Drug Injury Watch

David Graham's NEJM Letter Concerning Sanofi-Aventis Antibiotic Ketek

Suggests That Reports Of Acute Liver Failure Support A Ketek Recall

A November 22, 2006 Reuters article by Susan Heavey reports on the latest development as regards the continuing controversy surrounding Ketek (telithromycin), an antibiotic from Sanofi-Aventis.  The Reuters article summarizes a letter to the editor of The New England Journal of Medicine (NEJM) written by David Graham, a high-profile FDA staff member who has spoken out often about drug safety issues.  David Graham's letter, entitled "Telithromycin and Acute Liver Failure", was published in the November 23, 2006 edition of NEJM, a leading medical journal.

Essentially, Graham takes the FDA to task for the way the agency evaded the recommendation of a 2001 FDA advisory committee which had "voted against the approval of [Ketek] primarily because of concern about hepatotoxicity."  In his letter Graham describes the tactic in detail, but the basic point seems to be this:

Lacking reliable data to counter the advisory committee's concern, the FDA took the unprecedented step of requesting post-marketing data from voluntary case reports from Germany and France as proof of the drug's safety, rather than requiring another clinical trial....

The FDA interpreted the absence of a signal of acute liver failure in the overseas data as confirmation of [Ketek]'s safety when the data could not be used to identify the problem. In effect, the FDA's decision in 2004 to approve the use of [Ketek] for acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, and community-acquired pneumonia was made in the absence of reliable data disproving the concern expressed in 2001 by the advisory committee. 

According to the November 22 Reuters article, despite these facts, the FDA and the drug company Sanofi-Aventis maintain that the approval of Ketek was done properly and that this antibiotic should remain on the market:

• "FDA spokeswoman Kristen Neese said the agency was aware of the limitations of data gathered after marketing, but it was not uncommon to use such information or reports from other countries. The agency also weighed other data in approving Ketek, she added."
• "Company spokeswoman Lisa Kennedy said Ketek 'has been extensively studied' and that the drugmaker was required to submit all post-marketing data to the FDA."

David Graham, on the other hand, asserts in his November 2006 NEJM letter that the there is a case to be made that Ketek should be recalled for safety reasons:

A recent analysis of the FDA's post-marketing database showed that the rate of reporting of acute liver failure was 3.5 to 11 times as high for [Ketek] as for other antibiotics marketed for similar indications, with a reporting rate of 167 cases of acute liver failure per 1 million person-years of [Ketek] use, as compared with the expected rate of 1 case per 1 million person-years. Without accounting for underreporting (the actual incidence could be 10 times as high), this reporting rate is greater than that for troglitazone or trovafloxacin and is similar to that for bromfenac — three drugs previously removed from the U.S. market by the FDA because of the increased risk of acute liver failure. Given that [Ketek] is neither clinically superior to other drugs prescribed for respiratory tract infections nor uniquely life-saving, physicians, patients, and third-party payers might wish to reconsider their choice of antibiotic for such infections. 

As covered previously, in mid-December 2006 the FDA will convene a two-day meeting to consider whether Ketek should remain on the market, or not.

(Posted by: Tom Lamb)

Amount Of Epogen And Procrit Given To Patient Tripled Since Early '90s

Higher Levels Of Popular Anemia Drugs May Increase Risk Of Heart Problems And Death

The most recent discussion about safety issues surrounding the anemia drug epoetin -- sold by Amgen as Epogen, sold by Johnson & Johnson (J&J) as Procrit -- started with a November 8, 2006 article in the Boston Globe by Christopher Rowland.  He reported on the results of a study that was soon to be published in The New England Journal of Medicine as follows:

[Dr. Ajay Singh, clinical chief of the renal division at Brigham and Women's Hospital in Boston,] whose clinical trial linked aggressive use of anemia drugs to an increased risk of fatal heart attacks and strokes says the government is not doing enough to protect dialysis patients from the potential dangers.

... The trial, called CHOIR , was halted last year because patients whose red blood cell counts were boosted the most died at an unexpectedly high rate.

... In anticipation of the CHOIR study's publication, physicians and policy specialists are debating a basic question: How much Epogen is too much? Even though the drug is widely used to manage anemia in all kidney patients -- not just the 325,000 on regular dialysis -- as well as in cancer patients undergoing chemotherapy, definitive studies on its effectiveness and safety thresholds have not been performed.

Singh said the FDA should require Amgen and other manufacturers of the drugs -- synthetic hormones which stimulate red blood cell production in bone marrow -- to sponsor studies to establish a threshold for anemia treatment.

This was followed by a November 16, 2006 article called "Heart Risk Seen in Drug for Anemia", in The New York Times by Alex Berenson, from which we learn:

A medical study to be released today suggests that high doses of a best-selling drug used to treat anemia in dialysis and cancer patients may increase the risk of heart problems and deaths.

... The findings reinforce mounting concerns that kidney patients may be receiving too much epoetin, in part because dialysis clinics make bigger profits for providing larger doses. Studies show that the clinics make little, if any, profit on the actual dialysis services they provide for Medicare patients, who are the vast majority of patients.

The amount of epoetin received by the typical American dialysis patient has nearly tripled since the early 1990s....

But the studies show that the anemia of many patients is being overcorrected and that doctors should aim for lower levels of red blood cells in their patients, he said. The simplest way to do that would be to give patients less epoetin.

Indeed, the solution proposed by Dr. Singh seems sensible and simple enough to implement.  Why, then, is there resistance from Amgen to this solution? 

For that we turn to Merrill Goozner, who spent more than 25 years as a reporter for the Chicago Tribune and other publications.  In a November 20, 2006 email about his online newsletter, This Week in GoozNews, Mr. Goozner gives us some insight.

Nearly a decade ago, I was an economics reporter who stumbled onto the drug industry by attending hearings on Capitol Hill about the fate of Medicare. I eventually wrote a piece for the Chicago Tribune headlined "The Making of a Star Drug," where I documented the games played by Amgen around its best-selling drug Epogen, then as now the drug that Medicare spends more money on than any other. That story eventually became the first chapter of my book, "The $800 Million Pill." Epogen was back in the news last week. A new study appearing in the New England Journal of Medicine pointed what observers like myself have been arguing for years. The high doses of Amgen's pricey drug may be killing people on dialysis. Naturally, my posts last week focused on this issue. Read them and weep for the poor people on dialysis who have been victimized by this company.

Here are two recent articles by Mr. Goozner about this ongoing problem with epoetin:

• Amgen, NKF and the Dialysis Killing Fields  (November 17, 2006)
• The Trials of Amgen  (November 15, 2006)

Hopefully this renewed discussion about what levels of Epogen and Procrit are safe for use in patients with anemia will produce some results this time around.

(Posted by: Tom Lamb)

Is The End Near For Sanofi-Aventis Antibiotic Ketek?

December 2006 FDA Meeting Will Focus On Side Effect Risks, While Fraud Investigation Continues

A November 14, 2006 Associated Press (AP) article was the first to report that in December 2006 the FDA will convene an advisory panel of experts to focus on the reports of adverse drug reactions (ADRs) associated with Ketek and to weigh those ADR reports against the drug's therapeutic benefits.  A Reuters article with FDA comments and Ketek sales information provided additional details about the status of Ketek.

Ketek (telithromycin) is generally used as a short-term treatment for respiratory infections, bronchitis, sinusitis, and certain types of pneumonia.  Since being approved by the FDA in 2004 there had been enough serious side effect reports made to the FDA that in June 2006 a bolded warning was put on the Ketek label, or package insert, to warn doctors and patients about the possibility of liver failure, drug-induced hepatitis, and other liver damage.

Scheduled for December 14-15, 2006, this FDA meeting of experts is seemingly intended to give guidance to the agency about what to do with Ketek going forward.  The advisory panel of experts could suggest that more severe warnings should be put on the Ketek label, e.g., a so-called "black-box warning".  Or this advisory panel could go further and recommend that Ketek be withdrawn from the market because of an unfavorable safety profile, i.e., Ketek's benefits are outweighed by its distinct risk of serious side effects.

According to the November 14, 2006 AP article:

Sanofi-Aventis welcomes the opportunity to discuss Ketek, company spokeswoman Lisa Kennedy said. "Based on the data available to us, and in consultation with leading experts, we continue to believe the benefits of Ketek outweigh its risk when the drug is used as directed for its approved indications," Ms. Kennedy said.

In reality, however, the November 2006 announcement that an FDA advisory panel is being convened next month to discuss Ketek seemingly could not come at a worse time for Sanofi-Aventis.  The Senate Finance Committee is investigating how Ketek was approved by the FDA in the first place.  This Senate investigation is looking into, among other things, allegations that there was extensive misconduct, including fraud, involved with the clinical trials of Ketek prior to it being approved in 2004. 

It appears that things may finally be coming altogether unraveled for Ketek, and that the end may be near for Sanofi-Aventis' controversial antibiotic.

(Posted by: Tom Lamb)

Merck Settlement For Vioxx Cases Said To Be Several Years Away

UPDATE: Global Settlement Offer Made By Merck To End Vioxx Litigation According To November 9, 2007 News Reports

Merck Agrees to Settle Vioxx Suits for $4.85 Billion (NY Times)

Merck Is Expected to Announce Vioxx Settlement of $4.85 Billion (Wall Street Journal)

Merck May Pay $5 Billion to Settle Vioxx Cases, Lawyers Say (Bloomberg)

Two Vioxx Trials Now In Progress; Another 24,000 Cases Wait For Their Day In Court

On November 8, 2006 Merck's Chief Executive Richard Clark said during a speech at Reuters Health Summit in New York City that there may be some Vioxx lawsuit settlements in the future, but not to expect anything but more Vioxx trials for the next several years.

Merck stop selling its blockbuster arthritis drug Vioxx in September 2004 after a study showed that Vioxx use could double the risk of having a heart attack or a stroke.  During the two years that followed this Vioxx recall, the number of personal injury and wrongful death lawsuits filed against Merck has gone into the tens of thousands.  Merck, meanwhile, has remained more or less steadfast in its position that it will take these each of these Vioxx cases to court rather than trying for an early global settlement.

According to a November 8, 2006 Reuters article about the Vioxx litigation:

At last count, Merck was facing nearly 24,000 Vioxx lawsuits and the company has steadfastly insisted that it will fight each case in court individually rather than consider a large-scale settlement.

"We know our strategy is right. It's case by case, day by day, jury by jury," Clark said.

"We have won more cases than we've lost, so there's no reason to settle this," he added.

Clark pointed to some 3,000 cases that have been dropped so far in justifying the decision to ignore calls for a major settlement agreement that could put the Vioxx debacle behind the company.

"If we would have settled earlier, those 3,000 cases, which probably weren't worthy of being in the case load, we would have had to settle those," Clark said.

"It will take us years to understand that the cases that they have are quality cases; that indeed, first of all, that the patient actually took Vioxx. We have many cases where that didn't happen.

"This case by case (strategy) is going to take us years until we are satisfied that the case load is the proper case load. We're not there yet," Clark said.

Merck recently took a charge of $598 million for Vioxx legal expenses on top of the $685 million it had previously set aside for litigation reserves. But the drugmaker has yet to hand over any money in damages, even to plaintiffs who have won Vioxx trials.

At the time of these November 2006 remarks by Merck's Chief Executive, there were two ongoing Vioxx trials: Mason v. Merck, No. 06-0810, E.D. La., in New Orleans, part of the federal court Vioxx MDL; and, Arrigale v. Merck, No. 05CC03136, as well as Appell v. Merck, No. BC328858, Calif. Super., Los Angeles Co., two individual Vioxx cases combined for trial and part of the California state court coordinated Vioxx litigation in Los Angeles.  The Arrigale case originally had been set for a trial in June 2006.

According to a report that Merck filed recently with the U.S. Securities and Exchange Commission (SEC), as of October 9, 2006 the drug company had been named in about 23,800 Vioxx lawsuits which involved approximately 41,750 individuals.  In addition, this October 2006 SEC filing by Merck provided this additional detail:

• approximately 7,450 Vioxx lawsuits are part of the federal court MDL in New Orleans;
• another 13,850 Vioxx lawsuits are part of the New Jersey state court coordinated Vioxx litigation, in Atlantic County, NJ; and,
• an estimated 15,000 individuals claiming Vioxx-related injuries involving heart attacks or ischemic strokes have entered into so-called "tolling agreements", essentially a deal made by Merck with certain potential claimants by which the statute of limitations filing deadline has been suspended for their Vioxx case.

Of course, no one really believes Merck when they defiantly state that each and every Vioxx case will be resolved only by a trial.  It does seem, however, that there will be many more Vioxx trials before the day comes when Merck begins to implement any plan whereby some categories of Vioxx cases will be settled by the drug company.

(Posted by: Tom Lamb)

Ortho Evra: More Women Sue J&J Over Birth Control Patch

Lawsuits Allege Serious Blood Clots Conditions Such As Pulmonary Embolism, With One Young Woman Dying From Using Ortho Evra

In early November 2006 two new California Ortho Evra lawsuits were filed in San Francisco Superior Court, Bracken-Hodge v. Ortho-McNeil (Case No. 06-457523) and Abel v. Ortho-McNeil (Case No. 06-4575240), according to an Associated Press article published by the Washington Post. 

This November 1, 2006 article in the Post informs us that the first case concerns "25-year-old Kelly Bracken of Elk Ridge, Md., died of severe blood clots in her lungs and legs after she started wearing the skin patch," while the second case combines the personal injury claims of 43 women who suffered from various serious side effects caused by blood clots related to the women's use of the Ortho Evra birth control patch.

In September 2006 the FDA warned doctors and patients that women had an increased risk of developing blood clots in their legs -- called deep vein thrombosis or DVT -- and their lungs -- pulmonary embolism -- if they used the Ortho Evra birth-control patch instead of the traditional oral contraceptive pill.  Ortho Evra, which was approved by the FDA in 2001, is unique in that is a birth control patch that transfers the hormones estrogen and progestin through a woman's skin directly into the bloodstream.

The Post article tells us that the two companies named as defendants in the two new California Ortho Evra lawsuits filed in November 2006 are the drug's manufacturer, Ortho-McNeil Pharmaceutical Co., a subsidiary of Johnson & Johnson (J&J), and San Francisco-based distributor McKesson Corp.

In September 2006 the Ortho Evra package insert, or label, was updated by J&J to make doctors and patients aware of the results of two conflicting studies: one study that Ortho Evra doubled the risk of serious blood clots compared to the pill, while a second study found no difference in risk between the patch and the pill.

(Posted by: Tom Lamb)

Connection Between Fosamax And Osteonecrosis Of The Jaw (ONJ) Gains More Attention

Medical Journals Discuss Diagnosis And Treatment Of ONJ As Well As New Theory About Bisphosphonate-Induced ONJ

In the past year there has been increasing attention paid to a rare but serious side effect that is associated with the osteoporosis drug Fosamax: osteonecrosis of the jaw (ONJ), commonly referred to as jawbone death, bone decay, or jaw rot.

In October 2006 an article by medical researchers in Italy was published, "Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist's role", which reviewed some recently published reports of osteonecrosis of the jaw (ONJ) that had been related to bisphosphonates.  Besides reminding doctors who treat bone diseases with bisphosphonates that they need to be aware of this serious side effect, the authors provided those doctors with some timely guidance.  This October 2006 article brings doctors up-to-date as regards:

• systemic and local predisposing pathologies;
• preventive measures suggested before and during therapy with bisphosphonates; and,
• the most frequent clinical presentation of the oral lesions.

The article regarding this study also summarizes an expert panel's recommendations for the management and care of ONJ patients.

Next there is an editorial, "Osteonecrosis of the jaw: what do bisphosphonates do?", published in the November 1, 2006 edition of the journal Expert Opinion Drug Safety, that explores a new possible theory of how Fosamax and other bisphosphonates might cause the side effect osteonecrosis of the jaw (ONJ).

It is commonly assumed that the bisphosphonates somehow cause cell death... within the jawbone, which makes it prone to chronic infection. In this article, an alternative pathogenic theory is suggested, based on the normal effect of bisphosphonates. According to the new theory, the bone is alive until it is injured and infected, and the reduced receptive ability due to bisphosphonates hinders the formation of a fresh bone surface for re-establishment of bone cell coverage.

Our author of this November 2006 editorial, P. Aspenberg, points out that the several current competing causation theories of bisphosphonate-induced osteonecrosis of the jaw bone (ONJ) are based only on recent and very scarce literature concerning this relatively new side effect, and Aspenberg determines that:

None of them can be completely refuted, but the demonstration of living osteopaths within the lesion and the number of necessary assumptions speak against the theory of a primary, bisphosphonates-induced necrosis.

No doubt, with the increasing number of reports about people who used or are using Fosamax and developed osteonecrosis of the jaw (ONJ), there will be more medical journal articles about this serious side effect in the months and years to come.

(Posted by: Tom Lamb)