small segment of the overall Medicaid prescription drug market, the impact per unit sold is large (in this case, no rebate to 17.1% minimum).
Last but not least, there is a provision in the new rebate rules that attempts to recoup rebates on new formulations of products. The idea is that, if a sponsor changes a formulation and sets a new price point, it should still pay the same amount in rebates (or more) as it did under the old formulation.
We think that provision affects Synagis as well, since (as MedImmune disclosed in the 2006 10K filing), "during the fourth quarter of 2005, we successfully transitioned to the liquid formulation of Synagis in the US from the lyophilized formulation, which has resulted in a reduction in allowances for government rebates and an increase in net realized price during 2006."
That provision, however, is even less clearly defined in statute than the pediatric-only rebate--and CMS hasn't issued guidance on interpreting it yet. (We've written about the line-extension rebate in The RPM Report, here.)
So, net-net, AZ is paying much higher rebates on Synagis than it would have without health care reform. But, thanks to its special treatment under the law, they aren't quite as high as they might have been.
Comments? Email the author at windhover-dc@windhover.com
Monday, August 23 2010
Valeant Pharmaceuticals and GlaxoSmithKline’s epilepsy treatment Potiga (ezogabine) had an easy ride through its advisory committee, thanks in part to a post-marketing surveillance study to be conducted in partnership with WellPoint.
There is nothing new about Big Pharma companies working with managed care plans as part of their post-marketing surveillance plans, but the Potiga offers compelling evidence that those agreements will only become more common as the Food & Drug Administration and sponsors adapt to the new rules of drug safety created by the 2007 FDA Amendments Act.
The FDA panel voted unanimously (13-0) at the August 11 Peripheral and Central Nervous System Drugs Advisory Committee meeting that Potiga is effective as an add-on therapy for partial onset seizures in epilepsy patients who aren’t responding to their current therapy alone. (Valeant estimates that represents about one-third of the epilepsy population.)
More importantly, the committee voted 11-0 that patient monitoring for its main adverse event, urinary retention, can mitigate the risk. The committee also voted unanimously that monitoring should not be instituted for infection and urolithiasis.
As is so often the case at today’s FDA, efficacy wasn’t the issue for this product; safety was. Potiga was associated with about double the rate of urinary retention in clinical trials compared to placebo. The rate was still low (less than 1%) and there weren’t many indications of serious consequences from the cases that occurred, so GSK and Valeant could have taken the approach that it could be handled through labeling.
Instead, GSK proposed an extensive risk management and post-marketing surveillance program. Not only did the sponsor easily win over the committee, it seems to have won over FDA: the agency opted not to make its own presentation to the committee.
Potiga co-developer GlaxoSmithKline is responsible pharmacovigilance and risk management plan implementation. GSK was among a handful of sponsors who had extensive early experience with the REMS authorities, and the handling of Potiga suggests that GSK has taken those lessons to heart. (See “Waking Up to REMS,” The RPM Report, July 2009.)
(An approval of Potiga would also be a positive for Canadian pharmaceutical firm Biovail Corp, which is in the process of acquiring Valeant. That process is expected to conclude at the end of this year.)
GSK’s proposed ezogabine risk management plans include risk minimization (comprehensive communication plans for healthcare providers, patients and caregivers, including a medication guide) and risk assessment (a “robust pharmacovigilance system” and a prospective observational study of ezogabine to estimate the rate of its main adverse event, urinary retention, in patients on the therapy.)
All in all, the committee vote is a powerful message that a well-thought out REMS can indeed grease the skids towards approval. The next question to watch will be whether one piece of that plan--GSK’s observational study—will help it build better relationships with managed care gatekeepers to help the product perform well commercially.
100,000 Patient Observational Database
GSK and Valeant proposed a prospective observational, non-interventional study to estimate the rate of urinary retention in patients on ezogabine compared to other AED therapies.
The study would use health insurance claims data within the HealthCore Integrated Research Database (HIRD), which captures prescription drug use for individuals on WellPoint healthcare plans. WellPoint oversees about 100,000 patients with epilepsy.
Urinary retention will be identified by ICD9 codes and procedure codes for catheterization and adjudicated by medical record review.
“We will also provide rates of urinary retention within subgroups of interest, including elderly patients, those with risk factors of urinary retention, and those with cognition impairment,” said Susan Hall, PhD, head of neurology research and development and regulatory compliance at Valeant.
“In addition, we’ll build in a second analysis to compute the risk ratio of urinary retention in ezogabine users relative to rates in patients on other AUDs,” Hall said. “This will provide an estimate of the drug effect independent of risk factors of urinary retention.” The observational study will include data review and evaluation every six months at least three years post-marketing. The initial analysis will occur when there’s sufficient sample size, likely within three years or earlier.
“I think that the observational study is terrific as one idea, but another would be to more selectively or as a complement target specifically high-volume physician prescribers,” said G. Caleb Alexander, MD, MS, assistant professor of general medicine at the University of Chicago. Alexander suggested using pharmacy benefits manager claims to identify high prescribing physicians to target for outreach.
He also suggested analyzing Medicaid claims, which would complement the WellPoint claims and “allow for observation of people with much higher co morbidities and much lower rates of health literacy, much greater underserved population.” He added that EMR data would offer “greater fidelity to some degree than health claims with regard to look at use by indications.”
GSK, Others Use Claims Data More
Studies of claims data aren’t new, and GSK has plenty of experience with them. The company says it uses claims data for a whole host of functions, including to investigate clinical trial designs and drug safety, protocol assessments, decline background rates of clinical or safety outcomes, provide geographic distributions of disease, and to evaluate medication use and safety.
This January, GSK published studies using claims data to study antiepileptic drug prescribing patterns by history of mood disorder. The study used the IHCIS (Integrated HealthCare Information Services) insurance claims database as well as the UK’s General Practice Research Database. The study was published in Pharmacoepidemiology &Drug Safety.
Another example is Lotronex (alosetron hydrochloride) surveillance for bowel ischemia. Lotronex is a selective 5-hydroxytryptamine3 receptor antagonist approved in October 2000 to treat diarrhea-predominant IBS in women. Its marketing was suspended in November 2000 due to reports of colonic ischemia and serious constipation complications.
GSK initiated a study to compare the incidence of colonic ischemia, hospitalized complications of constipation, and bowel surgery in patients on Lotronex to the incidence in IBS patients not using Lotronex. The study used diagnoses, procedures and drugs recorded in the UnitedHealthcare insurance claims database, which were then adjudicated by chart review. The study included data from March to December 2000. Initially, this assessment was planned to last for three years, but the observation period was stopped by the end of 2000 due to the marketing suspension.
With an average follow-up time of 5 months in both groups, there were no instances of colonic ischemia. There were thirty instances of bowel surgery and three cases of hospitalized complications of constipation, but the incidence rates of both were similar in both groups.
Although the size and duration of the study were smaller than planned, , FDA approved a limited Lotronex reintroduction in the US market in June 2002.
Another high profile example involves Amylin/Eli Lilly’s type 2 diabetes drug Byetta (exenatide). Their, the sponsors used UnitedHealth data to assess the risk of pancreatitis associated with the drug as part of a response to safety concerns flagged in traditional post-marketing reports. (See “Byetta Does not Raise Pancreatitis Risk, According to Claims Data,” The Pink Sheet, March 23, 2009.) The study concluded that more comprehensive studies are needed to fully assess the risk; FDA was sufficiently satisfied to grant the product a new indication—along with a new REMS to mitigate the pancreatitis risk.
GSK also has ample experience being on the other side of observational analyses, with Medicare claims data forming one new basis for arguments against the continued marketing of its diabetes drug Avandia during a July re-review of the product.
Additional Risk Assessment Adds to Reassurance
The observational study was just one piece of GSK’s post-marketing safety program presented to the committee.
GSK’s proposed pharmacovigilance process includes: monthly review of adverse events to assess reports against background incidence for signal detection, and the use of statistical methodologies to explore potential associations (as abuse, overdose, age and drug interactions.)
“In addition to ongoing assessment of adverse events, we will also introduce enhanced pharmacovigilance to collect specific information regarding spontaneously reported urinary retention adverse events both in the post-marketing setting as well as in clinical trials,” Hall said. “All of the collected adverse event data will be reviewed and reported quarterly for the next three years and periodically thereafter.”
Stephanie Crawford PhD, MPH, associate professor and associate head of the department of pharmacy administration at the University of Illinois College of Pharmacy, wondered why the monitoring isn’t more aggressive, adding thatshe’s “not necessarily... advocating this.”.
“The REMS program proposed definitely has positive aspects, but my question is: Why was there not more aggressive monitoring, especially with respect to the urinary functioning, proposed at least during the earliest years of potential product introduction? It could be different forms including limits on initial fills, and adequate follow-up monitoring before refills, but right now it seems to be observational based on usual care. Why was there not more aggressive monitoring proposed?”
“[GSK does] have a very robust monitoring certainly for spontaneous adverse event, and with the recent introduction of SAEfetyWorks, a tool that allows us to also interrogate data from a number of health claims databases,” Brickel said. “It gives us access to a large population of patients that would allow us to rapidly see if there are changes we need to make to either the risk management plan, to the labeling, on a ongoing basis. So even though we’re not laying out stringent monitoring, this is something that we do very much as standard practice.”
SAEftyWorks was co-developed by GSK and ProSanos Corporation. It was implemented by GSK in 2008, and ProSanos has acquired the marketing rights to the software. As of 2009, several regulatory agencies have expressed interest in making use of SAEftyWorks. GSK implemented the first components of SAEfetyWorks in 2009, and this program received the 2009 BIO IT Award and was awarded first prize at the International Society of Pharmacoepidemiology Annual Meeting. (See “Redefining Data Mining: Taking Control of a Powerful New Tool,” The RPM Report, March 2007.)
The combined risk assessment strategy of robust pharmacovigilance plus post-marketing observational study helped address panel members concerns in other areas as well: Brickel said the potential for cardiac arrhythmias will be followed up with questionnaires. It also helped with the question of pediatric data. Brickel said the pharmacovigilance will capture age data on any patient that reports an adverse event to GSK and “With regards to the observational data, we will get a sense of the demographics of the patients being reported, so it would be expected that we would see data in patients if it is being used patients under 18 years of age.”
“So if there’s somebody who gets ezogabine and gets catheterized and they’re six, then your observational study will pick it up?” Anderson asked. Brickel said yes.
As well-thought out as the program was, Potiga benefitted from the committee’s feeling that the risk factor is one that could be mitigated with patient monitoring. As Inger Rosner, MD, Urologic Oncology at Walter Reed, said, if there’s a good patient-physician relationship, she’s confident people would present with their complaints because “everyone needs to urinate.”
The deadline for action on the application is August 30.
Comments? Email the author at windhover-dc@windhover.com