Drug Injury Watch

New Jersey / NJ Vioxx Trial: Humeston Case Goes to Jury After Closing Arguments

Humeston v. Merck Verdict: Will The Jury Weigh In For The Plaintiff or Defense?

Today, after a seven-week trial, a New Jersey state court jury in the Humeston v. Merck Vioxx case should hear closing arguments from the plaintiff and defense attorneys.  Thereafter, the jury will begin their deliberations about whether to hold Merck liable in this closely watched Vioxx trial. 

The closing arguments had been scheduled for this past Friday, but were postponed until today in order to allow time for the plaintiff and defense lawyers to meet with New Jersey State Superior Court Judge Carol E. Higbee for the purpose of discussing jury instructions and other legal issues.  It was reported that, in part, the lawyers met with Judge Higbee to discuss jury instructions for New Jersey's Consumer Fraud Act and New Jersey's Products Liability Act, the statutory bases for the legal claims in the Humeston v. Merck case.

As background, Idaho postal worker Frederick "Mike" Humeston sued Merck & Co. for the heart attack he suffered Sept. 18, 2001. At this New Jersey Vioxx trial, Merck apparently acknowledged that there is a link between Vioxx and heart attacks, but only after 18 months of Vioxx use.  Merck's  defense in the Humeston case, however, is that Mr. Humeston took Vioxx for only two months.  Moreover, Merck asserts that Mr. Humeston had the 2001 heart attack because of his own health problems, not as a result of taking Vioxx.

After the Octorber 31, 2005 closing arguments, Judge Higbee will instruct the jury on the relevant legal issues, and then the jury will begin their deliberations in Humeston v. Merck.

We will keep you posted on the outcome of this second Vioxx trial.

(Posted by: Tom Lamb)

FDA Probably Will Not Require Longer Studies Of New Psychiatric Drugs

Advisory Panel Rejects FDA Proposal: Good Idea, But Wrong Approach

In late October 2005 an FDA advisory panel rejected the agency's recent proposal that would have required the drug companies to do longer-term studies before any new psychiatric drug could be brought to market in the U.S.

The FDA had convened this advisory panel to discuss the agency's proposal whereby before a new psychiatric drug would be approved for use in the U.S. the drug companies would be required to submit "longer-term efficacy data".  The FDA proposal covered any new prescription drugs that are intended to treat:

• depression;
• bipolar disorder;
• schizophrenia; and,
• a range of other psychiatric illnesses.

Rather than voting on the entire proposal, however, the FDA advisory panel stopped after voting (12-0) against one part of the proposal that would have required long-term efficacy data for new psychiatric drugs intended to treat major depressive disorder, the first category listed above.  The panel decided to not vote on whether the proposal should be applied to the several other psychiatric disorders categories listed above.  Instead, the advisory panel said the FDA should consider each psychiatric disorder separately -- as the panel itself did with its lone vote concerning the depression category -- as opposed to the FDA arguably pushing a "one-size-fits-all" approach, i.e., covering all the new psychiatric drugs.

As expected, the pharmaceutical industry argued against any proposal requiring long-term efficacy studies before a drug is approved.  Essentially, representatives from several drug companies, including Merck & Co., Pfizer Inc. and GlaxoSmithKline PLC, argued that the FDA proposal would delay the already lengthy process of developing new psychiatric drugs. 

Previously, in an earlier piece about the FDA psychiatric drug proposal, we had concluded with this remark: "We will watch to see whether the FDA stands its ground against Big Pharma on this change in course as regards the approval of new psychiatric drugs."  Seemingly, we now have our answer.

The FDA will "very likely" take the advisory panel's suggestion, said Dr. Thomas Laughren, the FDA's director of the division of psychiatry products. Further, Dr. Laughren said that if and when the FDA ever establishes any new requirements for psychiatric drug studies, such a change would likely be customized for each type of psychiatric disorder -- as the panel advisory suggested.

In more detail, the FDA advisory panel members were unanimous in taking the position that the agency's current procedure -- allowing the drug companies to conduct their long-term studies on a drug's effectiveness in treating psychiatric illnesses after the drug is approved -- was superior to the recent FDA proposal.

This advisory panel was chaired by Dr. Wayne Goodman, the chairman of the psychiatry department at the University of Florida. Dr. Goldman acknowledged to reporters that he was concerned the public might "misinterpret" the advisory panel's vote as being generally against what would appear to be an FDA proposal "to raise the bar" on data required for new psychiatric drug approvals. Attempting to clarify the situation, Dr. Goldman said the panel's "No" vote was more about the fact that the panel had disagreed with the FDA's "one-size-fits-all" approach, and that the advisory panel was not against the underlying idea about a need for some change.

In fact, a few of the advisory panel members remarked that the FDA should be able to require that the drug companies provide long-term efficacy data within two years of their new psychiatric drug being approved and made available in the U.S. market -- which, to the surprise of some, the FDA cannot do at present.

(Posted by: Tom Lamb)
            

"Off-label" Prescribing of Psychosis Drugs For Alzheimer's Has Risks

Careful Consideration Needed When Prescribing Zyprexa or Risperdal for Alzheimer's-related Dementia

Elderly patients with Alzheimer's disease who are prescribed antipsychotic drugs such as Zyprexa and Risperdal have a higher risk of dying than patients who are given a placebo such as sugar pills according to a new meta-analysis of earlier drug-safety studies.

The new study appeared in the October 19, 2005 (Vol. 294 No. 15) edition of the Journal of the American Medical Association ("JAMA"). Lead investigator Lon S. Schneider, of the University of Southern California, said his meta-analysis of 15 trials involved about 5,000 patients.  His study found that the risk of death rose from 2 percent to 3 percent for patients taking the antipsychotic drugs in clinical studies that lasted about 12 weeks. Schneider observed that most of the patient deaths came from cardiac problems or respiratory disorders.  These findings lend support to the FDA's decision earlier this year to require new warnings on the package inserts, or labels, for Zyprexa and Risperdal.

Significantly, Zyprexa and Risperdal were approved by the FDA for treatment of psychoses in adults.  These drugs, however, have not been specifically approved for use among elderly patients with dementia.  As such, doctors are engaging in "off-label" prescribing when they have their dementia patients take these antipsychotic drugs, i.e., doctors prescribing Zyprexa or Risperdal for this group are relying on their clinical judgment.

Peter V. Rabins, a professor of psychiatry at Johns Hopkins University School of Medicine, reviewed the new meta-analysis by Schneider and wrote an editorial about it in the same October 2005 edition of JAMA in which the study is published.  In an October 19, 2005 article by Washington Post reporter Shankar Vedantam, Dr. Rabins commented:

These medications are only modestly effective and have significant side effects associated with them.  The drugs should not be used for trivial problems like difficulty sleeping at night and anxiety.  Clinicians first need to really weigh the potential risks and benefits in deciding whether the potential harm from the symptoms is worth the risk.

About 4 million to 5 million Americans are diagnosed with Alzheimer's disease, a degenerative brain disorder.  It is estimated that a third of those patients are given antipsychotic drugs.

Samuel E. Gandy is chairman of the medical and scientific advisory council of the Alzheimer's Association, a nonprofit research and advocacy group.  He believes the new study by Schneider emphasizes the fact that careful consideration must be used when prescribing Zyprexa or Risperdal for dementia.  "It should make physicians cautious when putting patients with dementia or any frail patient on medicines of this sort that are basically major tranquilizers," Gandy said, according the October 19 Washington Post article.

The consensus among experts in the field seemed to be that this new study should help doctors better weigh the risks and benefits of this off-label prescribing practice.

(Posted by: Tom Lamb)

Public Citizen Petitions FDA To Add Black-Box Warning On Impotence Drugs

Erectile Dysfunction Drugs Viagra, Cialis, and Levitra Linked to NAION Vision Loss

In mid-October 2005 the consumer-advocacy group Public Citizen petitioned the FDA to add a "black-box" warning to the labels of Pfizer Inc.'s Viagra and other impotence or erectile dysfunction ("ED") drugs.  This action was based on reports of ED users who have gone suddenly blind, some permanent and some reversible cases.  In July 2005 the FDA had ordered the respective drug companies to add some new warnings which noted that some users of Viagra, Cialis, and Levitra have suffered sudden vision loss.  Those revised labels, however, "cautioned" that it was not possible to know whether or not the Viagra, Cialis, or Levitra was to blame for the blindness.

Now, Public Citizen wants the more prominent and top level black-box warning added to the package inserts, or labels, for the several ED drugs -- Viagra (Eli Lilly and Co.), Cialis (ICOS Corp.), and Levitra (co-marketed in the U.S. by Schering-Plough Corp. and GlaxoSmithKline PLC) -- and one hypertension drug, Revatio (Pfizer) -- which is similar to Viagra.

There have been reports about users of Viagra, Cialis, and Levitra who have developed NAION, or nonarteritic ischemic optic neuropathy, a loss of vision that is frequently irreversible. It needs to be noted, however, that NAION is considered a relatively common cause of sudden vision loss in older people.  Among the risk factors are diabetes and heart disease -- which are also two of the leading causes of impotence.  The occurrence rate of NAION is 1,000 to 6,000 new cases a year.

As reported by the Associated Press on October 20, 2005:

"It is the Food and Drug Administration's job to immediately and coherently tell consumers about the risks associated with the drugs they put into their bodies," said Sidney Wolfe, director of Public Citizen's Health Research Group. "The agency has once again failed in this responsibility. These drugs need much stronger warnings, especially a black box warning such as the one we have proposed."

In July 2005 the FDA had this guidance for the use of impotence drugs:

• Tell your doctor if you have ever suffered an episode of sudden vision loss, because such patients are at increased risk of a second episode; and,
• You should stop taking the ED pills (Viagra, Cialis, and Levitra) and call a doctor if you experience any sudden or decreased vision loss in one or both eyes.

According to the Public Citizen petition, apart from the 50 cases of NAION that have been reported to the FDA for these drugs, there have been another 60 cases of optical side-effect conditions.  Public Citizens informs us that these reports include "blindness, blindness unilateral visual field defect, scotoma, or optic nerve infarction".

(Posted by: Tom Lamb)

After Two-year Search, FDA Names New Director For Office of Drug Safety

FDA Scientist Gerald Dal Pan Will Be Director of FDA Drug-Safety Office

In October 2005 the FDA named staff scientist Gerald Dal Pan its new director of the agency's Office of Drug Safety.  This FDA department watches for serious side effects after prescription drugs are approved by the FDA to go on the U.S. market.

Significantly according to the FDA, Dr. Dal Pan will report directly to the head of the FDA's Center for Drug Evaluation and Research -- whereas under the current FDA bureaucracy, the agency's drug-safety office had reported to another division within the FDA.

It is old news by now that the public's perception of the "independence" of the FDA's Office of Drug Safety had started to erode in 2004 with the FDA's handling of safety issues involving the use of antidepressants by children and heart problems associated with the use of Vioxx and other COX-2 drugs.

While the new FDA bureaucratic scheme may raise the drug-safety office's profile within the agency, not all FDA critics are satisfied.  Senator Charles E. Grassley, who is chairman of the Senate Finance Committee, said in a statement:

The [Office of Drug Safety] needs to be able to make judgments that aren't affected by the conflicts of interest existing within the office of new drugs.

Dr. Gerald Dal Pan joined the FDA in 2000.  Dr. Dal Pan is trained in neurology and internal medicine, and has worked as a drug-safety reviewer.

(Posted by: Tom Lamb)

FDA Wants Longer Studies Done Before Approving New Psychiatric Drugs

Will The FDA Stand Its Ground Against Big Pharma On This Change In Course?

Leila Abboud and Anna Wilde Mathews, of The Wall Street Journal ("WSJ"), reported on October 18, 2005 that the FDA is considering whether drug companies submitting new psychiatric drugs for approval should be required to perform longer drug studies than have had to be done previously.

In their WSJ article, Ms. Abboud and Ms. Mathews point to documents they found on the FDA's web site which indicate that for the past six months the FDA has been asking drug companies to provide "longer-term efficacy data" for psychiatric drugs intended for the treatment of chronic conditions.  According to Thomas Laughren, acting director of the FDA's division of psychiatry products, however, the change in course has met with some resistance from drug companies and clinical researchers who contend that such a change will slow the development process for new psychiatric drugs.

David Michelson, executive director for neuroscience medical research at Eli Lilly & Co., called the FDA's change in course a "stepping up of requirements for psychiatric drugs" and said further:

If you require that chronic studies be done prior to filing a new drug application, you have potential to delay the approval of new drugs significantly. That has implications for patients.

The FDA will discuss the intended change requiring longer drug studies of new psychiatric drugs -- namely, antidepressants, antipsychotics, and other drugs for long-term psychiatric conditions -- at an advisory panel meeting scheduled for October 25, 2005.  The discussion will include how such studies should be designed, about which the FDA's Dr. Laughren commented: "It's a very important clinical question."

It is reported that representatives of several drug companies, including Eli Lilly & Co. and GlaxoSmithKline PLC, plan to testify at this FDA advisory panel meeting.

Up until the recent change in course, Dr. Laughren said that the FDA only required relatively short studies, typically less than three months, before a psychiatric drug might get marketing approval from the FDA. Thereafter, the submitting drug company would conduct post-marketing studies concerning safety and efficacy.

According to the October 2005 WSJ article by Abboud and Mathews:

Now, the FDA is considering whether such longer-term studies, which can take two to three years altogether for depression patients, should be required before a drug goes on the market. The agency has long been moving toward such a requirement, Dr. Laughren said. But the limited data available during last year's debate over possible risks of antidepressants to young patients, which centered on short-term trials, helped to spark action on the issue, Dr. Laughren said.

Apparently, some European Union drug regulators already require that the longer drug studies -- similar to what the FDA is proposing -- be submitted prior to the granting of market approval for new psychiatric drugs in certain EU countries.  For this reason and others, the WSJ article concluded that the FDA's new proposal, or approach, regarding psychiatric drug approval would not result in significant increased costs for the submitting drug companies.

We will watch to see whether the FDA stands its ground against Big Pharma on this change in course as regards the approval of new psychiatric drugs.

(Posted by: Tom Lamb)

Eli Lilly Sends "Dear Doctor" Letter Regarding Cymbalta and Liver Injury

FDA Warning: Cymbalta May Cause Liver Damage For Patients With Chronic Liver Disease

On October 17, 2005 the FDA and Eli Lilly & Co. said in a MedWatch drug alert that the antidepressant Cymbalta (duloxetine hydrochloride) should not be used in patients with preexisting liver problems because Cymbalta might worsen the underlying liver condition.

The package insert, or label, for Cymbalta had already warned about the possibility of liver injury.  In an October 5, 2005 "Dear Doctor" letter, Lilly is informing prescribing doctors that patients with underlying liver disease should not be prescribed Cymbalta based on "several reports" of liver injury made to the FDA and Lilly.  There have also been reports of Cymbalta-induced jaundice, a liver disorder that can cause the yellowing of the skin and eyes. "Review of these cases suggests that patients with underlying chronic liver disease may be at increased risk" of liver damage with Cymbalta, Lilly said in the Dear Doctor letter.

This October 5 letter from Lilly also advises doctors not to prescribe Cymbalta to patients "with substantial alcohol use" because postmarketing drug-safety studies have shown that some patients experienced liver damage when they consumed Cymbalta and alcohol.

The FDA MedWatch safety alert for Cymbalta, which was posted on the FDA's web site on October 17, said that Cymbalta has been associated with increased risk of liver injury in patients with chronic liver disease.  In relevant part, the MedWatch alert stated:

Postmarketing reports of hepatic injury (including hepatitis and cholestatic jaundice) suggest that patients with preexisting liver disease who take duloxetine may have an increased risk for further liver damage. The new labeling extends the Precaution against using Cymbalta in patients with substantial alcohol use to include those patients with chronic liver disease. It is recommended that Cymbalta not be administered to patients with any hepatic insufficiency.

Cymbalta was first approved by the FDA in August 2004 to treat major depressive disorder. Since then the FDA has approved Cymbalta for treatment of diabetic peripheral neuropathic pain, or nerve pain associated with diabetes. More than one million patients have been prescribed Cymbalta, according to Lilly.

(Posted by: Tom Lamb)

FDA To Hold Two-Day Direct-To-Consumer Advertising Meeting In November 2005

Public Meeting to Review Rules Concerning Prescription Drug DTC Advertisements

The FDA is considering revising rules about, first, how much side-effect risk information prescription drug commercials must include and, second, whether all direct-to-consumer ("DTC") advertisements must be reviewed by the FDA before being broadcast or published.

On November 1 and November 2, in Washington, D.C. the FDA is convening a public meeting with patients, doctors, drug companies, and others to discuss possible changes to its marketing requirements for DTC materials. According to a September 13, 2005 Federal Register notice about the two-day meeting -- which noted the current lack of regulations specific to DTC advertising, as opposed to marketing material directed to doctors -- the FDA will ask whether "the indications of a drug or device can be effectively communicated to a lay audience under the confines of DTC promotion and, in particular, whether the limitations of benefit can be properly communicated".

Recently, Thomas Abrams, head of the FDA's Division of Drug Marketing, Advertising, and Communications, told food and drug regulatory lawyers at a Washington conference the FDA knows that the quality of DTC consumer ads has deteriorated during the last several years, but the FDA has no power to review those ads before they are broadcast or published.  Rather, under the current regulations, the drug companies are required to submit their DTC advertisements for FDA review only at the time of broadcast or publication. Some drug companies have voluntarily provided the advertisements for FDA review before the circulate, and at the November 2005 public meeting the FDA will be considering whether that pre-circulation review should become mandatory.

Television pharmaceutical ads, which first hit the U.S. airwaves in 1997, are apparently of particular concern to the FDA.  "The tone at times is trivializing the risk of the drugs," said the FDA's Thomas Abrams.

In August 2005, Pharmaceutical Research and Manufacturers of America (PhRMA) President Billy Tauzin, said the DTC ads need to improve.  To that end, PhRMA has released some voluntary DTC ad guidelines.  The industry proposal includes plans to voluntarily submit DTC ads to the FDA sooner. PhRMA's new DTC ad guidelines also aim to provide more balanced risk information, Tauzin said.

FDA officials have said that the PhRMA DTC ad guidelines will be discussed during the November 2005 public meeting.  "We're hopeful that this first step by PhRMA represents a growing commitment by the industry to raise the quality of (consumer advertising)," the FDA's Abrams said.

As outlined in the Federal Register notice about this public meeting, the FDA will collect public input on whether current direct-to-consumer promotion of medical products disseminates information in an "accurate, nonmisleading, balanced and understandable" manner.  Additionally, "the agency is interested in hearing why consumers and healthcare providers may believe that risk information is not being communicated as clearly as benefit information, even though that information is present" in advertising.

On another aspect, according to the Federal Register notice, during the two-day meeting the FDA will consider whether changes to the presentation of a medical product's package insert - or "brief summary" - in print advertising and inclusion of a "major statement" in broadcast advertising could "improve the usefulness of this information for consumers".

Finally, the FDA will ask the meeting participants to address how the agency should respond to novel approaches to DTC advertising by drug companies in the future.

(Posted by: Tom Lamb)

1500 New Vioxx Lawsuits Filed Against Merck Since Late August

3,481 NJ Vioxx Cases, 2625 MDL Cases, 450 "Others": October 2005 AP Report

Reporter Linda A. Johnson, through the Associated Press ("AP"), informed us on October 13, 2005 that Merck now faces more than 6,500 Vioxx lawsuits, up from about 5,000 Vioxx cases reported in Merck's last update on the Vioxx litigation. 

The new Vioxx lawsuit total includes 3,481 Vioxx cases that were filed in the New Jersey state court system as of October 13, 2005.  More than 1,000 new Vioxx cases have been filed in New Jersey since late August 2005, including 800 new Vioxx lawsuits in September 2005.

Turning to the federal court Vioxx Multi-district Litigation ("MDL"), there are 500 new cases that have been filed since late August 2005, according to the AP's October 13 article.  In total, there are 2,200 federal Vioxx cases already filed, and about another 425 Vioxx cases recently transferred to the federal court Vioxx MDL, which is being handled by the Eastern District of Louisiana -- which currently has its court personnel working in Houston, due to Hurricane Katrina.

Lastly, according to the AP's report by Linda Johnson, another 450 Vioxx cases were pending in various state courts other than New Jersey as of August 15, 2005.

Nearly all of the Vioxx lawsuits filed to date are based on product liability legal theories. As personal injury or wrongful death suits, however, these Vioxx cases are subject to many different filing deadlines, called the "statute of limitation", across the nation.  It is speculated that most of the recently filed Vioxx lawsuits involved Vioxx plaintiffs who resided in Kentucky, Louisiana, and Tennessee, where people apparently had a one-year statute of limitation using the "discovery rule".  As such, these Vioxx lawsuits had to be filed before September 29, 2005 -- because Merck pulled Vioxx from the market on September 30, 2004.

For the most part, individual Vioxx lawsuits have been filed with the underlying Complaint alleging that Vioxx caused cardiovascular problems, including heart attacks and ischemic strokes. These personal injury lawsuits and wrongful death lawsuits seek legal compensation for people who have been injured by their use of Vioxx. 

In contrast, there are some filed (potential) class action lawsuits that seek future medical monitoring costs reimbursement for Vioxx users who have not yet had any injury from their use of Vioxx. 

Rather brashly, in the face of it all, Merck says it has set aside financial reserves of $675 million for its legal defense costs, but (Merck asserts) has not set up any compensation fund to pay for Vioxx settlements or jury awards against the drug company.

What about the massive verdict from the first Vioxx trial in Texas?

(Posted by: Tom Lamb)

Trileptal May Cause Toxic Epidermal Necrolysis and Stevens Johnson Syndrome

Trileptal-induced TEN, SJS, and Hypersensitivity Reactions Reported to FDA

In April 2005 the FDA and Novartis Pharmaceuticals Corp. issued a MedWatch safety alert about the risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with use of Trileptal (oxcarbazepine) in adults and children. Information regarding numerous reports of these serious skin reactions, as well as a limited number of multi-organ hypersensitivity reactions that have been reported to the FDA, was set forth in an April 18, 2005 "Dear Doctor" letter concerning Trileptal.

Trileptal, which comes in tablet form and as an oral suspension, is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and in children aged four to 16 years.

According to the April 2005 FDA MedWatch alert about Trileptal, there have been reports of serious and potentially life-threatening dermatologic reactions, including SJS and TEN, in adult and pediatric patients receiving Trileptal. According to the FDA and Novartis, the median time of onset was 19 days and some patients required hospitalization to treat the most serious of the serious skin reactions.

The incidence of reports about Trileptal-induced Stevens-Johnson syndrome and toxic epidermal necrolysis made through the FDA Adverse Events Reporting System ("AERS") -- which reporting level is generally considered an underestimate due to the widely-held belief that only ten percent of adverse events are ever reported to the FDA -- exceeds the background incidence rate estimate (0.5 - 6.0 cases/million person-years) for SJS and TEN by a factor of 3- to 10-fold.  Due to the general "under-reporting" problem, the real factor number is probably significantly higher.

Replacement of Trileptal with another antiepileptic medication should be considered in patients who develop a serious skin reaction during Trileptal treatment.

Multi-organ hypersensitivity reactions have also been reported after initiation of Trileptal therapy in adult and pediatric patients, with a median time to detection of 13 days (range, 4 - 60 days). Although the number of hypersensitivity reaction reports is limited, many of these patients required hospitalization, some for life-threatening conditions.

Signs and symptoms of the Trileptal-induced hypersensitivity reactions were diverse due to the variable nature of disease expression, but patients typically presented with fever and rash associated with other organ system involvement. Manifestations included -- but were not limited to -- lymphadenopathy, hepatitis, liver function test abnormalities, hematologic abnormalities (eosinophilia, thrombocytopenia, neutropenia), pruritis, nephritis, oliguria, hepatorenal syndrome, arthralgia, and asthenia.

Replacement of Trileptal with alternative therapy is recommended if multi-organ hypersensitivity is suspected.

(Posted by: Tom Lamb)