Drug Injury Watch

Subpoenas Issued For Witnesses To Appear At February 2008 U.S. House Committee Hearing On Ketek

Congress Wants To Know When Sanofi-Aventis And The FDA Learned About Fraud Involved With Ketek Study 3014

(Posted by Tom Lamb at DrugInjuryWatch.com)

Soon after noon on January 29, 2008 Ed Silverman posted on his Pharmalot blog an article, "House Committee Will Subpoena FDA Over Ketek", which reported this breaking news about the Congressional investigation into Ketek, Sanofi-Aventis, and the FDA:

At its hearing this morning, the House Energy and Commerce Committee’s Subcommittee on Oversight and Investigations voted unanimously to approve a motion to subpoena FDA officials and investigators over clinical trial data for the Sanofi-Aventis antibiotic [Ketek], which has been linked to liver failure.

This same Pharmalot post about Ketek provided access to a January 25, 2008 memorandum sent by the committee's chairman, John Dingell, and Bart Stupak, the head of a subcommittee, both from Michigan, which had previewed the actions that would be taken at this January 29 meeting.

More detail came soon thereafter in this CQ Today Midday Update article, "House Energy Panel OKs Subpoenas in FDA Probe", published January 29 online:

The subcommittee is seeking testimony from:

• FDA special agent Douglas Loveland.

• FDA special agent Robert West.

• Robert Ekey, former special agent at the FDA.

• Ann Marie Cisneros, a clinical researcher who was involved in the testing.

The panel also authorized a subpoena to Health and Human Services [(HHS)] Secretary Michael O. Leavitt for records related to FDA Commissioner Andrew C. von Eschenbach’s testimony before the House Energy and Commerce Committee on March 22.

Stupak, who offered the motion, said "the FDA has been less than forthcoming with either witness or document production in connection with our drug safety investigations."

The Michigan Democrat added that the panel requested briefing books and related documents six days after the March hearing, but the agencies refused to provide them, and "no legal authority has been provided to the committee to support this refusal."

And not much later the same day we got reactions to this latest development in the Ketek investigation from a Reuters January 29 article, "US panel OKs subpoenas in Sanofi antibiotic probe", by reporter Lisa Richwine:

FDA spokeswoman Karen Riley said the agency had provided more than 80,000 pages of Ketek information to House investigators and would continue to cooperate with the probe.

"We also have made staff available who have met with the committee, and we have made every effort to be responsive to the committee's requests," she added.

HHS spokeswoman Christina Pearson said the health department had "worked hard to be responsive to congressional requests related to Ketek" for the past two years.

"We will continue to work with the House toward a solution that is responsive but will not compromise investigations or the ability of senior officials to obtain accurate information and frank advice from their staffs," she said.

Sanofi-Aventis spokeswoman Julissa Viana repeated earlier comments saying Aventis was not aware of the fraud in Study 3014 until after it was submitted to the FDA.

"We have critically reviewed the record of the clinical study being reviewed and have identified important lessons learned to improve policies and procedures," she said.

Elsewhere on Capitol Hill, as some may recall, in December 2007 Senator Charles Grassley wrote a letter to the FDA that raised questions about the agency's approval of Ketek in 2004.

We look forward to the meeting of this House Energy and Commerce Committee’s Subcommittee on Oversight and Investigations, currently scheduled for February 12, 2008.  According to the January 29 Reuters article, their Ketek investigation will continue in this manner:

The panel wants to question the witnesses about "their knowledge of whether Aventis was aware of substantial data integrity problems in Study 3014 at the time of submission to FDA," Stupak said.

Be assured that we will report out what is learned at this February 12 Congressional hearing about the who-knew-what-and-when as regards this now infamous Ketek Study 3014.

P.S.  According to a February 13, 2008 Bloomberg News article, "White House rejects subpoena", yesterday HHS Secretary Leavitt refused to comply with that subpoena issued by this investigative subcommittee of the House Energy and Commerce Committee regarding papers used to prepare FDA Commissioner von Eschenbach for testimony that he had given at a hearing on Sanofi-Aventis' antibiotic Ketek in March 2007.  (2/13/08)

Avandia Label Is Getting Some Additional Contraindications And A New Warning In Europe

January 2008 Revisions Follow An Avandia Safety Review That Was Completed By EMEA In October 2007

(Posted by Tom Lamb at DrugInjuryWatch.com)

On January 24, 2008 GlaxoSmithKline (GSK) announced that the European label for its diabetes drug Avandia (rosiglitazone maleate) will be revised pursuant to a decision by the European Medicines Agency (EMEA)’s Committee for Medicinal Products for Human Use (CHMP).

An article published by Reuters, "EU experts add new warnings to Glaxo's Avandia - UPDATE 1", reported what little was known about the Avandia label change in Europe as of noon EST on January 24:

European regulators on Thursday recommended that patients with heart disease or leg pains -- a possible sign of heart problems -- should not take GlaxoSmithKline's (GSK.L: Quote, Profile, Research) diabetes drug Avandia.

The European Medicines Agency also said in its decision to update Avandia's label that the drug must not be used by people having a heart attack or with conditions such as angina....

In October, Europe's drug watchdog said prescribing information should be updated to include a warning that patients with heart disease should only be given the drug after a careful examination of their individual risk.

A GSK press release issued earlier on January 24, "GlaxoSmithKline to revise Avandia® (rosiglitazone maleate) label in Europe following assessment by CHMP", provided some additional detail about the revisions to the European version of the Avandia package insert, or label:

The label will be revised to state that available data indicate that rosiglitazone may be associated with an increased risk of myocardial ischaemic events. It will also state that this risk was not confirmed or excluded in three long-term clinical trials and the data in their entirety on myocardial ischaemia are inconclusive.

There are limited clinical trial data in patients with ischaemic heart disease and/or peripheral arterial disease, especially those with myocardial ischaemic symptoms. The revised label will state that as a precaution, the use of rosiglitazone is not recommended in these patients. This information will appear in the warnings and precautions section of the label.

Patients with acute coronary syndrome (unstable angina, NSTEMI and STEMI) require urgent hospital treatment and have an increased risk of developing heart failure. This high-risk patient population has not been studied in rosiglitazone controlled clinical trials, and revised labelling will advise prescribers that rosiglitazone is contraindicated in patients with acute coronary syndrome.

This January 24 GSK press release also specified the affected products:

The label changes will be applied to all approved rosiglitazone-containing products: Avandia ® (rosiglitazone maleate), Avandamet ® (rosiglitazone maleate and metformin hydrochloride) and Avaglim ® (rosiglitazone maleate and glimepiride).

In October 2007 the EMEA concluded that the benefits of Avandia as well as the other diabetes medications in the thiazolidinediones (TZDs) class of drugs outweighed the risks.  These Avandia label changes in January 2008, however, are reportedly a result of that earlier safety review.

Reports Of Anti-Smoking Pill Chantix Causing Depression And Suicidal Ideation Made To FDA

Pfizer Increases Warning About Abnormal Behavior Of Patients Using Its Smoking Cessation Medication In January 2008

(Posted by Tom Lamb at DrugInjuryWatch.com)

On November 20, 2007 the FDA issued an "Early Communication About an Ongoing Safety Review Varenicline (marketed as Chantix)" to inform healthcare providers about reports the agency had received of people exhibiting various types of abnormal behaviors while using Chantix.  These reports included new-onset of depressed mood and suicidal ideation, as well as other unusual changes in emotion and behavior within days to weeks of initiating Chantix treatment.

In that November 2007 Early Communication item regarding Pfizer Inc.'s anti-smoking pill Chantix, the FDA recommended the following measures:

• Healthcare professionals should monitor patients taking Chantix for behavior and mood changes.
• Patients taking Chantix should contact their doctors if they experience behavior or mood changes.
• Patients should use caution when driving or operating machinery until they know how quitting smoking with Chantix may affect them.

And in the closing part of that Early Communication:  "FDA is considering, but has not reached a conclusion about whether this information warrants any regulatory action."

Only two months later it was announced that the package insert, or label, for Chantix was getting a stronger warning about such abnormal behavior in people taking this smoking cessation drug.

From a January 18, 2008 Bloomberg report, "Pfizer's Chantix Gets Warning Over Suicidal Thoughts (Update1)", we get these details about the announcement concerning the increased Chantix warning:

A possible link between the drug and reports of agitation, depressed mood and suicidal thoughts among some patients taking it can't be ruled out, Pfizer said today in a statement. The behavior could be worse in people with a pre-existing mental illness, the New York-based company said....

"A causal relationship between Chantix and these reported symptoms has not been established," Pfizer said in the statement.  "In some reports, however, an association could not be excluded."...

An advisory about the symptoms was already included in the drug's prescribing information under the "post-marketing experience" section. The enhanced warning will make the advisory more prominent to doctors and advise them to monitor for unusual behavior in their patients, Pfizer said. The drug was approved in the U.S. in 2006.

For those interested, we have provided links so that you can see how this new warning appears in the January 2008 Chantix package insert -- in the new WARNINGS section -- and compare it to the November 2007 version of the Chantix.

P.S.   On February 1, 2008 the FDA issued these two items concerning Chantix and the associated side effects discussed above:

Public Health Advisory; and,

Healthcare Professional Information Sheet.

We will continue to watch Chantix for further drug-safety developments.  (2/2/08) 

Blood-Clot Warning On Ortho Evra Birth Control Patch Increased, Again, In January 2008

Label For "The Patch" No Longer Has Conflicting Information About Its Increased Risk Of Blood Clots

(Posted by Tom Lamb at DrugInjuryWatch.com)

A January 18, 2008 WebMD article, "Stronger Warning for Birth Control Patch", provided a concise summary of the latest news about the Ortho Evra Contraceptive Transdermal (Skin) Patch manufactured by Ortho-McNeil Pharmaceuticals, a division of Johnson & Johnson (JNJ):

The FDA today strengthened its warning on the risk of serious blood clots in women using the Ortho Evra birth control skin patch.

The warning about venous thromboembolism -- clots in veins that may be life-threatening if they travel to the lungs and cause pulmonary embolism -- isn't new. It's been on the Ortho Evra patch label since September 2006.

What's new is that now, the patch's label no longer notes conflicting information about that risk.

Previously, the Ortho Evra patch's label mentioned mixed results from two studies on clotting risk. One study showed that patch users were twice as likely as birth control pill users to develop venous thromboembolism. The other study showed that patch users and pill users were equally likely to develop venous thromboembolism.

Now, results from a third observational study are in, and that study shows that the odds of developing venous thromboembolism are higher for women who use the Ortho Evra patch than for women using birth control pills.

Today, the FDA ordered the results of that new study to go on the Ortho Evra patch label.

In February 2007 the Obstetrics and Gynecology medical journal published a study report which concluded that women who used the Ortho Evra birth control patch seemed to be at double the risk of developing a dangerous blood clot in their veins as were women who used oral contraceptives.

As background, in November 2005 the FDA announced a label change for Ortho Evra to warn that the use of this contraceptive patch exposes women to higher levels of estrogen than a typical birth control pill and, in turn, women using Ortho Evra for birth control are at an increased risk of developing blood clots.

Blood clots -- sometimes called venous thromboembolisms (VTEs) -- can lead to deep vein thrombosis (DVT) and pulmonary embolisms (PE), which can be fatal.   

Results from two studies that were preliminarily released in February 2006 prompted another label change for Ortho Evra in September 2006.

A January 18 FDA News item, "FDA Approves Update to Label on Birth Control Patch", explains the connection between studies involved in the September 2006 label change and this new warning about blood clots related to Ortho Evra:

The [January 2008] label changes are based on a study conducted by the Boston Collaborative Drug Surveillance Program (BCDSP) on behalf of Johnson and Johnson. The patch was studied in women aged 15-44. These recent findings support an earlier study that also said women in this group were at higher risk for VTE....

In September 2006, FDA revised the label for Ortho Evra to warn women of the risk of VTE based on two epidemiology studies. One study, conducted by i3 Ingenix, showed that some women using the patch were at a two-fold greater risk of developing VTE. The other study, conducted by BCDSP, showed they were not at increased risk compared to women using birth control pills containing 30-35 micrograms of estrogen and the progestin norgestimate.

Ortho Evra, sometimes simply called "The Patch" by women, was approved by the FDA in 2001.

The FDA Aims To Improve Its Detection Of Drug Safety Signals

Public Workshop On January 29, 2008 To Focus On Adverse Drug Reaction Reporting

(Posted by Tom Lamb at DrugInjuryWatch.com)

In recent years the FDA has been roundly criticized for its failure to timely recognize emerging drug safety issues.

To improve its performance on this aspect of its work, the FDA is holding a public workshop as a means to look for ways by which to improve the collection of adverse event (AE) reports and the analysis of those reports for the purpose of better detecting drug safety "signals" in the future. 

In more detail, this public workshop, “Maximizing the Public Health Benefit of Adverse Event Collection Throughout a Product’s Marketed Life Cycle”, will be held at The Conference Facility (terrace level) located at 5635 Fishers Lane, Rockville, MD 20857 on January 29, 2008, from 8:30 a.m. to 5 p.m., with seating on a first-come, first-served basis.

A notice about this FDA public workshop published in the Federal Register, at 72 Fed. Reg. 73029 (Dec. 26, 2007), states that there will be a panel discussion about how the FDA currently uses spontaneous adverse event reports and other methods of drug safety signal detection.  Some of the anticipated issues to be discussed include:

• What are the roles of serious and non-serious outcome AE reports in drug safety issue identification and subsequent FDA action?
• How do the roles of these AE reports change over the life-cycle of a prescription drug?
• Are there any types of AE reports that are not helpful in detecting drug safety signals?

For those unable to attend, the FDA will open a docket to receive written comments concerning issues discussed during this public workshop.  That docket will remain open through February 29, 2008.

Information gathered at this January 29 public workshop will be used later by the FDA when the agency attempts to identify qualified organizations to do specific research about how emerging drug safety issues can be discovered as early as possible to avoid unnecessary additional adverse events in patients using unsafe drugs.

Zetia And Vytorin: Steven Nissen Calls For A "Moratorium" On Their Use Due To Failed Study

Long-Awaited Results Of ENHANCE Study Show Zocor + Zetia (= Vytorin) Does Not Improve Patient Outcomes

(Posted by Tom Lamb at DrugInjuryWatch.com)

A January 14, 2008 Bloomberg article, "Merck, Schering's Vytorin No Better Than Generic (Update 2)", reported the long-awaited results of a study concerning Zetia and Vytorin as well as the immediate fall-out: 

Merck & Co. and Schering-Plough Corp. said their combination cholesterol drug Vytorin worked no better than an older, generic medication in reducing the buildup of artery-clogging fat in a key study.

Steven Nissen, head of cardiology at the Cleveland Clinic in Ohio, immediately called for a "moratorium" on the use of Vytorin and Zetia. Vytorin is a combination of Zetia and simvastatin, the generic medication used in the trial. The two cholesterol drugs generated $1.3 billion in third-quarter sales....

"In the absence of any evidence of a clinical benefit, these drugs should now be used as a last resort," said Nissen, who was not involved in the study, in a telephone interview.

Some basic information about the underlying study and its outcome was set forth in a January 14, 2007 Dow Jones Newswire piece, "Merck: No Significant Difference Between Grps In ENHANCE Trial":

ENHANCE was a surrogate endpoint trial conducted in 720 patients with Heterozygous Familial Hypercholesterolemia.

All analyses were conducted in accordance with the original statistical analysis plan. The primary endpoint was the mean change in the intima-media thickness measured at three sites in the carotid arteries (the right and left common carotid, internal carotid and carotid bulb) between patients treated with ezetimibe/simvastatin 10/80 mg versus patients treated with simvastatin 80 mg alone over a two year period.

There was no statistically significant difference between treatment groups on the primary endpoint. There was also no statistically significant difference between the treatment groups for each of the components of the primary endpoint, including the common carotid artery. Key secondary imaging endpoints showed no statistical difference between treatment groups.

Schering-Plough issued a press release about the ENHANCE study results -- that was oddly dated "Nov. 19, 2007" when accessed the morning of January 14 -- which announced:

Merck/Schering-Plough has submitted an abstract on the ENHANCE trial for presentation at the American College of Cardiology meeting, which will be held in March 2008, and is awaiting notification of acceptance from the College.

Vytorin is a combination of Zetia (ezetimibe) and simvastatin (brand name: Zocor).  There have been reports that Zetia may cause drug-induced hepatitis and liver failure.  The potential for Zetia to cause liver injury was first raised by Health Canada in February 2005.  This drug-safety issue received renewed attention in December 2007 when an article in The New York Times suggested that Merck and Schering-Plough, in fact, knew about these Zetia side effects but that this information was withheld by the drug companies.

P.S.  In response to the frenzy following the ENHANCE study results being released, the American College of Cardiology (ACC) has stated "There should no be reason for patients to panic", and advises doctors "that major clinical decisions not be made on the basis of the ENHANCE study alone."  This ACC Statement on ENHANCE Trial was issued on January 15, 2008.  (1/16/08)

Where Are The Medical Journal Articles About Problems With Studies On Zetia And Vytorin?

Dr. Blumsohn Shines His Bright Light On This Troubling Situation And Provides A Lengthy List Of Recent Blog Posts About Zetia And Vytorin

(Posted by Tom Lamb at DrugInjuryWatch.com)

Over at the Scientific Misconduct Blog, Dr. Aubrey Blumsohn has posted an article, "Ezetimibe - where are our medical journals?", which makes one wonder if Zetia and Vytorin are getting off easy in the medical journal world.

From Dr. Blumsohn's Jaunuary 11, 2008 post on Zetia (ezetimibe):

The huge ethical and scientific problems with the drug Ezetimibe have been discussed widely in the lay press (especially in the New York Times). The problems have been discussed by patients, on the internet and in the blogsphere. However as of today, a search of our key medical journals reveals no hint of any ethical discussion. No discussion of the principles of good science. Not even a worthy news report. Nothing at all.

• The British medical Journal : No discussion
• The Lancet: On 24 November 2007 in the midst of the saga, the Lancet published a review entitled "The safety of statins in clinical practice" Jane Armitage, Vol. 370, Issue 9601 Pages 1781-1790. There was no relevant discussion or associated editorial in that issue or in any subsequent issue.
• NEJM: No discussion
• JAMA: No discussion

Dr. Blumsohn then contrasts this "silence" in the medical journals to the discussion of these problems with Zetia and Vytorin duting the last few months in articles by bloggers who write regularly about medical and pharmaceutical topics.  His list of 35 blog posts includes our earlier article, "Cholesterol Drug Zetia May Cause Serious Liver Injury Including Hepatitis And Liver Failure".

And to Dr. Blumsohn's list of recent blog articles about this troubling situation we can add "Behind The Curtain: That Secret Vytorin Panel", which was posted by Ed Silverman at his Pharmalot blog on January 11.

We close with this observation by Dr. Blumsohn:

One wonders how long our key medical journals will retain any credibility as honest impartial portals for discussion of science and the principles of good medicine.

Of course, we will continue to watch for developments concerning Zetia and Vytorin.

Video Of January 2008 Vioxx Settlement Panel Discussion Is Available Online

Lawyers And Law Professors Discuss The Good, The Bad, And The Ugly Of Merck's Proposed "Global Settlement" Of All U.S. Vioxx Lawsuits

(Posted by Tom Lamb at DrugInjuryWatch.com)

We learned from a January 9, 2009 post, "Webcast of Vioxx Settlement Panel" -- which we found when taking our daily look at the Drug and Device Law blog -- that you can now view online for free C-SPAN's broadcast of "The Vioxx Settlement" panel discussion which took place in Washington, D.C. on the afternoon of January 7, 2008 at the American Enterprise Institute (AEI).

In addition, on the AEI web page for this January 2008 panel discussion of Merck's proposed Vioxx settlement there is a link to the video, at top of right side bar.  (One small advantage to using this means of viewing "The Vioxx Settlement" event is that you don't have to watch some of those people in attendance eat their lunch at the start, as you do on the C-SPAN webcast.)

From that the AEI "The Vioxx Settlement" web page we get this introduction to the panel members:

At this event cosponsored by AEI and the Federalist Society, a panel of experts will explore these and other questions. Speakers include Vanderbilt law professor Richard Nagareda, author of Mass Torts in a World of Settlement; Virginia legal ethics professor George Cohen; author and leading pharmaceutical mass torts defense attorney Mark Herrmann; Andy Birchfield, a member of the Vioxx Plaintiffs’ Steering Committee; and Ted Frank, director of the AEI Legal Center for the Public Interest. AEI resident scholar John E. Calfee will moderate.

A January 7, 2008 post on "The BLT: The Blog of Legal Times" entitled "AEI on Vioxx" provides this same-day report on what was said about Merck's Vioxx Settlement Program by some of the panel members:

In November of last year, Merck & Co. negotiated a settlement proposal with plaintiffs attorneys that, if 85 percent of the claimants agree to it, will give $4.85 billion to the thousands of claimants and their lawyers. But as the AEI panel showed, opinions vary greatly on the settlement.

Mark Herrmann, a defense attorney with Jones Day in Chicago, said the settlement “made sense. It was logical, and it, in fact, was predictable from the start.”

But George Cohen, a law professor at the University of Virginia, had some ethical concerns with the proposed settlement. The terms of the agreement could stand in the way of lawyers giving their clients adequate advice. “The temptation will be, I fear, that lawyers will want to recommend this to people even if it’s not in their best interest,” says Cohen.

Andy Birchfield, an attorney at Beasley Allen and co-lead counsel on the Plaintiffs’ Steering Committee for the federal Vioxx litigation, countered that the settlement had been designed so that plaintiffs attorneys couldn’t “game the system” or cherry pick the best cases to leave out of the settlement.

As a caveat, we point out that this "The Vioxx Settlement" webcast weighs-in at just over two hours in duration (according to the C-SPAN site).  While we understand that most of our readers will not have sufficient curiosity about Merck's proposed Vioxx Settlement Program to sit in front of their computer that long, we wanted to make these webcast links available to those of you who do have the requisite interest and time.

P.S.  A January 10, 2008 article, "Vioxx Settlement Plan Heads for Key Deadlines", published by The Wall Street Journal, provides additional details about Merck's proposed Vioxx Settlement Program and its current status.  (1/10/08)

Reports Of Tendon Ruptures Caused By Antibiotics Levaquin, Cipro, And Avelox

Public Citizen Files Lawsuit Against FDA Seeking "Black Box" Warning About This Painful And Lingering Side Effect

(Posted by Tom Lamb at DrugInjuryWatch.com)

____________________________________________________________________

UPDATE:  For recent developments regarding personal injury lawsuits that involve Levaquin and tendon-related side effects, visit the Levaquin Information page over at our Drug Injury Law web site.   (7/30/09)

____________________________________________________________________

According to a January 3, 2008 Reuters article, "Group sues U.S. in push for new antibiotic warning", the consumer group Public Citizen has filed a lawsuit intended to force the FDA to consider whether stronger warnings should be added to certain antibiotics such as Johnson & Johnson's Levaquin as well as Bayer AG's Cipro and Avelox. This Public Citizen lawsuit was filed in federal court, specifically the U.S. District Court for the District of Columbia.

In August 2006 Public Citizen petitioned the FDA to add a "black box" warning to alert doctors and patients about the risk of tendon injury and rupture associated with Levaquin, Cipro, and Avelox, as well as generic antibiotics sold under the name ciprofloxacin -- all being in the fluoroquinolones class of drugs.

According to the January 3 Reuters article about the new Public Citizen lawsuit:

The possibility of tendon rupture is now mentioned in the drug's prescribing instructions, but the warning "is buried in a long list of possible adverse reactions and is far too easy to miss," said Dr. Sidney Wolfe, director of Public Citizen's Health Research Group....

"While the FDA sits idly by and ignores the problem, more people will suffer serious tendon ruptures that could have been prevented," Wolfe said.

The FDA has received 336 reports of tendon rupture in patients treated with fluoroquinolones from November 1997 through March 2007, Public Citizen said. The actual number is likely higher because only a fraction of potential side effects are typically reported to the agency.

Levaquin, Cipro, and Avelox, as well as similar generic antibiotics, are widely prescribed in the U.S. and elsewhere for gastrointestinal, respiratory, and urinary tract infections.

P.S.  On July 8, 2008 the FDA announced that a so-called "black-box" Warning would be added to the package insert, or label, to strengthen existing warnings about the increased risk of developing tendinitis and tendon rupture associated with the following fluoroquinolones:

Ciprofloxacin (marketed as Cipro and generic ciprofloxacin)
Ciprofloxacin extended release (marketed as Cipro XR and Proquin XR)
Gemifloxacin (marketed as Factive)
Levofloxacin (marketed as Levaquin)
Moxifloxacin (marketed as Avelox)
Norfloxacin (marketed as Noroxin)
Ofloxacin (marketed as Floxin and generic ofloxacin)

For more details, see the July 8 press release, "FDA Requests Boxed Warnings on Fluoroquinolone Antimicrobial Drugs".  (7/9/08)

Senator Grassley's December 2007 Letter To FDA Questions Agency's Approval Of Ketek

Sanofi-Aventis Antibiotic Has Been Subject Of Controversy Since Reports of Liver Damage Surfaced In Early 2006

(Posted by Tom Lamb at DrugInjuryWatch.com)

The safety concerns about Ketek (telithromycin) began in early 2006 after Health Canada and the European Union's European Medicines Agency (EMEA) issued alerts based on the online "early" release of an article about Ketek that would later be published in the March 21, 2006 edition of the Annals of Internal Medicine.  This article reported three cases in a North Carolina hospital where there was liver failure associated with Ketek use.

In May 2006 Senator Charles Grassley (R-Ill.) as well as Congressmen Edward Markey (D-Mass.) and Henry Waxman (D-Calf.) asked the FDA for some explanation about the agency's decision to approve the antibiotic Ketek in 2004.  This scrutiny from Capitol Hill followed in the wake of a May 1, 2006 investigative piece in The Wall Street Journal about how the FDA approved Ketek despite knowing about some problems with a key study -- known as trial 3014 -- which was submitted to the FDA by Ketek's manufacturer, Sanofi-Aventis (SNY).

Finally, in October 2007 the FDA posted on its web site a copy of an 11-page "Warning Letter" to Sanofi-Aventis about problems with Ketek Study 3014.

Most recently, on December 19, 2007 Senator Grassley, ranking member of the U.S. Senate Committee on Finance, sent a 22-page letter to FDA commissioner Andrew C. von Eschenbach, M.D., regarding the Committee's ongoing investigation of Ketek.

In his letter Grassley reports what has been learned over the past 16 months, during which time the Committee's staff reviewed documents and information obtained from the Department of Health and Human Services (HHS), the FDA, FDA advisory committee members, and the drug company Sanofi-Aventis.  The primary focus of Grassley's letter is the FDA's review of Sanofi-Aventis' Study 3014, and the FDA’s unprecedented reliance on adverse-events data collected in foreign countries for evidence of Ketek’s safety when approving this antibiotic for sale in the U.S.

Also in his December 19 letter to the FDA Commissioner Grassley presents the Committee's findings as regards some of the inspections and investigations conducted by FDA’s Division of Scientific Investigations (DSI) and Office of Criminal Investigations (OCI) concerning alleged improprieties and misconduct associated with Study 3014.

As regards the FDA's approval of Ketek on April 1, 2004, from the first few pages of this December 2007 letter from Senator Grassley we learn the following:

Current and former FDA employees alleged that FDA relied solely on foreign postmarketing adverse event reports as evidence of Ketek’s safety for marketing when the Agency could no longer rely on the large safety study, Study 3014. These employees questioned whether or not the use of such data as the primary basis for the Agency’s safety assessment of Ketek met the standards for approval of the drug....

FDA appears to have relied primarily on foreign post-marketing safety data to
assess the safety of Ketek as a new antibiotic for marketing. Based on interviews with current and former FDA staff, heavy reliance on foreign post-marketing safety data in this context is unprecedented. A week before Ketek was approved, FDA’s Division of Scientific Investigations concluded that the data from a large clinical trial were unreliable. The study was conducted to evaluate specific adverse events associated with Ketek. In place of the large clinical trial, the FDA based its assessment of the safety of Ketek on foreign post-marketing adverse event reports, despite inherent limitations with that data, including underreporting and reporting bias. When asked by Committee Staff, FDA managers and reviewers could not identify any other case where FDA relied on foreign postmarketing data as the primary basis of its safety assessment for the approval of a new antibiotic.

As the stated purpose of this December 19 letter to Dr. von Eschenbach was not only to report the Committee's findings but, also, to "request your comments and responses regarding these findings and some of the other allegations and concerns that have been brought to the Committee’s attention", we will likely be reporting more about Ketek and Study 3014 in the months to come.