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• Advair: � This asthma medication contains the long-acting beta-agonist (LABA) salmeterol. � A 2006 study of 19 trials, which was published in the Annals of Internal Medicine, revealed that with regular use, LABAs can increase asthma attack severity. � Salmeterol is more widely prescribed than other LABAs, thus the danger is greater and may contribute to as many as 5,000 asthma-related deaths in the United States annually. � Another study that same year led the US Food and Drug Administration (FDA) to label Advair with a "black box,” the FDA’s strongest warning. �
• Avandia: � In September, the Journal of the American Medical Association (JAMA) revealed in a study that those taking diabetes drug Avandia—or rosiglitazone—for at least one year suffered an increased risk of heart failure (109 percent) or a heart attack (42 percent). � One possible reason is that Avandia may cause dangerous fluid retention or raise artery-clogging LDL cholesterol. � The FDA asked Avandia maker, GlaxoSmithKline, to conduct a long-term study assessing users' heart risks; however, that study is not expected to commence until later this year.
• Celebrex: � This pain medication is linked to increased risks of stomach bleeding, kidney trouble, and liver damage. � According to a 2005 New England Journal of Medicine study people taking 200 mg of Celebrex twice daily more than doubled their risk of dying of cardiovascular disease; those on 400 mg twice daily more than tripled their risk. � By the way, two other drugs in this drug class—Bextra and Vioxx--were banned for similar heart damage risks, yet Celebrex remains available.
• Ketek: � This antibiotic, generally prescribed for respiratory-tract infections, carries a higher risk of severe liver side effects, has been linked to heart-rhythm problems and liver disease, and can interact with other medications. � Although still prescribed, the FDA limited Ketek’s usage to the treatment of pneumonia early last year.
• Prilosec and Nexium: � The FDA has investigated a suspected link between cardiac trouble and acid-reflux drugs Prilosec and Nexium. � Also, because both drugs are proton-pump inhibitors, they may be overly effective at stopping stomach acid production, raising pneumonia, bone loss risk, and fracture risk (this, by over 40 percent in patients on long-term use).
• Original Visine: � Because Visine shrinks ocular blood vessels in the same way Afrin does nasally, overuse of its active ingredient tetrahydrozoline can create an endless loop of vessel dilating-and-constricting that may cause more redness, increasing the need for more Visine, causing more redness, and so on.
• Pseudoephedrine: � Other than that this decongestant is a critical component in methamphetamine, it can raise blood pressure and heart rate, has been linked to heart attacks and strokes, and can increase symptoms of benign prostate disease and glaucoma.

Ketek was approved by the FDA in 2004 to treat respiratory tract infections, bronchitis, sinusitis and community-acquired pneumonia. Soon after its approval however, the FDA began to receive reports that Ketek was causing liver damage in some patients. This past February, the FDA added black box warnings about liver damage to the Ketek label. In total, the FDA had reports of at least 53 cases of liver damage linked to Ketek. At least five of those cases were fatal, and one required a liver transplant. The FDA also withdrew Ketek’s approval to treat sinusitis and bronchitis.

In February, the subcommittee issued subpoenas to Health and Human Services (HHS) Secretary Michael Leavitt, asking him to produce unredacted records prepared for the FDA commissioner’s appearance at a March 2007 hearing on Ketek. Leavitt’s department oversees the FDA. The committee also approved subpoenas for two current FDA investigators, one former FDA investigator and a former employee of a company that monitored the fraudulent Ketek clinical trials. The subpoenas were necessary because the Bush Administration had refused to release the documents or allow any of the officials to testify. At first Leavitt refused to turn over the documents, but finally gave in when he was threatened with Contempt of Congress charges.

Those documents in question deal with FDA Commissioner Andrew von Eschenbach's written testimony regarding events surrounding the Ketek drug approval. According to an article on the American Chronicle website, the committee subsequently learned from an FDA insider and those familiar with the approval that the testimony was not truthful.

According to American Chronicle "Von Eschenbach is a cancer-industry insider who took the job at the FDA so he could get quick approval of new biotech drugs while using humans for cruel experiments in the name of "progress." His nomination as permanent head of the FDA took place during the 2006 lame duck session of Congress and was rubber stamped by Big Pharma friendly Senators."

During Von Eschenbach's confirmation hearings, Senator Charles Grassley, a Republican, criticized the Bush Administration on the floor of the Senate for naming Von Eshenbach to head the FDA. "People ought to be ashamed of saying Dr. Andrew von Eschenbach has done a superb job in the position he is currently occupying [acting head of the FDA].…That is an insult….In my interactions with the Department of Health and Human Services and the FDA these last 8 months, I have seen a complete and utter disrespect for congressional authority and hence the law.… This body [the Senate] should not walk hand in hand with the executive branch and sit idly by as instances of abuse and fraud continue to endanger the health and safety of American people," Grassley said. 

If Americans "knew how little the FDA did to assure the food and drug supply, if the truth ever came out...people would be marching in the street," Stupak told The Wall Street Journal recently. "That's (Accutane) just one drug. There are many like that," Stupak says. � Now, as the FDA is under fire for mistakes over international inspections and other issues, Stupak—an eight-term Democratic congressman and chairman of the Subcommittee on Oversight and Investigations of the House's powerful Energy and Commerce panel, which has jurisdiction over the FDA—is at the center of an aggressive effort by congressional Democrats to spotlight what they say are problems with the Bush administration's position on consumer-safety issues. �

Stupak's subcommittee is probing the FDA's handling of Baxter International Inc.’s heparin, the blood-thinning drug that has been potentially linked to hundreds of patient reactions and four deaths. � The subcommittee is also examining Pfizer Inc.'s Lipitor, Vytorin from Schering-Plough Corporation and Merck & Company, and anemia drugs sold by Amgen Inc. and Johnson & Johnson. � Ketek, an antibiotic from Sanofi-Aventis SA, has been under review for over a year. � Stupak is holding hearings on the safety of imported food, medicines, and medical devices and says he has a bigger agenda adding, that "It's a broken agency."

Stupak called for the resignation of FDA commissioner, Andrew von Eschenbach and other top officials and says that step has nothing to with partisan politics, adding that Republican Senator Tom Coburn of Oklahoma—a medical doctor—would be a good replacement. � Coburn's opposition to abortion rights would make him unacceptable to many Democrats.

Democratic lawmakers are expected to pass only limited legislation this year, with the Senate divided and President Bush resisting some Democratic initiatives. � Republicans complain that some of the Democrats' moves seem aimed at getting attention, such as Representative Michael Burgess, a Texas Republican and a member of Stupak's subcommittee. � Burgess says he wants the FDA examined, but "sometimes it just seems like we want to call names and point fingers, not pursue solutions."

von Eschenbach, who was confirmed to lead the FDA in late 2006, says they introduced a new food-safety plan, hired a chief information officer to manage information technology issues, and are working to install inspectors in countries including China and India. � The Bush administration's budget included a proposed increase for the FDA.

Stupak and Representative John Dingell, the Michigan Democrat who is chairman of the full Energy and Commerce panel, say the investigations are building a case for broader efforts to overhaul the FDA. � Dingell says he plans far more ambitious FDA legislation, "The import bill is a good beginning, but it isn't far enough." � Stupak says he'd like to look at granting the FDA subpoena power, regulating drug-industry consumer ads, and increasing the agency's funding. 

Ketek was approved by the FDA in 2004 to treat respiratory tract infections, bronchitis, sinusitis and community-acquired pneumonia. � � Soon after its approval however, the FDA began to receive reports that Ketek was causing liver damage in some patients. � � This past February, the FDA added black box warnings about liver damage to the Ketek label. � In total, the FDA had reports of at least 53 cases of liver damage linked to Ketek. � At least five of those cases were fatal, and one required a liver transplant. � The FDA also withdrew Ketek’s approval to treat sinusitis and bronchitis.Earlier this month, the subcommittee issued subpoenas to Health and Human Services (HHS) Secretary Michael Leavitt, asking him to produce unredacted records prepared for the FDA commissioner’s appearance at a March 2007 hearing on Ketek. Leavitt’s department oversees the FDA. � The committee also approved subpoenas for two current FDA investigators, one former FDA investigator and a former employee of a company that monitored the fraudulent Ketek clinical trials. � The subpoenas were necessary because the Bush Administration had refused to release the documents or allow any of the officials to testify.

Rep. John Dingell (D-Mich), chairman of the committee, said yesterday he would consider holding Leavitt in contempt after the HHS Secretary refused to turn over the FDA briefing documents subpoenaed by the committee. � The documents were used to prepare FDA Commissioner Andrew von Eschenbach for his appearance before lawmakers last year.

The Ketek briefing documents might include information regarding a Sanofi-Aventis Ketek study that was rife with fraud. � When the FDA audited Ketek study participants recruited by the drug’s maker Aventis (now Sanofi-Aventis) they found one family doctor in a small Alabama town had signed up 407 patients for the study. The doctor’s entire staff was enrolled in the trail, and it even appeared that some of the patient signatures on consent forms where forged. Eventually, that doctor was charged with fraud, and sentenced to prison. The FDA also visited several other sites with high numbers of participants, and found serious irregularities at every one.

That study prompted the FDA to issue Sanofi-Aventis a warning letter, but the fraud did not keep Ketek off the market. � Last year, Von Eschenbach testified that the FDA did not use the flawed safety study to approve Ketek. � Dingell and others on the committee say that statement may be untrue, and they need access to the briefing documents to make that determination.

At yesterday’s Ketek hearing, lawmakers heard from three government staffers who were also issued subpoenas. � Robert West, an FDA agent who first investigated Ketek, said he tried to get permission in 2002 to look into whether Aventis was aware of fraudulent data when it submitted the study. West said his request was blocked by senior FDA officials, although he said he did not know which ones. 

Ketek was approved by the FDA in 2004 to treat respiratory tract infections, bronchitis, sinusitis and community-acquired pneumonia. � � Soon after its approval however, the FDA began to receive reports that Ketek was causing liver damage in some patients. � � This past February, the FDA added black box warnings about liver damage to the Ketek label. � In total, the FDA had reports of at least 53 cases of liver damage linked to Ketek. � At least five of those cases were fatal, and one required a liver transplant. � The FDA also withdrew Ketek’s approval to treat sinusitis and bronchitis.

At the same time, the FDA updated the Ketek label to include information about reports of fatal worsening of the neuromuscular condition, myasthenia gravis. At the time of the label change, the FDA knew of three reported deaths in myasthenia gravis patients taking Ketek.

Many Ketek critics say the dangerous antibiotic should never have been approved for use because of the widespread fraud committed by doctors involved in the drug’s clinical trials. � � When the FDA audited Ketek study participants recruited by the drug’s maker Aventis (now Sanofi-Aventis) they found one family doctor in a small Alabama town had signed up 407 patients for the study. The doctor’s entire staff was enrolled in the trail, and it even appeared that some of the patient signatures on consent forms where forged. Eventually, that doctor was charged with fraud, and sentenced to prison. The FDA also visited several other sites with high numbers of participants, and found serious irregularities at every one.

In October, the FDA sent a Warning Letter to Sanofi-Aventis, outlining various instances of misconduct by doctors involved in the Ketek clinical trial, and criticizing the drug maker for ignoring those issues. � But it appears the FDA ignored the fraud as well, because it still approved Ketek in spite of the irregularities found in the clinical trials.

The congressional subcommittee has been trying to figure out why the FDA went ahead and did so. � � But the FDA hasn’t been very cooperative, so the subcommittee was forced to take the drastic action of issuing subpoenas. � "Unfortunately, the FDA has been less than forthcoming with either witness or document production in connection with our drug safety investigations," said Rep. Bart Stupak, the Democratic chairman of the subcommittee on oversight and investigations.

Yesterday, the subcommittee voted 12-0 to issue a subpoena to Health and Human Services (HHS) Secretary Michael Leavitt, asking him to produce unredacted records prepared for the FDA commissioner's appearance at a March 2007 hearing on Ketek. Leavitt's department oversees the FDA. � � The FDA and HHS have refused to provide those documents in the past.

The panel also approved subpoenas for two current FDA investigators, one former FDA investigator and a former employee of a company that monitored the fraudulent Ketek clinical trials. � The lawmakers want 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.

The subcommittee will hold a third hearing into the Ketek debacle on February 12. 

Shortly after its approval, Ketek was linked to serious side effects, including sometimes fatal liver damage. The FDA eventually confirmed 53 cases of liver failure in patients using Ketek, including five deaths. This past February, the FDA finally added black box warnings to the Ketek label and severely restricted its use.

Congressman Bart Stupak and John Dingell, both Michigan Democrats, want to know why Ketek was able to be approved even though the FDA found instances of serious fraud in its clinical trials. Doctors participating in those clinical trials were paid $400 by Aventis (now part of Sanofi-Aventis) for every patient they convinced to participate in the Ketek study.

That huge financial incentive was too much for some doctors to resist. When the FDA audited study participants, they found one family doctor in a small Alabama town had signed up 407 patients for the study. What else they found during the audit at Dr. Ann Campbell’s was shocking. The doctor’s entire staff was enrolled in the trail. It even appeared that some of the patient signatures on consent forms where forged. So gross were Dr. Campbell’s violations that she was eventually convicted of fraud and sentenced to prison. The FDA also visited several other sites with high numbers of participants, and found serious irregularities at every one.

This afternoon, the House Energy and Commerce Committee Subcommittee on Oversight and Investigation, headed up by Dingell and Stupak, is scheduled to vote on whether or not to subpoena several FDA officials who investigated Ketek trials. The subpoenas are needed to compel the testimony of Ann Marie Cisneros, a clinical researcher who found fraudulent data in a Ketek study, two current FDA investigators, Robert West and Douglas Loveland, and one former investigator, Robert Ekey.

According to the Associated Press, the subcommittee will also consider issuing a subpoena for internal FDA documents connected with the investigators' work. Congressional aides were told the documents summarize the FDA's investigation of whether Sanofi-Aventis was aware of problems with one of its safety studies before it was submitted to an advisory committee. The document "may recommend prosecution of certain individual and/or entities for the fraudulent trials," according to a memo issued by the subcommittee.

Stupak is also seeking to subpoena the briefing book for Commissioner Andrew C. von Eschenbach to determine whether he was misled in the preparation of his testimony dealing with Ketek. 

Ketek, a powerful antibiotic, was approved by the Food & Drug Administration (FDA) in 2004 to treat sinus infections. This approval came despite serious concerns with the way clinical trails of Ketek had been conducted. Because cheaper antibiotics, like amoxicillin, were already available to treat sinus infections, the FDA required Aventis to design a study showing that Ketek would work at least as well as existing treatments before it could be approved. Aventis eventually signed up 1800 private physicians to participate in these clinical trails. These doctors were given $400 for every patient they convinced to participate in the Ketek study. That huge financial incentive was too much for some doctors to resist. When the FDA audited Ketek study participants, they found one family doctor in a small Alabama town had signed up 407 patients for the study. � The doctor’s entire staff was enrolled in the trail. It even appeared that some of the patient signatures on consent forms where forged. That Ketek Clinical trial doctor was eventually convicted of fraud and sentenced to prison. The FDA also visited several other sites with high numbers of participants, and found serious irregularities at every one. � In October, the FDA issued Sanofi-Aventis a warning letter for failing to respond to problems with Ketek clinical trials.

Shortly after its approval, Ketek was linked to serious side effects, including sometimes fatal liver damage. The FDA eventually confirmed 53 cases of liver failure in patients using Ketek, including five deaths. This past February, the FDA finally added black box warnings to the Ketek label and severely restricted its use.

The 47 plaintiffs involved in the Ketek lawsuit come from Illinois, North Carolina, South Carolina, Tennessee, Indiana, Arizona, Florida, New York, Pennsylvania, Kansas, Missouri, West Virginia, Utah, Maine, Delaware, Iowa, Texas, Arkansas, Virginia, Georgia, Mississippi and New Jersey. � They allege that Ketek is a defective and dangerous pharmaceutical product. � The complaint states that Sanofi –Aventis “engaged in deception, fraud, false pretense, false promise, misrepresentation, or the knowing, concealment, suppression, or omission of material facts regarding the risks of harm associates with the use of Ketek...," The suit claims that Sanofi-Aventis intentionally concealed from the FDA results of a study which showed serious harm associated with the use of Ketek.

The Ketek lawsuit, which was filed in St. Clair County Circuit Court on Nov. 15, seeks damages for personal and economic injuries. 

Ketek, a powerful antibiotic, was approved by the FDA in 2004 to treat sinus infections. This approval came despite serious concerns with the way clinical trails of Ketek had been conducted. However, the FDA maintains that it did not rely on the Ketek study detailed in yesterday’s Warning Letter when it approved the drug. Shortly after its approval, however, Ketek was linked to serious side effects, including sometimes fatal liver damage. The FDA eventually confirmed 53 cases of liver failure in patients using Ketek, including five deaths. This past February, the FDA finally added black box warnings to the Ketek label and severely restricted its use

Because cheaper antibiotics, like amoxicillin, were already doing a good job of treating sinus infections, the FDA required Aventis to design a study showing that Ketek would work at least as well as existing treatments before it could be approved. Aventis eventually signed up 1800 private physicians to participate in these clinical trails. These doctors were given $400 for every patient they convinced to participate in the Ketek study.

That huge financial incentive was too much for some doctors to resist. When the FDA audited study participants, they found one family doctor in a small Alabama town had signed up 407 patients for the study. What else they found during the audit at Dr. Ann Campbell’s was shocking. The doctor’s entire staff was enrolled in the trail. It even appeared that some of the patient signatures on consent forms where forged. So gross were Dr. Campbell’s violations that she was eventually convicted of fraud and sentenced to prison. The FDA also visited several other sites with high numbers of participants, and found serious irregularities at every one.

In yesterday’s Warning Letter, the FDA said that Aventis’ own records showed that there were many instances of “serious protocol violations and regulatory noncompliance by clinical investigators” involved in the Ketek clinical trial. According to the Warning Letter, the FDA found no evidence that Aventis did anything to correct the problems with the Ketek clinical trial, or remove doctors responsible for violations from the study. The FDA also criticized the drug maker for failing to make sure the Ketek clinical trail was run properly and for allowing unqualified investigators to participate.

For its part, Sanofi-Aventis claims that it acted in good faith in conducting the Ketek clinical trail. The company said it was working on a response to the FDA Warning Letter. 

In the past several years, the FDA’s drug approval process has been criticized for allowing defective drugs to go on the market even when serious questions were raised about their safety. Ketek is a prime example of the FDA’s lax approval process. Ketek, an antibiotic used to treat sinus infections, was granted FDA approval in 2004, even though the FDA had found serious irregularities in clinical trials conducted by its manufacturer, Sanofi-Aventis. At least one doctor involved in the trial falsified data and was sent to prison for fraud. Still, Ketek was approved by the FDA in 2004. Shortly after it approved Ketek, the FDA began receiving reports that linked it to liver problems. The FDA eventually confirmed 53 cases of liver failure in patients using the antibiotic, including five deaths. This past February, the FDA finally added black box warnings to the Ketek label and severely restricted its use.

Vioxx, another FDA approved drug, has been linked to severe heart problems. In 2004, an FDA study estimated that this defective drug could have contributed to 27,785 heart attacks and sudden cardiac deaths between 1999 and 2003. After Vioxx was pulled from the market in 2004, it was revealed that the FDA had tried to silence the drug expert who headed that study. Dr. David Graham, associate director for science in the FDA Drug Center's Office of Drug Safety, told Senate investigators that he had been subjected to veiled threats and intimidation when he informed the FDA of his findings.

Avandia is another drug that has caused the FDA a great deal of embarrassment. In May, a study by the Cleveland Clinic found that the diabetes drug increased a patient’s risk of heart attack by 43-percent. In June, a congressional committee convened hearings to investigate problems with the drug. The committee heard testimony from Dr. John Buse, a diabetes expert who raised questions about Avandia’s cardiac risks in 1999. Dr. Buse told the committee that he felt pressured by the drug’s maker, SmithKlineBeecham (now part of GlaxoSmithKline) to sign a clarifying statement drafted by the company that downplayed his concerns. Testimony at that hearing also revealed that the manufacturer and the FDA had known about Avandia’s heart attack risk as far back as September 2005. However, the agency felt that more investigation was needed before conclusions could be made about Avandia’s possible safety issues.

All of these scandals have damaged the public’s confidence in the FDA’s ability to insure drug safety. The fact that the FDA has approved fewer new medications this year could be a sign that the agency is finally starting to take that seriously. 

Though the Senate also passed its own bill (S 1082), the House version is seen as offering consumers the most protection against defective drugs. Both bills increase drug company user fees and grant the FDA more authority to monitor safety once a medicine is on the market. But the House version includes several provisions that should greatly improve the safety of approved drugs. For instance, the new legislation allows the FDA to conduct safety reviews of a drug seven years after it has been approved. Drug companies would also be required to submit their Direct-to-Consumer (DTC) advertisements to the FDA for approval, and would increase penalties for deceptive drug advertising. DTC ads would also be required to a carry a toll-free number and web address that consumers could access to report side effects.

The bill includes two other changes to the FDA drug approval process long sought by consumer advocates. The first limits so-called “Conflict of Interest” waivers on FDA drug advisory panels to one. Currently, these waivers are unlimited, and as a result, advisory panels are often riddled with pharmaceutical industry insiders. The House bill also makes FDA and industry negotiations more transparent by allowing consumer groups and the public to attend fee negotiations between the Agency and drug companies. The bill also requires that a transcript of such negotiations be published.

Finally, the House bill allows for better access to clinical trial results by the public than the Senate version. While both bills require that a clinical trails database be set up to keep the public informed about the effectiveness and risks of prescription drugs, the House version mandates that this be done within a year. The Senate version gives the FDA 2 � years to set up the database, and is vague as to what information would be included.

A House-Senate committee now must work out the differences between the two bills before sending the legislation to President Bush. The White House has expressed more support for the Senate version, as has the pharmaceutical industry. The pharmaceutical industry is seen as one of the Bush Administration’s most important and influential constituencies. 

Ketek was granted approval by the Food and Drug Administration (FDA) in 2004 despite serious concerns with the clinical trials conducted by its manufacture, Sanofi-Aventis. An expensive antibiotic, Ketek was created to treat sinus infectious. But because other cheaper antibiotics (most notably, the more mundane amoxicillin) were extremely effective in treating this condition, the FDA required Aventis to design a study showing that Ketek would work at least as well as existing treatments. Aventis eventually signed up 1800 private physicians to participate in these clinical trails. These doctors would be given $400 for every patient they convinced to participate in the Ketek study.

That huge financial incentive was too much for some doctors to resist. When the FDA audited study participants, they found one family doctor in a small Alabama town had signed up 407 patients for the study. What else they found during the audit at Dr. Ann Campbell �€™s was shocking. The doctor �€™s entire staff was enrolled in the trail. It even appeared that some of the patient signatures on consent forms where forged. So gross were Dr. Campbell �€™s violations that she was eventually convicted of fraud and sentenced to prison. The FDA also visited several other sites with high numbers of participants, and found serious irregularities at every one. Still, Ketek was approved by the FDA in 2004.

Last December, the FDA began investigating reports that Ketek was linked to liver problems. The FDA eventually confirmed 53 cases of liver failure in patients using the antibiotic, including five deaths. This past February, the FDA finally added black box warnings to the Ketek label and severely restricted its use.

Considering that there were many reliable antibiotics on the market to treat sinusitis, whey did the FDA approve Ketek despite the serious problems with its clinical trails? And Ketek has been far from the only problem drug. FDA safety recalls of medicines are double what they were a decade ago, while adding new warnings to already marketed drugs is also on the rise. What can account for this?

While there is no one factor that can explain away these problems, some FDA critics say the agency has become too cozy with the very pharmaceutical companies it is supposed to regulate. For instance, the FDA collects more than $300 million in user fees from drug companies every year. This amounts to more than half the agency �€™s drug review budget. As a result, many believe that the culture at the FDA has shifted to the point that the drug manufacturers are now considered the agency �€™s clients.

Whatever the reason, the ramifications of the problems at the FDA are all too apparent. More Americans are getting sick from the very medicines that should be keeping them well. And the FDA, the one agency that is supposed to protect patients, seems to have forgotten them. 

According to the company, �€œThe prescribing information has been revised to add a boxed warning and contraindication for myasthenia gravis patients. In addition, the indications for the treatment of acute exacerbation of chronic bronchitis (AECB) and acute bacterial sinusitis (ABS) have been removed from the labeling. These revisions follow discussions with the Food and Drug Administration (FDA) regarding its decision to follow recommendations of a December 2006 Advisory Committee that the balance of the benefits and risks no longer support continued marketing of Ketek for these two indications. It is important to note that Ketek continues to be indicated only for the treatment of community-acquired pneumonia (CAP) of mild to moderate severity. �€ �

Sanofi adds, �€œSafety information regarding visual disturbances and loss of consciousness, previously in the precautions section, has been added to the warnings section. In prescribing Ketek, it is important for healthcare professionals to inform and discuss with patients the four highlighted toxicities: exacerbation of myasthenia gravis, hepatotoxicity, visual disturbances, and loss of consciousness. �€ �

The company notes that �€œKetek may cause visual disturbances particularly in slowing the ability to accommodate and the ability to release accommodation. Visual disturbances included blurred vision, difficulty focusing, and diplopia. Most events were mild to moderate; however, severe cases have been reported. �€ � They also point to �€œpost-marketing adverse event reports of transient loss of consciousness including some cases associated with vagal syndrome. Because of potential visual difficulties or loss of consciousness, patients should attempt to minimize activities such as driving a motor vehicle, operating heavy machinery, or engaging in other hazardous activities during treatment with Ketek. �€ �

The company also reiterated its warnings related to hepatotoxicity (liver damage), first issued in June of last year. �€œAcute hepatic failure and severe liver injury, in some cases fatal, have been reported in patients treated with Ketek, �€ � they note. �€œThese hepatic reactions included fulminant hepatitis and hepatic necrosis leading to liver transplant, and were observed during or immediately after treatment. In some of these cases, liver injury progressed rapidly and occurred after administration of a few doses of Ketek. Physicians and patients should monitor for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, or hepatomegaly. �€ �

�€œIn addition, �€ � they report, �€œless severe hepatic dysfunction associated with increased liver enzymes, hepatitis, and in some cases jaundice was reported with the use of Ketek. �€ �

The FDA announced the most recent changes in February. At the time, the FDA said, �€œThe joint advisory committee, which met on December 14 and 15, 2006, advised that the available data including data acquired since the initial approval of Ketek support a conclusion that the benefits of Ketek outweigh the risks in patients with community acquired pneumonia, but not for patients with acute bacterial sinusitis or acute bacterial exacerbation of chronic bronchitis. �€ �

Ketek was originally approved by the FDA in 2004, but the approval process for the controversial drug has come under scrutiny by both houses of Congress as the issue of prescription drug safety has gained momentum in recent months. The FDA originally rejected Ketek in 2001, citing risks including liver damage and blurred vision. In response, Sanofi-Aventis commissioned a rather dubious study of the drug that suffered from falsified data, inappropriate subjects, criminal doctors, and significant violations of the study �€™s guidelines.

Though that study was rejected and a subsequent clinical trial was rife with inaccuracies, an FDA advisory panel pushed for Ketek �€™s approval in 2003. Although the full FDA declined approval that year, they reversed their decision the following year. The controversy has ignited calls from medical professionals and congressmen for more stringent standards in the FDA �€™s approval of pharmaceuticals. 

�€œThe agency has determined that the balance of benefits and risks no longer support approval of the drug for these indications, �€ � the FDA explained. �€œKetek will remain on the market for the treatment of community acquired pneumonia of mild to moderate severity (acquired outside of hospitals or long-term care facilities). �€ �

Additionally, the FDA has asked drug maker Sanofi Aventis to add a �€œblack box �€ � warning to Ketek �€™s labels, stating that Ketek should not be used in patients with myasthenia gravis, a disease that causes muscle weakness. The company has also been required to strengthen the warning section regarding adverse events including visual disturbances and loss of consciousness. (In June of last year, warnings for hepatic toxicity severe symptoms of liver disease were bolstered.)

�€œThe joint advisory committee, which met on December 14 and 15, 2006, advised that the available data including data acquired since the initial approval of Ketek support a conclusion that the benefits of Ketek outweigh the risks in patients with community acquired pneumonia, but not for patients with acute bacterial sinusitis or acute bacterial exacerbation of chronic bronchitis, �€ � the agency noted.

Ketek was originally approved by the FDA in 2004, but the approval process for the controversial drug has come under scrutiny by both houses of Congress as the issue of prescription drug safety has gained momentum in recent months. The FDA originally rejected Ketek in 2001, citing risks including liver damage and blurred vision. In response, Sanofi Aventis commissioned a rather dubious study of the drug that suffered from falsified data, inappropriate subjects, criminal doctors, and significant violations of the study �€™s guidelines.

Though that study was rejected and a subsequent clinical trial was rife with inaccuracies--an FDA advisory panel pushed for Ketek �€™s approval in 2003. Although the full FDA declined approval that year, they reversed their decision the following year. The controversy has ignited calls from medical professionals and congressmen for more stringent standards in the FDA �€™s approval of pharmaceuticals. 

In conjunction with Sanofi-Aventis Canada Inc., the drug �€™s producer, Health Canada has provided this updated safety information to all consumers and providers of Ketek. Of gravest concern to Ketek patients is the possibility of potentially fatal liver damage. (Health Canada had issued a previous warning to patients with liver problems in February.) Ketek consumers have been urged to be aware of symptoms including fatigue, jaundice, dark urine, and loss of appetite.

Health Canada has strongly recommended that patients suffering from myasthenia gravis, a chronic autoimmune condition characterized by varying degrees of weakness in skeletal (voluntary) muscles, find alternatives to Ketek.

This is not the first time that the safety of Ketek--or the drug-approval process at the Food and Drug Administration--has been called into question. The FDA rejected Ketek in 2001, citing risks including liver damage and blurred vision. In response, Sanofi-Aventis commissioned a rather dubious study of the drug that suffered from falsified data, inappropriate subjects, criminal doctors, and significant violations of the study �€™s guidelines.

Though that study was rejected--and a subsequent clinical trial was rife with inaccuracies--an FDA advisory panel pushed for Ketek �€™s approval in 2003. Although the full FDA declined approval that year, they reversed their decision the following year. The controversy has ignited calls from medical professionals and congressmen for more stringent standards in the FDA �€™s approval of pharmaceuticals.

In January of 2006, three cases of severe liver damage (and one fatality) at a North Carolina hospital were linked to Ketek. In May, the FDA reported that 12 cases of liver failure, including four fatalities, had been connected to the drug. An internal FDA memo also surfaced in May, and it seemed to indicate that the administration was more aware of the health risks than previously thought. The FDA responded in June by forcing Sanofi-Aventis to add a new warning to Ketek labels about the risk of liver problems, but has not moved to take Ketek off the market. More than 5 million patients have taken Ketek since the FDA �€™s approval two years ago. 

In what is undoubtedly only the beginning of another prescription drug fiasco, the evidence is mounting against both the safety of the antibiotic, Ketek, and the trustworthiness of its questionable approval by the FDA.

To be sure, the FDA has its staunch supporters among those who actually believe it is doing its best to ensure the public �€™s safety when it comes to approving and monitoring prescription drugs. There are also many who champion the cause of the pharmaceutical industry as being devoted to advancing the cause of human wellness and longevity.

Those who challenge these entrenched �€œtrue believers �€ � through personal injury lawsuits or public watchdog groups are often seen as unscrupulous opportunists who do not see the forest for the trees. As the current battle over Tysabri makes clear, there are those willing to risk a 1/1000 or even 1/500 chance of dying in order to obtain a treatment for a serious disease.

While beauty is often �€œin the eye of the beholder, �€ � deception, fraud, greed, and the other human moral failures are not. They are what they are for all to see and explaining them away by �€œspinning �€ � the facts or reinventing history is a practice only those who seek to justify the unjustifiable engage in.

Why do responsible scientists, consumer advocates, attorneys, and the public cast such a jaundiced eye at the pharmaceutical industry and the agency they believe has come to be its rubberstamp, the FDA? Because both make it so easy to do, that �€™s why.

Each time a major catastrophe occurs with respect to a prescription drug, one has to ask; Was it the public, the consumer advocates, the FDA whistleblowers, the scientists, or the attorneys who were to blame, or was it an over-zealous drugmaker and completely ineffective drug approval process that caused it?

Within the past month alone, numerous articles have exposed the problem of serious potential conflicts of interest on the part of �€œindependent �€ � experts impaneled by the FDA for any number of advisory roles. Most of those experts are far from independent and have either long-standing relationships with the drug industry or have taken substantial sums of money from one or more drugmaker.

The absolute failure of the post-approval drug monitoring program is not a matter of conjecture; it is a matter of fact. Drug companies often fail to deliver on promises to complete drug trials, conduct follow-up studies, or provide additional documentation to support a drug �€™s approval. In fact, in many cases, that missing data was supposed to be provided as a condition of approval.

This is not a �€œred state �€ � versus �€œblue state �€ � or partisan politics issue either. The harshest critic of the FDA and the shenanigans of the pharmaceutical industry is Republican Senator Charles Grassley (Iowa). Republicans as well as democrats in the House and Senate have become quite impatient with all of the cloak and dagger goings on with respect to recent drug debacles.

Earlier this year, for example, a story was carried by hundreds of news outlets, including newsinferno.com, of an eagerly awaited diabetes drug, nearing final approval by the FDA, which significantly increases the risk of heart attacks, strokes, or death, as reported by researchers in a study published in the Journal of the American Medical Association (JAMA).

Was this an example of an isolated incident of a potentially dangerous prescription drug �€œslipping through the cracks �€ � in an otherwise secure drug approval process at a responsible federal agency? Hardly.

Instead, it was yet another situation that raises serious questions concerning the reliability of the FDA �€™s drug approval process and whether it is unduly biased in favor of the pharmaceutical industry.

Muraglitazar, which would be marketed as Pargluva by Merck and Bristol-Myers Squib, was recommended for approval last month by an 8-1 FDA advisory committee vote.

Using the very same data the FDA panel and staff examined, however, the JAMA study researchers identified several extremely serious health concerns about the drug including almost a threefold greater risk of heart failure, heart attack, stroke,

"Ten of 1,000 patients would die, have a heart attack or a stroke," said lead author Steven Nissen of the Cleveland Clinic. "Those are serious irrevocable events."

The new study came from the highly respected researchers at the Cleveland Clinic, the same team that broke the story on the cardiovascular dangers of Merck �€™s anti-inflammatory drug Vioxx.

The researchers, including the highly respected cardiologist, Dr. Steven Nissen, found these findings to be �€œparticularly concerning because the significant excess of adverse events was observed after only limited drug exposure ranging from 24 to 104 weeks. Real-world exposure would likely substantially amplify the risk. Taken as a whole, these data demonstrate that [Pargluva], if approved by the FDA, would constitute an unacceptable patient hazard."

Thus, how did the FDA advisory committee that recommended the drug for approval by a vote of 8-1 ignore both the indisputable clinical data as well as the FDA �€™s own analysts who had themselves identified evidence of cardiac risk?

In a scenario similar to the Vioxx narrative, however, those analysts did not highlight this cardiac risk to patients as significant, except in cases where the drug was used in conjunction with other therapies.

Bristol-Myers concluded that there was no significant increase in heart risk for patients. The analogy to the Vioxx debacle is inescapable. (As Yogi Berra would say; �€œThis is like deja vu all over again. �€ �)

The Pargluva story is merely a small chapter in what is now becoming an all too familiar scenario of a regulatory agency being strongly influenced by the very industry it is supposed to be regulating.

This pattern is just a symptom of a more serious disease, however, and that is the premature approval and marketing of dangerous drugs which are ultimately found to pose far greater risks than any benefit they may have had.

Since the late 1990s, there has been a dramatic increase in the number of drugs that have had to be withdrawn from the market. The institution of an industry-funded �€œfast track �€ � drug approval process has lead to inadequately tested drugs being rushed to market and the need for more and more serious ( �€œblack box �€ �) warnings.

Moreover, today �€™s drugs are being marketed without dosing charts or information with respect to the well-known fact that each person will metabolize a drug differently.

Between 1997 and the beginning of 2005, 19 drugs have been withdrawn from the market. These include:

• Palladone (hydromorphone) �€“ 2005
• Bextra (valdecoxib) �€“ 2005
• Tysabri (natalizumab) �€“ 2005
• Vioxx (rofecoxib) �€“ 2004
• Duragesic Patch (fentanyl transdermal patch) �€“ 2004
• Ephedra �€“ 2004 (withdrawal order vacated by a federal judge)
• Baycol (cerivastatin) �€“ 2001
• Raplon (rapacuronium bromide) �€“ 2001>
• Rezulin (troglitazone) �€“ 2000
• Propulsid (cisapride) �€“ 2000
• Lotronex (alosetron) �€“ 2000
• Hismanal (astemizole) �€“ 1999
• Raxar (grepafloxacin) �€“ 1999
• Posicor (mibefradil) �€“ 1998
• Duract (bromfenac) �€“ 1998
• Seldane (terfenadine) �€“ 1997
• The Diet �€œCocktail �€ �: Fen-Phen (fenfluramine); Pondimim; and Redux (dexfenfluramine) - 1997

Many see the FDA as having placed itself in a conflict-riddled position by accepting huge sums of money from the pharmaceutical industry to fund the agency �€™s Approval Division which is now expected to �€œfast-track �€ � drugs to market. Recently, the industry portion of that funding exceeded 50% for the first time.

Unfortunately, no such funding is given to the FDA for post-approval monitoring of adverse reactions and side effects. Fast-track approvals, which are usually based on short-term testing of small test groups, have had disastrous results when used for drugs which are specifically designed for long-term or lifetime use by large segments of the population.

Once Vioxx was pulled from the market (on September 30, 2004) in the largest drug recall in history, a growing number of experts, elected officials, and public watchdog organizations began to raise serious questions about the FDA �€™s drug approval process.

In order to understand how the FDA �€™s credibility and integrity became so compromised it is necessary to take a fresh look at the FDA drug approval process as well as the necessary steps and reasons for the removal of a drug from the market.

On November 18, 2004, a federal drug safety reviewer told a Congressional panel that the FDA is �€œvirtually incapable of protecting America from unsafe drugs. �€ � He accused the agency easily surrendering to the demands of pharmaceutical companies.

Dr. David Graham, an Associate Director for Science and Medicine in the FDA �€™s Office of Drug Safety is a scientist with impeccable credentials as well as a man of unchallenged integrity who has devoted his entire professional life to making a real difference in the cause of patient safety.

Although Dr. Graham fought long and hard against Vioxx based upon the overwhelming evidence of its serious cardiovascular risks, he was little more than �€œa voice crying in the wilderness �€ � who received no support within the FDA. His stunning testimony before the Senate Finance Committee chaired by Sen. Grassley can be found by clicking here.

Dr. Graham presented the evidence against Vioxx in painstaking detail. He also set forth the disturbing facts surrounding the FDA �€™s efforts to suppress his research, censor and alter his scientific and medical findings and conclusions, and discredit his work.

The most striking portion of Dr. Graham �€™s testimony involved his carefully formulated opinion that (even using Merck �€™s own VIGOR and APPROVe trials) some 88,000 to 139,000 Americans alone have already suffered heart attacks as a result of taking Vioxx and of that number, �€œ30-40% probably died. �€ � (Note that another respected expert, Dr. Eric Topol, estimated the heart attack figure to be up to 160,000).

The history of the pharmaceutical industry and its interaction with the FDA is replete with well-publicized instances of fabricating and falsifying data, concealing negative information and adverse event reports, ethical violations, conflicts of interest, undue influence, favoritism, and other forms of conduct designed to improperly influence FDA decision making.

When such factors are considered in conjunction with the administrative problems faced by the FDA on an ongoing basis, the mix is quite problematic.This is most disturbing, however, in situations where a drug, which should never have been marketed in the first place, must be withdrawn from the market. In those cases, the pharmaceutical company involved will invariably seek to avoid liability by setting up the defense that the FDA's approval of the drug is the best evidence that the drug is safe and effective.

When it comes to approving new drugs, however, is FDA approval the "gold standard" or something dramatically less? An analysis of the FDA's review process (generally) with particular emphasis on what occurred in the case of Rezulin demonstrates the degree to which FDA approval is open to question.

Rezulin was the first drug to be granted "fast track" status under the Food and Drug Administration Modernization Act of 1997. This meant that the FDA had only 6 months to review the NDA before Rezulin was approved in January, 1997.

The FDA Medical Office initially in charge of reviewing the Rezulin NDA (Dr. John Gueriguian) a twenty year veteran of the FDA, was removed from the project in November, 1996, only weeks before the FDA's Medical Advisory Board was set to consider whether to recommend approval of the drug.

The removal came at the request of Warner Lambert, ostensibly because he had used intemperate language in describing the safety and efficacy profiles of the drug. Significantly, this medical officer had concluded that Rezulin was no more effective in treating diabetes than other drugs already on the market yet it had potential hepatic (liver) and cardiac (heart) side effects.

This scenario of either removing, discrediting, or ignoring the FDA �€™s own reviewing officer has become a recurring theme �€“ it happened in the cases of Vioxx and Pargluva as well.

As a result of inadequate study, Rezulin was marketed in March, 1997 without any warning of liver toxicity while representing its adverse effects were no worse than those seen with placebo.

Almost immediately, the FDA began receiving reports of severe liver failure (as predicted by Dr. Gueriguian). By November, 1997, the FDA had received 35 reports of liver damage, including liver transplants and death.

Although Rezulin was withdrawn from the market in England in December, 1997 and despite the warning of the FDA's own (new) Medical Officer, Dr. Robert Mishbin, that 12,000 patients may suffer liver damage, the FDA reaffirmed its commitment to Rezulin.

Notwithstanding the extreme dangers posed by Rezulin, the warnings lagged far behind, and required four major revisions between November, 1997 and June, 1999.

Even in the face of overwhelming evidence that the risks posed by Rezulin far outweighed any benefit the drug had, the FDA Advisory Panel did not recommend withdrawal of the drug.

On March 21, 2000 the FDA withdrew Rezulin from the market. By that time, the FDA was aware of 90 liver failures, 63 deaths, and 7 liver transplants.

Based upon the above, many experts and consumer advocates concluded that the FDA is no longer "the Gold Standard" for the safety and efficacy of a new drug. In addition to the above information, the Rezulin debacle presented additional indications that the FDA approval process is highly suspect.

Dr. Anne Peters, an endocrinologist at the University of California at Los Angeles, noted that the serious problems associated with Rezulin had been apparent while the drug was being tested.

In fact, the abnormal test results were so extreme; Dr. Peters stated that they should have been regarded as a "red flag." Many doctors believed that Rezulin should have been marketed from the very beginning with strong warnings and the requirement that those taking the drug have frequent tests of liver function. The drug was marketed with no such warnings. (All of this is eerily similar to what happened in the case of Vioxx.)

In addition, the FDA threatened its own Medical Officer, Dr. Mishbin, with disciplinary action and dismissal from federal service for his January 24, 2000 e-mail to his superiors which stated: "I see no reason why any well-informed physician would continue to prescribe {Rezulin}."

He also stated that he saw no reason why the "FDA should delay in taking steps to remove [Rezulin]} from the market." Dr. Mishbin, who had originally supported the approval of Rezulin, was joined by four senior FDA physicians in calling for the withdrawal of Rezulin.

In 1999, the FDA �€™s own Dr. David Graham (yes, that same Dr. Graham) warned the agency's Advisory Committee that every Rezulin user was at risk for sudden liver failure even with monthly monitoring.

Finally, Dr. Gueriguian, who was removed from the review of the Rezulin NDA in November 1996 after voicing strong reservations about the drug, saw his negative review of Rezulin purged from FDA files. Hardly a ringing endorsement of the agency's commitment to safeguarding the public by conducting comprehensive reviews that are beyond reproach.

When the FDA announced it would hold hearings regarding the safety of COX-2 inhibitors, the hope was that the agency would finally shed its image as guardian of the pharmaceutical industry.

If ever there was a perfect opportunity for the FDA to reverse years of accusations and innuendoes concerning its questionable record in protecting the public; that was it.

With Merck �€™s unprecedented massive voluntary withdrawal of Vioxx, the revelation of previously unreported adverse study results, a highly respected (FDA employee) �€œwhistleblower �€ � and other well respected scientists poised to offer damaging testimony, the entire class of COX-2 inhibitors appeared to have �€œone foot in the grave and the other one on a banana peel. �€ �

When the testimony was in and the votes counted, however, Celebrex, Bextra, and yes, even Vioxx, rose from the ashes, like the Phoenix of myth and legend, to fly again with the renewed approval of the FDA.

Of the thirty-two government drug advisers who voted on the issue, 10 had consulted for Merck or Pfizer in recent years.

When the votes were tallied, the results were shocking to many but quite predictable if the FDA �€™s questionable track record in protecting the public was taken into consideration.

The committee voted unanimously that all of the drugs significantly increased the risk of heart attack and stroke. Despite this finding, which could not have been otherwise, Vioxx, a drug pulled from the market by its own manufacturer (Merck) only four months before, rose from the ashes on the wings of a 17-15 vote. (Without 9 of the 10 �€œquestionable �€ � votes going in favor of the drug, however, the committee would have voted 14-8 to ban Vioxx).

Bextra, a drug with its own serious legal problems, survived by a margin of 17-13-2 (abstentions). (That vote would have been 12-8 against Bextra without 9 favorable votes from the 10 advisers in question).

Celebrex survived by a 31-1 margin (even though the evidence against it was equally compelling). (The vote still would have been an amazing 21-1 in favor of Celebrex without the 10 �€œinterested �€ � voters).

The panel did recommend all COX-2 inhibitors carry �€œblack box �€ � warnings. Serious? Yes. Fatal? No.

The vote was met with shock and outrage by activists, medical experts, and researchers alike. Several highly reputable news agencies like CBS News, the New York Times, and Forbes, for example, also questioned whether the panel had been �€œstacked �€ � in favor of the pharmaceutical companies with advisers who had significant �€œconflicts of interest. �€ �

The FDA and its safety procedures have been criticized variously by investigative reporters, activists, FDA employees, and medical experts as follows:

� � �€œFDA Drug Oversight Fails Patients �€ � (AP 5/23/01)

� � �€œFDA Failing in Drug Safety, Official Asserts �€ � (The New York Times, 11/19/04)

� � �€œAre Too Many Unproven Drugs Receiving FDA Early Approval? �€ � (The Wall Street Journal, 3/1/05)

� � �€œA Rudderless, Leaderless FDA �€ � (Los Angeles Times, 1/18/05)

� � A broken agency that needs to be �€œfixed �€ � (Forbes, 1/13/05)

� � �€œStudy Faults Drug Approval Mechanism �€ � (Yahoo! News, 5/7/02)

Notwithstanding the fact that the FDA has been portrayed as a �€œfailure �€ � when it comes to protecting the public, such an analysis is far too simplistic.

In its 68 years of existence, the FDA has always been embroiled in the ongoing conflict between consumer safety and corporate profits. In 1927, Congress created the Food, Drug and Insecticide Administration. It was renamed the Food & Drug Administration (FDA) in 1937.

In 1933, President Roosevelt drafted legislation to strengthen the FDA and protect the public from unsafe, ineffective drugs. However, drug industry lobbyists kept the legislation trapped in committee for 5 years. Eventually, the bill was �€œgutted �€ � it of its efficacy requirements.

A major disaster and a public outcry to bring about reform came in 1937, when "Elixir of Sulfanilamide," containing a sulfa "wonder drug" mixed with a solvent closely akin to radiator antifreeze, caused 108 deaths; most of them children.

This prompted new legal requirements that safety be proven before new drugs could be marketed. The comprehensive Food, Drug and Cosmetic Act of 1938 remains the basic law governing the FDA. Drugs marketed before 1938, however, were permitted to remain on the market without proof of safety.

Being able to influence the drug approval process is the industry �€™s goal and it has limitless funds with which to accomplish that objective.

The reason for this is that the FDA has the potential to: (1) affect billions of dollars in pharmaceutical industry profits; (2) cause significant stock market fluctuations; (3) have an impact on pending and prospective litigation; and (4) make determinations which could (and has) actually cause a drug company to go out of business.

Unfortunately, on the other side of this �€œtug of war �€ � is the noble ideal of protecting the public. Activists, �€œwhistleblowers, �€ � professors, and other crusaders, however, cannot even begin to match the financial and political clout possessed by the pharmaceutical industry as a whole or individual corporate giants like Pfizer, Sanofi-Aventis, Merck, Novartis, Roche, GlaxoSmithKline, J&J, and AstraZeneca.

In fact, the pharmaceutical lobby is the largest in the country. When it comes to buying �€œaccess �€ � and influencing politicians, drugmakers are in a league of their own.

Pharmaceutical companies are in business to make money. The industry is highly competitive, with several companies often racing to be the first to market with a particular type of drug for a specific disease or illness.

Winning the race can mean billions of dollars in profits before other companies even get their drug approved. (This was the case with Viagra which, for years, monopolized the market as a treatment for erectile dysfunction until Levitra and Cialis were approved.)

The fierce nature of the competition has also flooded the market with multiple versions of the same class of drug (COX-2 inhibitors like Vioxx, Celebrex, Bextra, Arcoxia, and Prexige for example) or different treatments for the same condition (statins, resins, fibrates, and niacin for high cholesterol).

The race to get new drugs approved and on the market as quickly as possible has made (pre-marketing) long-term studies a thing of the past. As a result, the public either turns out to be the test group for long-term use or is exposed to a drug for years before on-going long-term studies disclose its dangerous side effects.

Pharmaceutical companies often claim that it is more important to get a new drug to the people that need it and that massive longitudinal studies would only delay the release of the drug.

The FDA abides by a simple yet essential question in its approval process: Do the benefits of a drug outweigh its risks? This idea of risk vs. benefit was first adopted about 30 years ago but it is now the basis for new drug approval.

The current law states that all new drugs need proof that they are effective, as well as safe, before they can be approved for marketing. The problem with the current approval process, however, is that even when the answer to this question turns out to be �€œno, �€ � many dangerous drugs have either been approved or permitted to remain on the market for considerable lengths of time.

For example, Michael Elashoff, an FDA reviewer and biostatistician, was asked to review the flu drug Relenza back in 1995. Elashoff recommended against approval due to the lack of efficacy of the drug and the agency advisory committee agreed and voted 13 to 4 against approving Relenza.

Yet Relenza was ultimately approved by the FDA and Elashoff was told that he would no longer make presentations to the advisory committee. Rezulin and Vioxx were both approved and marketed for years despite the fact that strong evidence of their potentially dangerous side effects was well known while the drugs were still being tested.

In the case of Rezulin, the drug was quickly approved by the FDA despite many unanswered questions about safety and efficacy. Also, despite several indications of liver problems and the withdrawal of Rezulin in Britain, the FDA repeatedly dismissed and ignored warnings of the scientists entrusted with the responsibility of approving new drugs.

This very same failing persists today as witnessed by the Vioxx debacle. Clearly, nothing will change until either a new approval mechanism is put in place or a new agency with greater accountability and resources is formed.

Despite the complex nature of today �€™s drugs, the FDA is processing new drug applications at a record pace. From 1993 to 1999 the FDA approved 232 drugs known as �€œnew molecular entities. �€ �

This term is used to describe a new drug which does not already exist in prescription or over-the-counter form. During the previous seven years, the FDA only approved 163 new molecular entities.

Dr. Solomon Sobel, director of the FDA �€™s metabolic endocrine drugs division throughout the 1990s, said that there was extreme pressure to meet deadlines and complete reviews. �€œThe basic message, �€ � he said, �€œis to approve. �€ �

It is important to know and accept the fact that all drugs have the potential to cause side effects or allergic reactions. It is also true that the list of side effects that accompany any drug will never be totally complete as there are always cases of people having unpredicted and unprecedented reactions to new drugs as well as drugs which have been on the market for years.

Many dangerous interactions between two or more drugs, between a drug and another substance like food or alcohol, or between a drug and something as common as sunlight are not discovered until after a drug is on the market.

Public Citizen, a respected public watchdog organization (www.citizen.org/hrg/), has drafted a guideline for consumers called the Seven-Year Rule which states that you should wait at least seven years from the date of release to take any new drug unless it is one of those rare �€œbreakthrough �€ � drugs that offers you a documented therapeutic advantage over older proven drugs.

This �€œrule �€ � is based on three major factors: inadequate testing, the probability that a dangerous drug will be withdrawn within seven years, and the addition of adverse reaction warnings to new drugs within their first seven years on the market.

In April of 2002, the Journal of the American Medical Association (JAMA) published a study led by Dr. Karen Lasser of Cambridge Hospital and Harvard Medical School which concluded that one in five new drugs has unrecognized adverse drug reactions (ADRs) that do not show up until after the drug has been approved.

The study analyzed 548 drugs approved from 1975 through 1999 and discovered that 56 of them were later given a serious side-effect warning or even taken off the market completely.

Dr. Sidney Wolfe of Public Citizen, who worked on the study, said: �€œMost troublesome drugs do not represent any advance in treatment and are at best no better than older, safer drugs already on the market. �€ �

The study specifically focused on black box warnings, which highlight the most serious side effects that were added to the drug �€™s label after its release. If one of the more life-threatening side effects is not detected prior to release, it can cause major problems and create a serious hazard for the general public once the drug is on the market.

Unfortunately, once a prescription drug is approved for marketing, it is extremely difficult to have it withdrawn. Public Citizen has petitioned to have many dangerous drugs banned including the COX-2 inhibitors, Meridia, Crestor, Accutane, Xenical, and Tequin. World-renowned experts have offered clinical studies and scientific proof that numerous drugs are far too dangerous to be on the market or should not be prescribed to certain groups of patients, especially children and adolescents. Highly experienced FDA drug reviewers have advised against approving many drugs that were later withdrawn from the market.

Even though every one of these challenges was well-founded and meticulously documented, none has ever been relied upon as a basis for withdrawing an approved drug from the market. Public Citizen �€™s petitions have not been successful, the experts have been ignored, and (probably worst of all) the FDA reviewers have been ignored, humiliated, transferred, and otherwise discredited by their own agency.

When the FDA finally believes a drug is no longer safe to use, it will ask the manufacturer to withdraw the drug voluntarily. Usually, the company agrees and the drug is immediately pulled. Sometimes, as in the case of Vioxx, a drug is voluntarily withdrawn when the manufacturer determines it can no longer be safely marketed.

Today, most withdrawals can be traced directly to either inadequate pre-application testing, inadequate disclosure in the application process, or inadequate FDA scrutiny of existing data and expert opinions.

Although known side effects cause more injuries and deaths than unknown side effects, it can be quite unnerving for a patient to experience a reaction he or she was not warned about. Sometimes, an unknown side effect can be even more serious than the existing ones.

Limited studies (both in duration and in group size) are more likely to �€œmiss �€ � a particular side effect or potential risk than studies conducted on large test groups over an extended period of time.

Robert Temple, M.D., director of the FDA �€™s office of medical policy claims that test groups cannot be made larger and research studies cannot be dragged out since the public requires �€œreasonably rapid �€ � access to needed drugs.

Unfortunately, once a drug is placed on the market, millions of people will be exposed to it for extended periods of time. Thus, short-term studies involving limited test groups offer little assurance that all serious side effects, allergies, dangerous interactions, and long-term problems have been discovered prior to marketing.

It is for this very reason that Public Citizen �€™s �€œseven-year rule �€ � makes sense. Regrettably, during that seven year period, the public itself is acting as the test group.

The editors of the Journal of the American Medical Association (JAMA) recently made an extremely valid point about the position of the FDA. They argued that it was �€œunreasonable to expect that the same agency that approves drugs to also be committed to actively seek evidence to prove itself wrong. �€ � They suggested the creation of an independent drug safety board to monitor the safety of drugs and medical devices following FDA approval, as it is no longer the �€œgold standard �€ � it once was.

With all of this in mind, the Ketek story burst upon the scene yesterday in a long well-written and thoroughly researched article by Anna Wilde Mathews in The Wall Street Journal.

Taking the essential elements of that story and others that have now appeared (Reuters, etc.) it becomes obvious that what has occurred (again) is little more than �€œthe same story, different day. �€ �

In April 2004, Ketek, an antibiotic manufactured by pharmaceutical giant Sanofi-Aventis, was approved. That approval, however, was not without its previous problems.

In 2001, Ketek was not approved because of evidence of side-effects such as liver damage, blurred vision, and others was found in a review of the manufacturer �€™s earlier trials. Further support for the application was requested by the FDA before it would even reconsider Ketek for approval.

At this point, the manufacturer was eager to gain approval so it embarked on a study (labeled �€œ3014 �€ �) that was contracted out to Pharmaceutical Product Development Inc. (PPD).

Making a very long story shot, the study that involved over 24,000 subjects was rejected by the FDA as completely unreliable. Why? Well, just for starters were the following facts:

• One doctor, who was enrolling subjects at a record pace at her weight-loss clinic, turned out to have falsified data, used relatives and friends, used subjects who did not have respiratory infections, and used subjects who never even received the medication. This doctor, who enrolled 407 subjects (at $400 per subject or $162,800), is now in federal prison.
• One doctor who enrolled 214 subjects was on probation at the time of the study (for gross negligence and failing to keep adequate records) and later lost his license after an arrest for domestic violence, cocaine possession, and holding a loaded semiautomatic handgun.
• One doctor, who enrolled 150 subjects, was found to have committed over 20 violations of the study �€™s guidelines.
• One doctor, who enrolled 251 subjects, failed to follow the study guidelines and did not report adverse drug reactions.
• One doctor agreed to stop doing research because of serious irregularities in his data including backdating consent forms and failing to record which drugs his patients were taking.
• PPD did not visit all of the test locations.

Thus, four doctors alone accounted for 1,021 (4.25% of the total) unreliable subjects whose data could not help but skew the overall results of the study. With this track record, it is difficult to imagine that the remainder of the study was any more accurate.

The $408,400 billed for the completely useless data on 1,021 subjects was a strong incentive indeed for processing data with an eye toward quantity and not quality.

Sanofi-Aventis claims that the study presented an accurate profile of Ketek despite the �€œdeviations. �€ � Moreover, an article in April �€™s New England Journal of Medicine suggested Ketek was as safe as other antibiotics. All six of the articles authors were linked financially to Sanofi-Aventis (five by consulting fees and one as an employee).

Now, as a public watchdog agency, you might expect the FDA would have steadfastly refused to approve Ketek for marketing. Clearly, the drug had failed to gain approval the first time around and its possible approval at a later date was specifically conditioned on favorable clinical test results.

When the clinical trial on which the renewed application for approval was based turned out to be full of inaccuracies, fraud, and otherwise unreliable data, the FDA was left with nothing new upon which to base an approval. Did that deter the agency, however? Not at all.

An advisory panel that met in 2003 recommended the approval of the drug although it was never told of the completely unreliable data in study 3014. The FDA then declined approval only to grant it in 2004.

Instead of erring on the side of the public, the FDA approved Ketek based on the prior data (already found to be inadequate) and the fact that the drug had been marketed in other countries with only minimal problems. Of course, this simplistic analysis ignored the well-known fact (often cited by the FDA itself) that adverse events and side effect are grossly underreported by between 90% and 99%.

Guessing that Ketek �€™s risk profile for liver-related problems is probably similar to other antibiotics, the FDA is currently assessing the numerous reports of liver damage while it insists that the drug is �€œsafe and effective when used according to the label. �€ �

Other drugs have either been pulled from the market (Rezulin) or significantly restricted (Trovan) for similar incidence rates for liver failure.

Remarkably, even though study 3014 was discredited by the FDA, the agency cited the study when agreeing with a report that suggested the drug �€™s safety record was reassuring. Of course, the report was based on the discredited study also. One litigation attorney we spoke with said errors like this which always favor the drug companies and not the public are unconscionable.

Senator Grassley along wit other lawmakers are already questioning the Ketek approval and the faulty and inadequate data that approval was based on. In an April 27 letter to the FDA, Grassley pointed out that the data supporting the agency �€™s approval was "beset by systemic data integrity problems."

Democratic Reps. Edward Markey of Massachusetts and Henry Waxman of California also questioned the Ketek approval in a separate letter to the FDA. According to a statement from Waxman: "The Ketek case demonstrates the urgent need for reform at the FDA and in the pharmaceutical industry. FDA approved the drug on flimsy data without resolving the safety issues, and it failed to penalize Aventis."

Amazingly, Ketek is being studied as a treatment for children with ear infections and tonsillitis although the FDA has rejected an application by Sanofi-Aventis to approve the drug for the same illnesses in adults.

When asked to comment on the FDA �€™s role as a public watchdog in the Ketek and other similar prescription drug scandals, a seasoned litigation attorney simply stated; �€œWith friends like that you don �€™t need enemies. �€ � 

• Healthcare providers should monitor patients taking telithromycin for signs or symptoms of liver problems. Telithromycin should be stopped in patients who develop signs of liver problems.
• Patients who have been prescribed telithromycin and are not experiencing side effects such as jaundice should continue taking their medicine as prescribed unless otherwise directed by their healthcare provider.
• Patients who notice any yellowing of their eyes or skin or other problems like blurry vision should contact their healthcare provider immediately.
• As with all antibiotics, telithromycin should only be used for infections caused by a susceptible microorganism. Telithromycin is not effective in treating viral infections, so a patient with a viral infection should not receive telithromycin since they would be exposed to the risk of side effects without any benefit.