Drug Injury Watch

Next Set of Vioxx Trials in New Jersey Assigned Court Dates By Judge Higbee

New Jersey Judge Sets A February 27, 2006 Trial Date for Next NJ Vioxx Case

In late November 2005 New Jersey Superior Court Judge Carol Higbee announced that she tentatively plans to consolidate the next two Vioxx injury cases into one trial, which she has scheduled to start on February 27, 2006.  At the same time, Judge Higbee set an April 24, 2006 trial for three other New Jersey Vioxx cases and, thereafter, a June 5, 2006 trial date for two more NJ Vioxx cases.

According to a November 28, 2005 Associated Press ("AP") article by John Curran, the plaintiffs in these two Vioxx cases are Thomas Cona and John McDarby.  The AP article reports that Merck opposes Judge Higbee's plan of trying two Vioxx cases at once, and lawyers for the drug company intend to file legal papers asking Judge Higbee to abandon the consolidated Vioxx trial plan.  The AP's John Curran reported that Judge Higbee left open the possibility of having just one case involved in the February 27 trial, with only the Cona v. Merck case going  forward on that date.

The November 28 AP article describes the plaintiffs in the two cases assigned this February 27 trial date as follows:

• Cona v. Merck:  "Cona, a 59-year-old businessman from Cherry Hill, [NJ] says he took the now-withdrawn painkiller for more than two years before suffering a heart attack in June 2003."
• McDarby v. Merck:  "McDarby, 76, of Park Ridge, [NJ] a retired insurance salesman, also took Vioxx for more than two years before being stricken in April 2004, according to his complaint."

Merck seemingly admits that its recalled painkiller Vioxx can cause an increased risk of heart attack and stroke where a patient has 18 months of Vioxx use or more.

Merck attorney Ted Mayer raised some doubt, however, about whether Mr. Cona and Mr. McDarby actually took Vioxx for more than 18 months, as alleged in their respective lawsuit complaints.  As reported by the AP, Mr. Mayer commented:  "They're both alleged to be 18 months or more. We never know what will turn up when we get to trial".

The first federal Vioxx case, Irvin v. Merck, started on November 29 in Houston with U.S. District Court Judge Eldon Fallon presiding.  The Irvin Vioxx trial is expected to last two weeks.

(Posted by: Tom Lamb)

Irvin / Plunkett v. Merck: Federal Court MDL Vioxx Trial Starts in Texas

AP Reports At Least 7,875 Vioxx Lawsuits Filed By Thanksgiving Day 2005

The first Vioxx federal trial, Irvin / Plunkett v. Merck, is scheduled to start today, November 29, 2005, in Houston, Texas.  This Vioxx case involves the late Richard "Dicky" Irvin Jr., a 53-year-old seafood distribution manager from St. Augustine, Florida, who had a fatal heart attack in May 2001 after taking Vioxx for about a month.  Irvin's widow, Evelyn Irvin Plunkett, is the plaintiff in this wrongful death Vioxx case, which is officially captioned Plunkett v. Merck, No. 05cv4046 (E.D. La., moved to S.D. Texas due to Hurricane Katrina).  U.S. District Judge Eldon Fallon will preside over the Irvin / Plunkett trial.

Significantly, Judge Fallon ruled November 16, 2005 that lawyers for Mr. Irvin's widow may present evidence at the trial showing short-term Vioxx use can trigger heart attacks and strokes.  In so ruling, Judge Fallon rejected Merck's contention that there is no reliable evidence of cardiac risks when Vioxx is taken for shorter periods.  As such, Judge Fallon also denied Merck's motion to dismiss the Irvin / Plunkett case for insufficient evidence regarding medical causation.

Moreover, Judge Fallon's ruling about allowing evidence of short-term Vioxx use causing heart attacks effectively blocked Merck's effort to have the Court dismiss all federal Vioxx lawsuits involving short-term Vioxx use.

The Associated Press ("AP") reported on November 27, 2005 that at least 7,875 Vioxx lawsuits, total, had been filed against Merck as of Thanksgiving day.  In addition, according to the AP report, Merck had extended the one-year statute of limitations' deadline on about 3,000 more cases by means of so-called "tolling agreements" with plaintiffs' lawyers.

At present, Judge Fallon is overseeing at least 2,900 federal Vioxx personal injury and wrongful death cases in the federal court Vioxx MDL.  After the Irvin / Plunkett Vioxx trial, Judge Fallon has scheduled three more federal Vioxx trials for Spring 2006.  Judge Fallon, according to the November 27 AP report, "then plans to meet with lawyers on both sides to discuss a global settlement for all federal Vioxx litigation."

Meanwhile, in the New Jersey state court system, Superior Court Judge Carol Higbee is overseeing more then 4,225 Vioxx cases. Judge Higbee has said that after presiding over Humeston v. Merck, a case involving short-term Vioxx use, she wants the next several trials to involve a heart attack or stroke after Vioxx use for at least 18 months.

Lastly, Merck's November 2005 victory in Humeston v. Merck, the first New Jersey state court trial, has been appealed.  According to the AP report, on or about November 23, 2005 lawyers for plaintiff Frederick "Mike" Humeston, who alleged his September 2001 heart attack was caused by short-term use of Vioxx, filed a motion for a new trial.

(Posted by: Tom Lamb)

Study On Cardiovascular Safety of Celebrex Reported at 2005 ACR Meeting

No Increased Risk Of Heart Attack Or Stroke For Patients Taking Celebrex   

According to a meta-analysis reported by Dr. Lee Simon, Associate Clinical Professor of Medicine at Harvard Medical School, the COX-2 specific inhibitor Celebrex (celecoxib) is not associated with an increased risk of serious cardiovascular thrombotic events compared to placebo or NSAIDs.  This meta-analysis, which covered 41 clinical studies involving 44,308 patients, evaluated the cardiovascular safety of Celebrex versus both placebo and nonselective NSAIDs ("ns-NSAIDs").

In summary, the meta-analysis showed that patients taking Celebrex had no more risk for heart attack, stroke, or CV death combined than those given placebo or ns-NSAIDs.

Dr. Simon presented his report about the meta-analysis at the American College of Rheumatology (ACR) 2005 Annual Scientific Meeting, held in mid-November at San Diego, California. Some of his findings included:

• “There were no cardiovascular signals that were any different to the active comparators. [Celebrex] was no different to non selective drugs in terms of cardiovascular risk,” Dr. Simon said. Comparators included placebo, naproxen, diclofenac, ibuprofen, loxoprofen, acetaminophen and ketoprofen.
• “In this large meta-analysis comprising studies of two weeks to three years duration involving patients with chronic conditions, [Celebrex] at doses of 200mg or more total daily dose was not associated with an increased risk of serious CV thromboembolic events compared with placebo or nonselective NSAIDs,” Dr Simon concluded.

Dr. Simon is a former Division Director of the Arthritis, Analgesic & Ophthalmologic Drug Product Division at the FDA's Center for Drug Evaluation and Research.

This meta-analysis was reportedly funded by the drug company Pfizer, which makes Celebrex.  Dr. Gail Cawkwell, a Senior Medical Director at Pfizer, said that this meta-analysis presented by Dr. Simon at the 2005 ACR meeting was being prepared for publication in a peer-reviewed journal.  Further, Dr. Cawkwell said the new meta-analysis data had been shared with the FDA as well as European Union regulators.

(Posted by: Tom Lamb)

Did GlaxoSmithKline Mislead The FDA As Regards Asthma Drug Serevent?

Consumer Group Public Citizen Allegation In Medical Journal The Lancet

In an early October 2005 edition of The Lancet, a British medical journal, a published letter by the American consumer group Public Citizen accused GlaxoSmithKline ("Glaxo") of misleading the FDA as regards company's asthma drug Serevent.  In particular, Public Citizen alleges that Glaxo manipulated data from the Salmeterol Multicenter Asthma Research Trial in order to make Serevent appear to the FDA that it was safer than the true trial data demonstrated.

The Public Citizen allegations of misconduct by Glaxo concern the Salmeterol Multicenter Asthma Research Trial, or SMART trial, which was a large 28-week trial involving tens of thousands of patients. The SMART trial was initiated in 1996 to address emerging safety issues concerning Serevent, a long-acting beta agonist ("LABA") used to help patients during an asthma attack.  Public Citizen alleges that when Glaxo submitted its final SMART trial results to the FDA in April 2003, the drug company included data from six months after the trial ended, thereby skewing the results.

In relevant part, during the 28-week SMART trial 13 patients taking Serevent suffered asthma-related deaths compared to the three asthma-related deaths involving patients taking the placebo in the SMART trial.  Accordingly, patients taking Serevent had four times as many deaths.

But six months after the SMART trial ended, the numbers had changed such that the death factor was reduced to just 2.5: patients in the Serevent group had suffered 15 deaths, while the placebo group had six asthma-related deaths.

Possible manipulation of the SMART trail data by Glaxo came to light when documents about Serevent were made public prior to an FDA Pulmonary-Allergy Drugs Advisory Committee meeting in July 2005.

It has been reported that some documents available on the FDA's web site indicate, at least, an FDA staff-level concern about the SMART trial data that was initially submitted by Glaxo. "The [FDA] Division disagrees with the inclusion of the post-study adverse event data in the analysis," one FDA review summary reportedly states.

According to Public Citizen, Salmeterol was dispensed in the U.S. more than 2.1 million times in 2004, and the combination product, Advair, was dispensed more than 16.1 million times in 2004.  Public Citizen listed Serevent as a “Do Not Use” drug in its Worst Pills, Best Pills newsletter in March 2003.

At present, Serevent, or salmeterol -- which asthma medication is known as Advair when it is combined with the steroid fluticasone -- carries a "black-box" warning about a small but significant increase in asthma-related deaths among patients who use Serevent.

(Posted by: Tom Lamb)

Serevent, Advair, and Foradil: Increased Risk of Severe Asthma Episodes and Death

FDA MedWatch Alert About LABA Asthma Drugs Follows Health Canada Warning In October 2005

On November 18, 2005 the FDA issued a MedWatch alert regarding Serevent, Advair, and Foradil to inform doctors and patients that the use of  use of inhalation powders containing long-acting beta 2-adrenergic agonists ("LABA") may increase one's risk of severe asthma episodes and death.

The asthma inhalation powders addressed in the November FDA warning are:

• Serevent Diskus (salmeterol), made by GlaxoSmithKline;
• Advair Diskus (salmeterol combined with fluticasone propionate), made by GlaxoSmithKline; and,
• Foradil Aerolizer (formoterol), made by Novartis Pharmaceuticals Corp.

The FDA MedWatch alert advised patients receiving these asthma medications to seek medical attention immediately if their asthma worsens.

In early October 2004, Health Canada issued a similar safety alert regarding these three asthma medications, and a couple more.  On October 4 Health Canada informed doctors and patients about the possible increased risks of asthma-related deaths associated with the use of asthma drugs known as long-acting beta-2 antagonists.  In addition to Serevent, Advair, and Foradil, the Health Canada alert covered two additional asthma brand-name drugs:

• Oxeze (formoterol), made by AstraZeneca Pharmaceuticals LP; and,
• Symbicort (formoterol in addition to an inhaled corticosteroid), made by AstraZeneca, also.

The Health Canada alert included a reminder to doctors and patients about the recommended uses of long-acting beta-2 antagonists. 

An article by Yael Waknine about the FDA MedWatch alert was published November 18, 2005 on the Medscape web site.  In relevant part, this Medscape article provides information about the proper prescribing and use of the several medications in this LABA class of asthma drugs:

Healthcare professionals with asthma patients receiving these medications should be aware that LABAs are not intended as first-line therapy and should be reserved for use in those who have demonstrated an inadequate response to other asthma-controller medications such as inhaled corticosteroids.

Current guidelines from the National Heart, Lung, and Blood Institute and World Health Organization recommend inhaled corticosteroids as the first step in controller therapy, with LABAs as optional add-on therapy if low- to medium-dose inhaled corticosteroids provide inadequate relief.

A spokesman for GlaxoSmithKline ("Glaxo") told Reuters that the drug company disagreed with the FDA's proposed revised labeling for Serevent and Advair.  According to a November 19, 2005 Reuters article, Glaxo maintains that "the revisions would be inconsistent with the standard of care for asthma treatment and could put many patients at risk of uncontrolled asthma."

In the same article, Reuters reported that a spokesman for Schering-Plough Corp., which markets Foradil in the U.S., said the drug company "is still discussing the proposed label changes with the FDA."
 
In July 2005 an FDA advisory panel convened to investigate the safety of Serevent, Advair, and Foradil concluded that these three asthma drugs were safe enough to stay on the U.S. market.  This FDA advisory panel observed that Glaxo's Serevent and Advair already had a "black-box" warning on its package insert, or label, related to one study showing that Serevent patients had a higher, but relatively small, risk of life-threatening asthma attacks and deaths.  This advisory panel recommended to the FDA that Novartis's asthma medicine Foradil -- given that it was part of the same LABA class of drugs -- should also carry a similar black-box warning.

Asthma is a chronic lung disease that afflicts about 15 million Americans, nearly 5 million of them children. Severe asthma attacks can be fatal.

(Posted by: Tom Lamb)

"Black-box" Warnings On Drug Labels Often Ignored By Doctors And Patients

Study Indicates Need For Better Presentation of Drug-safety Information

On November 18, 2005 the medical journal Pharmacoepidemiology and Drug Safety published findings from a new study which reveals that doctors and patients, both, often ignore the content of "black-box" warnings on the package insert, or label, of certain prescription drugs.  The FDA requires that drug companies put this black-box warning on some drugs in order to emphasize significant drug-safety information.  The fact that doctors and patients are not paying attention to the content of some black-box warnings suggests that this method of warning about serious side effects in not working well.

The study found in the November 18 edition of Pharmacoepidemiology and Drug Safety was led by Anita Wagner, an assistant professor in the department of ambulatory care and prevention at Harvard Medical School.  Working with researchers from Harvard Medical School as well as several hospitals and health plans, Dr. Wagner's team reviewed claims data for approximately one million patients who were enrolled in ten health plans across the country. In particular, the researchers investigated the "compliance" rate of patients who received one of 19 prescription drugs that the FDA had required include a black-box warning on its label.

The researchers found that compliance with the warnings varied substantially -- from extremely good for certain prescription drugs for which a black-box warning states cannot be taken during pregnancy, to poor for some drugs with a black-box warning about required diagnostic tests.

Dr. Wagner said the study's results indicate to her that more specific black-box warnings -- such as do not use this drug during pregnancy -- resulted in higher compliance rates than black-box warnings that were relatively vague in nature.  Valproic acid, which is used to treat epileptic seizures, migraines, and bipolar disorder, was offered as an example of a vague, as opposed to specific, warning.  The package insert for valproic acid has a black-box warning about liver toxicity.  It states that liver tests should be performed "prior to therapy and at frequent intervals thereafter, especially during the first six months." The study led by Dr. Wagner found, however, that 48.6% of all valproic acid prescriptions were issued without any initial liver test, and that 29.5% of patients who filled a prescription for valproic acid did not get the ongoing liver tests.

When asked for comment, the FDA's Paul J. Seligman, who heads up the agency's post-marketing drug surveillance, said that the study by Dr. Wagner and her colleagues demonstrate the need for more research concerning the best method by which to give doctors and patients clearer warnings about serious side effects.

(Posted by: Tom Lamb)

ReoPro Stroke Trial Halted by Lilly and J&J Due To Emerging Safety Issue

Higher Risk of Brain Hemorrhage In Acute Ischemic Stroke Patients Treated With ReoPro

On October 28, 2005 Eli Lilly & Co. and Johnson & Johnson's Centocor unit announced that they had permanently stopped a late-stage trial of ReoPro, a blood-clot drug being investigated for the treatment of acute ischemic stroke patients.  The reason given by the drug companies was that an independent safety committee had found a higher-than-expected rate of brain hemorrhaging among the 808 patients enrolled in the trial.

The history of this emerging safety issue started in May 2005, when ReoPro treatment was stopped for a small arm of this ReoPro Phase III clinical trial because of a higher risk of brain hemorrhage. At that time, the independent safety committee recommended continuing enrollment for this ReoPro trial, but with a wider group of stroke patients.  Next, on October 4, 2005 Eli Lilly & Co. ("Lilly") and Johnson & Johnson ("J&J") said that they had temporarily suspended enrollment for this ReoPro clinical trial.  Then, in late October, after reviewing more data from the ReoPro trial, the safety committee recommended stopping enrollment permanently.

Lilly and J&J both said in late October 2005 that they agreed with the safety committee's recommendation to permanently discontinue enrollment in this ReoPro stroke trial.

As background, it is estimated that about 85 percent of all strokes are "ischemic", meaning that the stroke was caused by a blood clot or plaque that blocks a blood vessel in the brain. At present, there are drug therapies used to treat patients within three hours of suffering an ischemic stroke, but most patients fail to make it to the hospital within the three-hour window. Lilly and J&J said that the purpose of their ReoPro stroke trial was to study whether ReoPro could be use to treat patients who suffered their acute ischemic stroke at least four-and-a-half hours earlier, i.e., outside the three-hour window period.

Because the information about which stroke patients took ReoPro and not the placebo in this drug trial will not be revealed until March 2006, it is unknown at present how many of the stroke patients taking ReoPro suffered hemorrhaging.

ReoPro was approved by the FDA in 1994 for use when patients are undergoing heart procedures to clear clogged arteries. As part of their announcement in late October 2005 about the ReoPro stroke trial being halted, Lilly and J&J said they are not aware of any new data to question ReoPro's safety in the context of this approved use.

(Posted by: Tom Lamb)

Increasing Number of New Drug Trials Are Ended Early Due To Benefits Found

The Downside: Potential Safety Problems May Remain Hidden Until Later

The "News roundup" section of the November 12, 2005 edition of the British Medical Journal ("BMJ") included an article by Michael Day about how an increasing number of new drug trials are ended early "on the grounds that apparent treatment benefits have emerged rapidly".  While this may get the drug companies' new drugs to market quicker, an unfortunate result is that drug-safety issues associated with those new drugs might not be found until later -- at the expense of patients taking the new drugs.

Dr. Victor Montori recently led a group of researchers from McMaster University, Ontario, Canada, who reviewed 143 randomized controlled clinical trials sponsored by drug companies in connection with their respective new drugs.  According to Mr. Day's article, Dr. Montori's group determined that (a) "the proportion of randomised trials halted early has doubled in the past 10 years" and (b) "the scientific validity of the data they provide is not proved". 

In more detail, according to the November 12 BMJ article, Dr. Montori said that the drug companies "often fail to explain adequately why trials were stopped early and often claim 'implausibly large treatment effects, particularly when the number of events is small.'"  In the final analysis, Dr. Montori expressed his belief that “[t]hese findings suggest clinicians should view the results of such trials with scepticism."

For his BMJ article, Mr. Day sought comment about the review done by Dr. Montori and his group of Canadian researchers from Stuart Pocock, a professor of medical statistics at the London School of Hygiene and Tropical Medicine.  Professor Pocock asserted:

• “There is clear evidence from this review that some of these clinical trials have been stopped too soon. In some cases the researchers have shown a lack of judgment.” and,
• “It’s likely that in many cases doctors halted the trials because they wanted to give what they see as treatment benefits to all patients. But it could be that many more people are adversely affected in the long term if misleading results are given credence."

In concluding his BMJ article, Mr. Day made reference to an article this past spring by Richard Smith, a former editor of the BMJ, which appeared in PLoS Medicine.  As characterized by Mr. Day, the message of that earlier piece by Mr. Smith was "that leading medical journals had become an 'extension of the marketing arm of pharmaceutical companies' by inadvertently publishing selective research and results that favoured the products of trial sponsors."

Along these lines, one may recall how the New England Journal of Medicine ("NEJM") handled the publication of a study report concerning Provigil earlier this year.

(Posted by: Tom Lamb)

Safety Warning Issued For Ortho Evra Birth Control Skin Patch

FDA: Possible Increased Risk of Blood Clots For Ortho Evra Users

In November 2005 the FDA announced that it had approved an updated label, or package insert, for the Ortho Evra contraceptive patch.  The purpose of the label change was to warn doctors and patients that the Ortho Evra birth control patch exposes women to higher levels of estrogen than a typical birth control pill. In turn, because of the higher levels of estrogen, women using the Ortho Evra skin patch for birth control are at an increased risk of developing blood clots and other serious side effects.

The new label, or package insert for Ortho Evra, includes a bold-letter, or "bolded", warning about higher exposure to estrogen for women using the weekly patch compared to taking a typical birth control pill.

A November 10 FDA News Release gives us a summary of the blood clot problem associated with Ortho Evra:

The addition of this new warning is a result of FDA's and the manufacturer's analysis directly comparing the levels for estrogen and progestin hormones in users of Ortho Evra with those in a typical birth control pill. In general, increased estrogen exposure may increase the risk of blood clots. However, it is not known whether women using Ortho Evra are at a greater risk of experiencing these serious adverse events.

The new bolded warning specifically states that women who use Ortho Evra are exposed to about 60 percent more estrogen than if they were taking a typical birth control pill containing 35 micrograms of estrogen. However, the maximum amount of estrogen to which women are exposed is about 25% lower with Ortho Evra than they are with typical birth control pills.

According to Dr. Sidney Wolfe, the Director of Public Citizen’s Health Research Group, the FDA's action is too late and too little:

The new warning by the U.S. Food and Drug Administration (FDA) belatedly acknowledges the increased dangers of using the drug. These dangers were noted by the FDA physician who reviewed the drug before the agency approved it. Despite the fact that the agency has now admitted  that “women who use Ortho Evra are exposed to about 60 percent more estrogen than if they were taking a typical birth control pill” - important because increased estrogen means increased risks - the agency still allowed the drug on the market and is stubbornly unwilling to ban it.

The Ortho Evra contraceptive patch is made by Ortho-McNeil Pharmaceutical, Inc., which is a unit of the drug company Johnson & Johnson.  The Ortho Evra skin patch has been used by more than five million women for birth control since it was approved by the FDA in 2002.

Ortho McNeil is reportedly in the process of conducting additional drug-safety studies for Ortho Evra about the degree of increased risk for women using Ortho Evra patch -- in comparison to women using typical birth-control pills -- of developing blood clots and other serious side effects.

(Posted by: Tom Lamb)

Danish Study Suggests Celebrex And Vioxx To Be Avoided After Heart Attack

Increased Risk Of Death For Post-Heart Attack Patients Taking COX-2 Drugs

In mid-November 2005 it was reported that Merck's Vioxx and Pfizer's Celebrex, as well as some similar painkillers, increase the risk of death among patients who had a previous heart attack, especially when the painkillers were taken in high doses.  These findings from a Danish study were released November 13, 2005 at the American Heart Association conference in Dallas, Texas.

The findings come from a study which was funded by the Danish Heart Foundation and the Danish Pharmaceutical Association.  This Danish study is reportedly the first to look at patients with known heart problems.  The study's lead researcher, Dr. Gunnar Gislason, of the Bispebjerg University Hospital in Copenhagen, said at the Dallas conference this study indicates that patients who have heart disease should not use Celebrex or Vioxx, also called COX-2 inhibitors.

The November 2005 Danish study results showed that heart disease patients 25 milligrams ("mg") of Vioxx or more on a daily basis had a 5.03 times greater risk of dying when compared to those patients not taking any COX-2 drug. For Celebrex, those post-heart attack patients taking 200 mg of Celebrex or more daily had a 4.24 times greater risk of dying, while patients taking 200 mg of Celebrex or less had a 1.7 times greater risk.

A Merck spokesman, Chris Loder, was "quick" to criticize the Danish study -- insofar that no one at Merck, according to Mr. Loder, had seen Dr. Gislason's study.  Merck's spokesman pointed out that randomized controlled clinical trials are the preferred way of establishing the safety of a drug, and that this study conducted by Dr. Gislason was not of this type. Mr. Loder asserted, "Randomized controlled clinical trials are the gold standard."

As is well-known by now, Merck pulled Vioxx off the market in September 2004 after such a clinical study showed an apparent increased risk of cardiovascular problems, including heart attacks and strokes, for patients who took Vioxx for at least 18 months. Merck maintains, however, that neither the earlier study nor any other randomized controlled clinical trial has established that there is an increased risk of death from using Vioxx, i.e., Merck disputes what this Danish study headed up by Dr. Gislason has found, now.

According to news reports, no Pfizer executives were immediately available to comment on the Danish study and its findings about Celebrex.

The Gislason study was based on the researchers' review of medical records for more than 58,000 Danish patients who had their first heart attack between 1995 and 2002.

(Posted by: Tom Lamb)