The Bitter Pill

The Official Blog of UNITE – uniteforlife.org

Lawmakers Say FDA Better Clean Up Its Act

Evelyn Pringle February 2007

For six years, the Bush administration has placed pharmaceutical industry interests ahead of public interest by appointing persons with strong ties to drug companies to high level positions at the FDA, and as a result, Congressional investigations and a recent survey indicate that the health and safety of all Americans is being compromised. 

On July 20, 2006, the Union of Concerned Scientists published the results of a survey that showed an insidious political influence of science within the FDA. According to the UCS press release, the survey was co-sponsored by Public Employees for Environmental Responsibility (PEER), and was sent to 5,918 FDA scientists.

The survey found that 61% of the responding scientists knew of cases where the “Department of Health and Human Services or FDA political appointees have inappropriately injected themselves into FDA determinations or actions.”

In responding to the survey, one scientist wrote: “Over the last several years I have noticed a significant increase in the number of decisions that have become politicized (e.g., increasing requests to review even simple regulations and changes, both by Congress and the Commissioner’s office and to make apparently politically-motivated changes in language and sometimes to alter bottom line results), and I think the integrity of scientific work could be improved by minimizing the ‘politics’ of the process.”

Out of the nearly 1000 scientists who responded, close to one-fifth or 18.4%, said they had “been asked, for non-scientific reasons, to inappropriately exclude or alter technical information or their conclusions in a FDA scientific document.”

In addition, 40% of the scientists said they fear retaliation for voicing safety concerns in public and more than one-third said they did not feel they can express safety concerns even inside the agency.

The survey also found that only 47% think the “FDA routinely provides complete and accurate information to the public,” and 81% agreed that the “public would be better served if the independence and authority of FDA post-market safety systems were strengthened.”

In a complaint aimed at the FDA’s Office of Regulatory Affairs, one scientist said it should “not ostracise scientists or black ball them because their foresight sees a problem with a drug, device, food, biologics, etc. that possess a potential hazard to health now or in the future.”

In response to the concerns raised by FDA scientists, the UCS recommends:

–  Accountability: FDA leadership must face consequences if they side with commercial or political interests and not with the American people.

–  Transparency: Scientific research and reviews should be open so any undue manipulation is immediately apparent.

–  Protection: Safeguards must be put in place for all government scientists who speak out.

“These disturbing survey results make it clear that inappropriate interference is putting people in harm’s way,” said Dr Francesca Grifo, Senior Scientist and Director of UCS’s Scientific Integrity Program, in the press release.

“All federal scientists,” he said, “need protections so they can speak out when their science is manipulated, and all federal agencies need fully functioning independent advisory committees.”

“FDA leaders,” Dr Grifo noted, “should act now to improve transparency and accountability and renew respect for independent science at the agency.”

“FDA leadership,” he stated, “must understand and support independent science and it is up to Congress to hold them accountable.”

But nothing about this survey is news to FDA officials. By use of the FOIA, the UCS and PEER, recently obtained a copy of a previously unpublished survey by the Health and Human Services Office of Inspector General from late 2002, that polled 846 FDA scientists, and with nearly half responding determined that:

Nearly one in five said that they “have been pressured to approve or recommend approval” for a drug “despite reservations about the safety, efficacy or quality of the drug”

Two-thirds lacked confidence that the FDA “adequately monitors the safety of prescription drugs once they are on the market”
 
Only 12% of the responding scientists were completely confident that FDA “labeling decisions adequately address key safety concerns,” and 30% were not at all or only somewhat confident
 
More than one-third were not at all or only somewhat confident that “final decisions adequately assess the safety of a drug”
 
Despite the above results, the report published by the OIG in March 2003, included the conclusion that FDA scientific reviewers “have high confidence in decisions FDA makes.”

On August 8, 2006, the UCS briefed acting FDA Commissioner, Andrew von Eschenbach, on the latest survey and discussed the political inference at the FDA. To restore integrity, UCS recommended that Dr von Eschenbach adopt and enforce three basic commitments:

(1) to ensure that data or results are never softened for any audience. Rigorous scientific debate must be valued at the FDA;

(2) to pledge to support scientists who speak out by taking adverse employment action against any manager who retaliates against a reviewer; and

(3) to commit to a culture that supports a collaborative process of testing and challenging scientific hypotheses.

Along with the recommendations, the group’s August 8, 2006, press release said, “The FDA must allow an open scientific process and recognize the need for scientists to pose and answer questions without consequences related to their status at the FDA.”

Critics claim that a major issue that needs to be addressed involves the rampant conflicts of interest among members of the FDA’s advisory panels who have financial ties to the pharmaceutical industry. In November 2005, a new law was passed that required members of the committees to disclose all financial ties to drug companies.

The categories for disclosure were broken down into dollar amounts and time frames, such as less than $10,000 a year or between $10,000 and $50,000 a year. After reviewing the financial disclosure forms, the FDA is permitted to grant waivers that allow experts to sit on panels even if they have financial ties to a drug company.

However, on April 21, 2006, the Boston Globe discussed the practical effects of the law since it was enacted and reported that FDA critics “say the new transparency has changed little, and scientists who have conflicts of interest can still guide FDA decision making.”

In less than 6 months after the law went into effect, the Globe determined the FDA had granted close to 100 waivers.

One of the latest FDA fiascoes, involves the approval of the antibiotic, Ketek, despite serious concerns about the drug’s safety and lack of efficacy, by top officials with full knowledge that the studies submitted to support its approval were fraudulent.

Several employees at told FDA officials that the liver damage associated with Ketek was known to its maker, Sanofi-Aventis, early in clinical trials but was covered up.

According to the FDA’s senior scientist, Dr David Graham, who blew the whistle on the agency’s mishandling of the Vioxx debacle, Ketek is at least as toxic to the liver as three other drugs that have been removed from the market and the FDA’s original approval of the drug was based on a study that the agency’s top officials knew was fraudulent.

Internal FDA emails that surfaced during the investigation show that at least four FDA safety officials, Dr David Graham, Dr Charles Cooper, Dr David Ross and Dr Rosemary Johann-Liang, had voiced serious concerns about the safety of the drug.

“I tried to argue that given Aventis’s track record in which they have proven themselves to be nontrustworthy that we have to consider the possibility that they are intentionally doing a poor job of collecting the postmarketing data to protect their drug sales,” Dr Cooper said in an email.

“It’s as if every principle governing the review and approval of new drugs was abandoned or suspended where telithromycin is concerned,” Dr David Graham wrote in an email that recommended Ketek’s “immediate withdrawal.”

“We don’t really know if the drug works;” he said, “no one is claiming it works better than other, safer drugs; and we’re flying blind as far as safety goes, except for our own A.D.R. data that suggests telithromycin is uniquely more toxic than most other drugs.”

In May 2006, Dr Johann-Liang called for a halt to tests of Ketek in children with ear infections, arguing that cutting the duration of ear pain by one day was hardly worth risking death.

The FDA’s actions in regard to Ketek are being investigated by Senator Charles Grassley’s (R-Iowa), Senate Finance Committee, and by Representatives, Edward Markey of Massachusetts, and Henry Waxman of California, ranking Democrats on the House Government Reform Committee.

In May 2006, the lawmakers released a statement that said although “the FDA has consistently assured the public of Ketek’s safety and efficacy, public documents obtained and examined by Representatives Markey and Waxman’s staff indicate that the approval process for this drug was seriously flawed.”

As Chairman of the Senate Committee, Senate Grassley has called for a “major overhaul and a culture change at the highest levels” of the FDA. In a May 1, 2006, press release, he noted concerns over the FDA’s complicity with the drug maker and its subsequent failure to ensure the integrity of a study on the benefits and risks of Ketek.

The Senator called it “mystifying” on May 16, 2006, that the FDA would continued to provide information that it knew was fraudulent, and warned that he planned to keep the pressure on the FDA to provide more information about Ketek’s approval and post-market surveillance.

“It’s no surprise to learn that the FDA didn’t listen to Dr. Graham on the dangers of Ketek,” Senator Grassley was quick to point out. “The FDA has made it their business to discredit Dr. Graham and others who aren’t willing to cater to the drug companies,” he noted.

In October 2001, doctors began enrolling subjects for the Ketek clinical trial known as Study 3014, and were paid $100 for each patient that signed up. The participating doctors would also receive another $150 when the study results were submitted, and a final $150 when all questions related to the study were resolved, according to the May 1, 2006, Wall Street Journal.

On July 24, 2002, drug maker Aventis submitted the results of the study to the FDA, but when FDA officials submitted the study to the advisory committee for review, they did not disclose that the Division of Scientific Investigation and Office of Criminal Investigation was investigating the integrity of the study.

The misconduct that took place during the clinical trials is so serious that critics say it calls the validity of the entire study into question. For instance, the doctor who signed up the 3rd highest number of patients, was in a chronic state of cocaine addiction while conducting the clinical trial, and was arrested and found to have cocaine hidden in his underwear, while holding his wife hostage with a gun, the same month the study results were submitted to the FDA.

Another doctor who participated in the study was totally disqualified as an investigator and prohibited from conducting any clinical trials in the future, and another who signed up 150 patients was cited for 20 violations of the study’s instructions.

Dr Anne Campbell, the doctor with the highest number of subjects in the study, was sentenced to nearly 5 years in prison in March 2004, after being charged in a 21-count indictment over her misconduct.

Senator Grassley is demanding a face-to-face interview with the FDA investigator who discovered the fraud and misconduct in the trials, who he contends “is key to understanding what the FDA did when it became clear that the safety study required by the FDA in order to approve the drug was fraudulent and faulty.”

This investigator authored a March 25, 2004, memorandum from the Division of Scientific Investigations titled, “DSI Recommendations on Data Integrity,” that states in part, that Study 3014 involved “multiple instances of fraud” and that “the integrity of data from all sites involved in [the] study … cannot be assured with any degree of confidence.”

After months of trying unsuccessfully to get an interview, Senator Grassley finally marched right over to the Department of Health and Human Services headquarters and asserted a congressional right to speak to the investigator.

After a brief conversation with senior officials, he left mad as a hornet. “This is extraordinary to me,” he said outside HHS headquarters. “I haven’t had to go to an agency like this since 1983 to get information I requested.

“I smell a cover-up,” he stated.

On June 22, 2006, Senator Grassley publicly announced a not too subtle warning to officials at the agency. “Two years ago I called a congressional hearing to probe the FDA’s handling of the withdrawn painkiller Vioxx,” he said in a statement.

“It might be time,” he warned, “to round up another oversight hearing after the runaround I got recently at the FDA.”

“The FDA,” he wrote, “refused to allow me to question an internal investigator who is leading an inquiry into alleged fraud involved with clinical trials for the antibiotic Ketek.”

“So for only the second time in 23 years,” he said, “I resurrected in June my unconventional means to fulfill my Constitutional oversight responsibilities.”

He said, “I appeared at the FDA’s doorstep,” and noted that agency officials refused to let the investigator speak to him.

However, he warned, “Bureaucratic stonewalling won’t deter this U.S. Senator.”

“I won’t rest,” Senator Grassley said, “until the light of day exposes what ought to be available for public consumption.”

“It all boils down to keeping the government accountable,” he wrote, “to the people and strengthening the public trust in government.”

In another statement released on June 29, 2006, he stated, “Ketek is another example where the F.D.A. accommodated a drug maker and turned a blind eye to serious safety concerns.”

Over the past couple of years, the suppression of the scientific process and the muzzling of scientific dissent at the FDA became evident first when officials forced Dr Andrew Mosholder to suppress a link he found between SSRI antidepressants and suicide in children, and Dr Graham went public with allegations about the FDA’s mishandling of the Vioxx matter.

On March 10, 2005, Senator Grassley gave a speech to the Consumer Federation of America and said these two whistleblowers had done more to shake up a complacent FDA than probably anybody in recent history and relayed parts of the story saying:

“Early last year I heard that the FDA was muzzling one of its own scientists. In February 2004 the FDA held a meeting to decide whether there was a link between some antidepressant drugs and suicidal behavior in kids.

“Dr. Andrew Mosholder – the FDA’s expert in this area — concluded there was a link. However, FDA management disagreed. So, when Dr. Mosholder stuck by his findings, his supervisors canceled his presentation to an advisory committee.

“Instead of allowing Dr. Mosholder to present his findings publicly and subject them to committee scrutiny, the scientific process and his peers, the FDA effectively muzzled him.”

But despite the FDA’s best efforts, Senator Grassley said, Dr Mosholder wouldn’t be silenced and months later he was proven right.

Citing information from the Department of Justice, he told the audience that there are currently under seal in the neighborhood of 100 whistleblower cases involving allegations against over 200 drug companies.

“During the past four years,” he stated, “the department recovered nearly 2 and a half billion dollars from whistleblower cases against drug companies.”

Senator Grassley called Dr Mosholder and Dr Graham great patriots. “Think about the guts it takes to undermine your career, and to go against your supervisors at a huge federal agency,” he said, “and in this case, the multi-billion-dollar drug companies.”

In an August 30, 2005, interview with Manette Loudon, the lead investigator for Dr Gary Null, Dr Graham discussed how FDA officials attempted to suppress the results of his study on Vioxx a year earlier. According to Dr Graham, prior to his Senate testimony in mid-November of 2004, there was an orchestrated campaign by senior FDA managers to intimidate him so that he would not testify about the adverse affects of Vioxx to Congress.

One attack he says, came when the acting FDA Commissioner, Lester Crawford, contacted the editor of the Lancet, a UK medical journal, and told him that Dr Graham had committed scientific misconduct and that the journal should not publish the paper that he had written showing that Vioxx increased the risks of heart attack.

The second attack came from other high level officials, he said, who contacted Senator Grassley’s office in attempt to prevent Senator Grassley from calling him as a witness.

And the third he says came from senior FDA officials who contacted Tom Devine, Dr Graham’s attorney at the Government Accountability Project, and attempted to convince him that the GAP should not represent Dr Graham because he was guilty of scientific misconduct.

According to Dr Graham, these officials posed as whistleblowers themselves, and told Mr Devine that Dr Graham was a “bully,” a “demigod,” and a “terrible person” that could not be trusted.

In one more last ditch effort to thwart Dr Graham’s testimony the week before he testified, he says, the acting Commissioner offered him a job in the Commissioner’s Office to oversee the revitalization of drug safety if he would just leave the Office of Drug Safety.

“Obviously he had been tipped off,” Dr Graham said in the interview, “by people in the Senate Finance Committee who are sympathetic to the FDA’s status quo that I was going to be called as a witness.”

To preempt his testimony, he told Ms Loudon, he was offered a job “which basically would have been exile to a fancy title with no real ability to have an impact.”

According to Dr Graham, by allowing Vioxx to stay on the market, the FDA is responsible for 140,000 heart attacks and 60,000 dead Americans. “That’s as many people as were killed in the Vietnam War,” he points out.

He says the FDA could have prevented many of the heart attacks and deaths simply by banning the high dose Vioxx back in 2000 when the agency learned about the results of the VIGOR Study. “But the FDA did nothing for almost two years,” he states. “They were “negotiating” with the company over a label.”

“The FDA made bad decisions,” Dr Graham said, “based of its culture and its institutionalized biases that favor industry, and as a result thousands of Americans died.”

During a July 18, 2005, speech on the Senate floor, Senator Grassley proclaimed, “this country’s confidence in the FDA has been shaken.”

It has not been shaken, he said, by one isolated incident or whistleblower. “It has been shaken because multiple drug safety concerns have been exposed by more than one courageous whistleblower.”

“Dr. Graham’s testimony before the Finance Committee,” he told members of Congress, “suggests that the problems are systemic.”

“Oversight of the FDA,” Senator Grassley advised, “exposed the cozy relationship that exists between the FDA and the drug industry.”

“It revealed that the FDA negotiated for almost two years with Merck,” he said, “about how to change the Vioxx label so people would know about the risk of heart attacks.”

According to Dr Graham, the Vioxx disaster would not have been as severe in the absence of direct-to-consumer advertising. “I submit,” he told Ms Loudon, “that the numbers would have been far lower than what they were.”

Due to heavy marketing of new drugs, Dr Graham says, lots of patients and doctors will use a new drug that is no better than another drug already on the market, even though the FDA does not require that new drugs be at least equivalent to, or better than, the drugs that are already there. All the drug maker has to prove is that a drug works better than a sugar pill, he says.

Silencing scientists to protect the industry has become habitual under the current politically appointed rulers of the FDA. According to Shane Ellison, author of “Health Myths Exposed,” pharmaceutically compliant politicians have “democratized” the drug industry. “This means that drug approval is a matter of 51% telling the other 49% that deadly drugs are safe and necessary,” he reports.

“Science and choice,” he warns, “no longer prevail at the FDA or at pharmaceutical companies.”

Mr Ellison is a former pharmaceutical industry chemist who says he felt a responsibility to reveal the truth about the industry’s sordid tactics after he witnessed first-hand how they deceive the public, according to a September 3, 2005, interview with Crusador Editor, Greg Ciola.

“To go against the 51% means losing your career,” Ellison said. “Therefore, the majority of scientists choose to please drug companies, not the general public.”

As an example, Mr Ellison discussed Dr Curt Furberg, a member of the FDA’s drug safety advisory committee. Dr Furberg, he says, came forward to reveal that Bextra also caused heart attack and stroke. In the British Medical Journal, Dr Furberg said that his studies showed Bextra to be no different than Vioxx, and warned that Pfizer was trying to suppress that information.

“Immediately thereafter,” Mr Ellison said, “Dr. Furberg was barred from serving on the panel that is responsible for considering the safety of cyclo-oxygenase-2 (COX 2) inhibitors.”

“The end result being more votes in favor of COX 2 inhibitors, the drug company wins by votes – not science,” Mr Ellison told Crusador.

In the case of the pain relieving Cox-2 inhibitors, the FDA’s advisory committee was stacked with experts with ties to the drug makers. Of the 32 advisers who would vote on the drugs, it has since become known that 10 of panel members had consulted in recent years for Vioxx maker, Merck, or Pfizer who made Celebrex and Bextra.

While the committee voted unanimously that all of the drugs significantly increased the risk of heart attack and stroke, in a 17-15 vote the panel said the FDA should allow Vioxx to remain on the market. A tally of the votes showed that without the 9 votes of the 10 members who consulted for the drug makers, the committee would have voted 14 to 8 to ban Vioxx.

However, the panel’s recommendation was met with scorn and outrage by medical experts and researchers alike in the media, and in a rare occurrence, the FDA went against the recommendation of its advisory panel and refused to allow Vioxx to remain on the market.

Critics also accuse the FDA of not properly monitoring the marketing activities of the pharmaceutical industry. An investigation by the House Committee on Government Reform found that since December 2001, there has been a sharp decline in enforcement actions taken against drug companies for illegally promoting their products.

The investigation determined that from 1999 to 2001, the FDA sent out 250 “Notice of Violation” or “Warning” letters to drug companies; but for the time period of 2002 through 2004, the agency sent out only 70 letters, which amounts to a reduction of more than two-thirds.

Since the Vioxx and SSRI debacles, Senator Grassley has jumped on the FDA every time there has been any indication that officials might be putting the industry’s interest over public safety. Earlier this year, he wrote a letter to the FDA saying he was concerned that it might be “dropping the regulatory ball” on stimulant drugs, prescribed to treat ADHD.

Specifically, he wrote, “I’m concerned FDA’s regulatory responsibilities haven’t kept pace with the explosion of prescriptions written to treat 2.5 million children with these drugs.”

Despite psychiatric and cardiovascular risk signals associated with the drugs, he noted, it appears the FDA has failed to promptly respond to their possible adverse effects. “Such events,” he wrote, “may include sudden unexplained deaths, strokes, cardiovascular irregularities or aggression, anxiety and depression.”

Sales of drugs, he said, “have zoomed to the moon, jumping from $759 million to $3.1 billion between 2000 and 2004.”

“And yet,” he wrote, “the FDA seems to have adopted a wait-and-see approach before charting a course of action to study these risks.”

In early February 2006, he noted, that an advisory panel had recommended adding the strongest black box warning to ADHD drugs to alert patients about the possible cardiovascular side effects.

“The recommendation,” Senator Grassley wrote, “brings even more urgency to the controversy surrounding the explosion of prescriptions being filled with these medicines.”

“As the debate unfolds,” he warned agency officials, “I will continue to closely track the FDA and urge its timely, thorough review of these drugs.”

“With millions of Americans, mostly children, regularly taking these medications,” he added, “it is essential the FDA leaves no stone unturned to investigate and review this class of drugs.”

No doubt in response to all the intense scrutiny from members of Congress, in late July 2006, the FDA outlined a series of changes it plans to make in the methods used to evaluate clinical trials. One of the proposed changes would require a drug company to notify the FDA immediately if it believes a researcher has committed fraud during a clinical trial.

As it is now, drugs companies are trusted to remove unreliable data and are not required to report any fraudulent activity to the FDA until they actually submit the application.

The agency also says it plans to clarify which adverse events in clinical trials must be reported to the review boards that monitor the studies. Other proposed change includes the standardization of forms used to collect information and a revision of the rules on how patients may qualify to participate in clinical trials.

However, people who are tempted to think that the FDA is capable of changing under the agency’s current team of politically appointed officials, had better think again.

According to an article by Russell Mokhiber and Robert Weissman, for Common Dreams on August 2, 2006, Dr Steven Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, was recently a member of a panel debating the topic of: “Government Science Panels: Fair and Balanced?” which was moderated by National Public Radio’s Snigdha Prakash, and sponsored the Center for Science in the Public Interest.

Dr Nissen spoke about the conflict-of-interest problems “evident at the highest levels of the FDA,” the article says.

“For years,” Dr Nissen said in describing FDA leadership, “we had an interim FDA Commissioner, Lester Crawford, who shortly after confirmation, abruptly resigns, apparently because he and his wife owned stock in regulated companies.”

“Then the administration appointed Andrew Von Eschenbach as interim commissioner, creating another conflict,” he noted.

“In his role as director of the National Cancer Institute,” Dr Nissen said, “Von Eschenbach must seek FDA approval for human testing or approval of new cancer drugs, an obvious conflict.”

But even worse, he said, “the administration appointed Scott Gottlieb as deputy commissioner.”

“He came to this job with no regulatory experience, directly from Wall Street, where he served as a biotech analyst and stock promoter,” Dr Nissen stated.

“Between them,” he said, “Drs. Von Eschenbach and Gottlieb have whined incessantly about the need to speed drug development.”

“So while the American people worry about the safety of drugs,” he continued, “the top FDA leadership tells us we need faster drug approval.”

On November 12, 2005, the Boston Globe reported that prior to his job at the FDA, Dr Gottlieb worked for the PR firm of Manning Selvage & Lee and that his clients included Roche, the manufacturer of Tamiflu, and Sanofi-Aventis, the maker of Ketek, and the parent company to the nation’s sole flu vaccine maker.

According to the Globe, the Manning PR firm paid Dr Gottlieb a monthly retainer of $12,500 for nine months, for working on projects that involved eight companies. Other firms regulated by the FDA that he was involved with include Inamed Corp, a company seeking the return of silicone gel implants to the market.

Between May and July 2005, Dr Gottlieb also was paid $9,000 for consultant work performed for VaxGen, a company that won an $878 million government contract to supply the US with 75 million doses of anthrax vaccine.

In any event, no matter who’s in charge, the Senator from Iowa is keeping the heat on. In July 2006, he wrote a letter to the Daniel Levinson, the Inspector General at the Department of Health and Human Services, asking for an investigation into whether Dr Brian Harvey of the FDA, conspired against Dr Graham by providing Merck with details about Dr Graham’s presentation on Vioxx, prior to the hearing in 2004 to help the company refute his testimony.

“It is no secret that Dr. Graham was and is a critic of the FDA,” he wrote to Inspector. “However,” he said, “that does not mean the FDA should scheme with drug sponsors to discredit its own employees.”

Filed under: 2007, Avandia, Bextra, FDA, Gottlieb, Graham, Ketek, Manning, Merck, Pfizer, SSRIs, Vioxx, whistleblower

Ending FDA’s Love Affair With Big Pharma

Evelyn Pringle November 2006

With the Democrats back in power, critics say officials at the FDA and representatives of Big Pharma had better plan on spending much of their time testifying on Capital Hill in Congressional hearings in 2007.

Democrats have spelled out their plans to change how the administration chooses experts to sit on FDA advisory panels and put an end to the suppression of dissenting opinions of FDA scientists.

These panels advise the agency on which drugs should be approved, what their warning labels should say, and how clinical studies should be conducted. The approximately 300 so-called experts make decisions that potentially affect billions of dollars in sales for Big Pharma and the FDA follows their recommendations almost exclusively.

Critics are demanding stricter conflict of interest rules for members of the panels and a November 17, 2006, session of the Senate Committee on Health, Education, Labor, and Pensions, gave the Democrats their first opportunity to indicate how they will deal with the out of control FDA once they become the majority in Congress next year.

The hearing titled, “Building a 21st Century FDA: Proposals to Improve Drug Safety and Innovation,” was held to push forward FDA reform legislation Senate Bill 3807, the “Enhancing Drug Safe and Innovation Act of 2006,” previously introduced by outgoing committee chairman, Senator Michael Enzi (R-WY), together with incoming chairman, Senator Edward Kennedy (D-MA). The two Senators began working on the bill when Vioxx was pulled from the market after it was found to cause heart attacks and strokes.

Cleveland Clinic physician-scientist, Dr Steven Nissen, MD, who has served as an expert on FDA advisory panels, testified at the hearing and described “a crisis in public confidence in the FDA following an unprecedented series of revelations about drug and device safety” and referred to the Senate reform bill as a “major step forward.”

“I am a strong supporter of this bipartisan effort to enhance the FDA’s effectiveness and improve drug and device safety,” he said. “I believe that this legislation represents the best chance we have had in a long time to make a real difference for patients in this challenging area.”

Dr Nissen said new laws are needed to strengthen the authority of the FDA. “Currently,” he explained, “the Agency must “negotiate” with industry to make even simple changes in drug labels.”

“I served on a 2001 Advisory Panel that recommended a warning label for Vioxx,” he informed the panel, “but it took 14 months before the FDA could secure agreement from the company to accept a weakly written warning.”

As for enacting new conflicts of interest rules for advisory panels, Dr Nissen testified that improvements “in the Advisory Committee process will help to ensure that FDA consultants are less likely to be influenced by financial conflicts of interest.”

Merrill Goozner, Director of Integrity in Science Center for Science in the Public Interest, testified about the blatant conflicts of interest involving the expert panel that reviewed Vioxx and the other COX-2 inhibitors, and how the panel concluded that Vioxx was safe enough to stay on the market, even though Merck had already removed it from the market.

Mr Goozner told the Senate committee that ten of the 32 scientists on the panel had financial ties to the drugs’ makers. “Had their votes been eliminated,” he said, “two of the drugs in the class would have been voted down by the panel.”

“The best way to solve all these problems,” Mr Goozner stated, “without undermining the quality of the advice offered to the FDA – is to completely eliminate conflicts of interest from these committees.”

Jim Guest, president and CEO of Consumers Union, publisher of Consumer Reports, testified that improvements are needed to help prevent future drug safety disasters and called for a rule specifying that at least 90% of the members on advisory committees who decide whether a drug should be approved be free of conflicts of interest from the pharmaceutical industry.

In “the wake of the Vioxx and Paxil disasters,” he told the committee, where tens of thousands of Americans needlessly suffered, we’ve educated our more than 20 million readers on the need for stronger state and Federal drug safety laws.

During his testimony, Mr Guest pointed out that GlaxoSmithKline had concealed the results of clinical trials linking Paxil to an increased risk in suicidality among adolescents, as proven, he noted, by New York Attorney General, Eliot Spitzer’s successful lawsuit against Glaxo.

Furthermore, he told the committee, the hidden trials also revealed that Paxil was actually less effective than placebos among adolescents.

Mr Guest also told the committee that these abuses by drug companies have not ended. As recently as September 29, 2006, he noted, the FDA released a Public Health Advisory that said Bayer, maker of Trasylol, failed to inform an advisory committee during a hearing held 8 days earlier to discuss Trasylol, of a new study that revealed an increased risk of death, serious kidney damage, congestive heart failure and stroke.

In addition, Mr Guest described problems created by fraud and falsification of studies used in the drug approval process. “In the recent case of Ketek,” told the panel, “the FDA found multiple instances of fraud in the company’s clinical trial of about 24,000 patients, some cases of which the maker Sanofi already knew about yet failed to notify the agency.”

Internal FDA emails that surfaced during a previous Congressional investigation revealed that the FDA was aware of the dangers with the drug and that at least four FDA safety officials, Dr David Graham, Dr Charles Cooper, Dr David Ross and Dr Rosemary Johann-Liang, had voiced serious concerns about the safety of Ketek (telithromycin).

“It’s as if every principle governing the review and approval of new drugs was abandoned or suspended where telithromycin is concerned,” Dr Graham wrote in an email calling for “immediate withdrawal,” of Ketek.

On the Republican side of the isle, the Democrats have a strong ally in Senate Finance Committee chairman, Senator Chuck Grassley (R-Iowa), who also has been one of the FDA’s most out-spoken critics since the Vioxx and SSRI disasters.

His latest focus has been on the FDA’s handling of the Ketek debacle. In a May 1, 2006 press release, Senator Grassley expressed concerns over the FDA’s complicity with the drug company and its subsequent failure to ensure the integrity of a study on the benefits and risks of Ketek. In another statement released on June 29, 2006, he said, “Ketek is another example where the F.D.A. accommodated a drug maker and turned a blind eye to serious safety concerns.”

Critics say the worst conflicts of interest within the FDA are the result of major Big Pharma influence over the Bush appointed officials at the top.

According to Robert Brava-Partain, an associate attorney at the national law firm of Baum Hedlund, the FDA has become an “approval factory” for drugs that are ineffective and dangerous. “This factory is manned by doctors who, in any other setting,” he says, “would have irreconcilable conflicts of interest with the companies the agency is supposed to be monitoring.”

And at the top of the factory, he says are, “political appointees who make no apologies for engaging in promanufacturer advocacy.”

On November 12, 2005, the Boston Globe reported that prior to his job at the FDA, Deputy Commissioner of Medical and Scientific Affairs, Dr Scott Gottlieb worked for the PR firm of Manning Selvage & Lee and that his clients included Ketek maker Sanofi-Aventis, which is also the parent company to the nation’s sole flu vaccine maker, and Roche, maker of Tamiflu.

According to the Globe, Manning paid Dr Gottlieb a monthly retainer of $12,500 for nine months for work involving 8 companies, and he was also paid $9,000 for consultant work for VaxGen, a company that won an $878 million government contract to supply the US with 75 million doses of anthrax vaccine.

Dr Gottlieb and Dr Nissen recently went head to head when they both participated in a debate on the topic: “Government Science Panels: Fair and Balanced?” moderated by National Public Radio’s Snigdha Prakash, and sponsored the Center for Science in the Public Interest, reported on August 2, 2006, by Russell Mokhiber and Robert Weissman, in Common Dreams.

To his credit, Dr Nissen can never be called a back-stabber because while sitting next to fellow panelist, Dr Gottlieb himself, Dr Nissen very candidly described the conflicts of interest which he described as “evident at the highest levels of the FDA.”

“For years,” he said of the FDA leadership, “we had an interim FDA Commissioner, Lester Crawford, who shortly after confirmation, abruptly resigns, apparently because he and his wife owned stock in regulated companies.”

“Then the administration appointed Andrew Von Eschenbach as interim commissioner,” he noted, “creating another conflict.”

“In his role as director of the National Cancer Institute,” Dr Nissen said, “Von Eschenbach must seek FDA approval for human testing or approval of new cancer drugs, an obvious conflict.”

But even worse, after that, Dr Nissen stated, “the administration appointed Scott Gottlieb as deputy commissioner.”

“He came to this job with no regulatory experience, directly from Wall Street, where he served as a biotech analyst and stock promoter,” Dr Nissen told the audience.

Dr Gottlieb’s reply to Dr Nissen’s remarks, was basically that he would not dignify the comments with a response.

This month, Dr Gottlieb presented an early Xmas gift to one of his former employers, Inamed Corp, when the FDA announced that it would lift restrictions on the sale of silicone gel breast implants on November 17, 2006.

Firms that Dr Gottlieb was involved with prior to his gig at the FDA, according to the Boston Globe, include “Inamed Corp., one of two companies seeking to return silicone gel implants to the market.”

As for the last FDA commissioner, 2 months after Mr Crawford was confirmed, MSNBC announced: “Embattled Food and Drug Administration Commissioner Lester Crawford abruptly resigned Friday, telling his staff that at age 67 it was time to step aside.”

In a resignation letter to Bush on September 23, 2005, Mr Crawford said his resignation was “effective immediately.”

On October 26, 2005, the Wall Street Journal stated: “As late as 2004, former Food and Drug Administration head Lester Crawford or his wife owned stock in companies that make or distribute products regulated by the agency.”

Six months later, on April 29, 2006, the New York Times reported that Mr Crawford, was under criminal investigation by a federal grand jury over allegations of financial improprieties and false statements to Congress, quoting his lawyer, Barbara Van Gelder.

On October 16, 2006, the Associated Press said that Mr Crawford had agreed to plead guilty to charges of failing to disclose a financial interest in firms regulated by his agency. “The Justice Department accused the former head of the Food and Drug Administration in court papers,” the article stated, “of falsely reporting that he had sold stock in companies when he continued holding shares in the firms governed by FDA rules.”

After leaving the FDA, Mr Crawford quickly moved on to a job with a firm called Policy Directions, Inc. A few of the firm’s accomplishments for clients listed on its Web site are: (1) achieved FDA advisory committee support for a product that had originally been voted down; (2) Interceded with FDA when the agency failed to provide final approval for client’s product because it had granted orphan drug status for a product by another company and client’s product was approved; (3) created a coalition of six biotechnology firms to promote legislation advantageous to client and meet with agency officials to prevent onerous rulemaking; (4) wrote industry-coalition draft of legislative authority for a regulatory agency that was included in final bill; (5) created and led coalition of universities, research institutions, pharmaceutical and biotechnology companies to lobby Congress to stop a federal agency from costly and ineffective rulemaking; and (6) led an industry coalition that stopped several negative amendments to agriculture/FDA appropriations bills.

On its Web site, the firm also states, “PDI has longstanding relationships with key personal and committee staffs in Congress, as well as with critical players at important agencies within the Administration.”

That appears to be an understatement since Mr Crawford joined the company. The firm should put modesty aside and inform potential clients that it now has inside information about the status of each and every drug, device, and company regulated by the FDA.

Although Mr Von Eschenbach has served as acting commissioner since Mr Crawford left in disgrace, critics say the likelihood of his confirmation as the permanent commissioner is not a done deal, especially now that Senator Grassley is protesting his confirmation and became the third Republican to join the campaign to block the nomination.

As for the Senator’s reasons, it seems that Mr Von Eschenbach has refused to cooperate with Senator Grassley’s investigation into the FDA’s approval of Ketek and has refused requests for agency documents and interviews with FDA staff, even after subpoenas were issued, according to a November 16, 2006 letter that Senator Grassley sent to Senate Majority Leader Bill Frist (R-TN).

“I am extremely disturbed,” Senator Grassley wrote, “by the Acting Commissioner’s continued failure to comply with the committee’s subpoenas over the past six months.”

There are three major FDA advisory committee meetings scheduled for December, 2006 to review: drug-eluting stents on December 7-8; SSRI use and adult suicidality on December 13; and Ketek on December 14-15.

But it does not appear that the FDA is too worried about improving the public image of the advisory panels because reports from persons wanting to speak at the SSRI hearing say the FDA is refusing to allow enough time for public comments and is refusing to release the complete list of names for members of the panel until the day before the hearing making it impossible to determine whether they have financial ties to SSRI makers.

Filed under: 2006, Avandia, FDA, FDA Crawford, Gottlieb, Ketek, Manning, Paxil, SSRIs, Trasylol

Congressmen on War Path Over FDA Approval of Ketek

Evelyn Pringle June 2006

French drug giant Sanofi-Aventis has stopped enrolling pediatric patients in clinical trials for Ketek. On June 9, 2006, the drug maker said it halted tests on its own to ensure that trials of the drug complied with FDA requirements.

The company denied that the studies were suspended because of safety concerns. However, the move jives with the recently initiated investigations into the FDA’s collusion with Aventis in the approval of Ketek by two powerful Congressional Committees.

The FDA’s conduct regarding Ketek is under investigation by House Representatives Edward Markey (D-MA), and Henry Waxman (D-CA), senior Democrats on the House Energy and Commerce Committee. On May 1, 2006 the lawmakers sent a letter to the FDA questioning its actions surrounding the approval of Ketek.

In a press release announcing the investigation, the lawmakers said, “though the FDA has consistently assured the public of Ketek’s safety and efficacy, public documents obtained and examined by Reps. Markey and Waxman’s staff indicate that the approval process for this drug was seriously flawed.”

Most recently, on June 8, 2006, the Senate Finance Committee sent a letter to the FDA asking: “Is the FDA considering temporary suspension of these trials until the serious concerns and issues related to Ketek are resolved?”

The company had been testing Ketek for treatment of ear infections and tonsillitis in nearly 4,000 children in the US and a dozen or so other countries. A search of the Clinical Trials.gov web site shows three ongoing trials in the US of children ages 6 months to 13 years, including:

(1) TELI COM – Telithromycin in Children With Otitis Media,

(2) TELI TON – Telithromycin in Tonsillitis, and

(3) Comparative Study to Evaluate the Efficacy and Safety of Telithromycin Given Once Daily Versus Cefuroxime Axetil Given Twice Daily in Children With Middle Ear Infections.

A fourth trial, “TELI TAD – Telithromycin in Tonsillitis in Adolescents and Adults,” involves children 13 and older.

The FDA approved Ketek on April 1, 2004, for the treatment of adults with community-acquired pneumonia, sinusitis, and acute exacerbation of chronic bronchitis.

Over the past several months, several allegations related to the FDA’s approval of Ketek have caught the attention of the Senate Finance Committee Chairman Senator Charles Grassley (R-Iowa).

The Senate Committee has jurisdiction over the Medicare and Medicaid programs and, accordingly, a responsibility to the more than 80 million Americans who receive health care coverage, including prescription drugs, under those programs.

Senator Grassley’s intense oversight of the FDA began in 2004 over the agency’s reluctance to allow information to become public about the risks of pediatric use of SSRI anti-depressants. He has since put pressure on the FDA to make administrative changes to improve its transparency and post-market surveillance of drugs, in addition to introducing legislation to implement these kinds of reforms.

Among the most serious allegations about Ketek is that the FDA approved the drug despite unresolved questions about the drug’s safety and efficacy, with full knowledge that some of the clinical data submitted to support the drug’s approval was tainted by integrity problems. Documents provided to the Senate Committee show that at least one of the clinical trials, Study 3014, was fraudulent.

In April 2001, Ketek’s initial approval came before the Anti-Effective Drugs Advisory Committee to consider whether its efficacy in treating respiratory infections supported its use given the risks of cardiac and hepatic toxicity and vision problems associated with Ketek.

Based on these concerns, the AIDAC recommended that Ketek not be approved and said Aventis should conduct a large clinical study. A letter to Aventis dated June 1, 2001, said in part: “This study should include the monitoring and analysis of all adverse events, with particular attention to hepatic, visual, cardiovascular, and vasculitic adverse events.”

Aventis subsequently hired Pharmaceutical Product Development (PPD) to conduct a study designed to enroll patients with respiratory infections in the offices of more than 1800 primary care physicians all across the country. Subjects were randomized for treatment with Ketek or Augmentin, another antibiotic.

In October 2001, doctors began enrolling subjects and were paid $100 for each patient they signed up, and another $150 when they submitted study results, as well as a final $150 after all questions were resolved, according to the May 1, 2006 WSJ.

The potential for money-making by doctors enlisted for this study was enormous. A fact that obviously did not go unnoticed by certain physicians who signed on to the study.

On July 24, 2002, Aventis submitted the results of Study 3014 to the FDA, but without fully disclosing the study’s integrity problems.

When the AIDAC reconvened to consider the study, the FDA presented it to the panel without disclosing that the agency’s Division of Scientific Investigation and Office of Criminal Investigation were investigating both the conduct and integrity of the study. Without the benefit of this information, the AIDAC voted to recommend the approval of Ketek.

In the end, a March 25, 2004 memorandum, prepared by the Division of Scientific Investigations titled, “DSI Recommendations on Data Integrity,” states that Study 3014 involved “multiple instances of fraud” and that “the integrity of data from all sites involved in [the] study … cannot be assured with any degree of confidence.”

In a press release on May 1, 2006, Senator Grassley said he was concerned about the FDA’s complicity with the drug maker and subsequent failure to ensure the integrity of a pivotal study about the benefits and risks of Ketek. Specific allegations under investigation by the Senate Committee include that FDA management:

(1) accepted the resubmission of a new drug application for Ketek, which included fraudulent data in support of approval;

(2) presented fraudulent study data to an advisory committee tasked with recommending Ketek’s approval or disapproval;

(3) instructed FDA scientists appearing before an advisory committee that they should present fraudulent data because discussing issues regarding data integrity and the conduct of the safety study would not be “productive;”

(4) approved a pediatric clinical trial, involving infants as young as six-months old, despite concerns related to known toxicities, including hepatic, visual, cardiovascular, and vasculitic adverse events; and

(5) continued to knowingly cite the fraudulent study in publicly released safety information on Ketek.

Given that the advisory committee had recommended conducting Study 3014 in the first place, theses allegations are “all the more outrageous,” according to Senator Grassley.

The AIDAC members certainly would have been interested to know that the highest enrolling doctors were being investigated and that there appeared to be significant under reporting of adverse events.

For example, the investigator at the highest enrolling site, Dr Ann Campbell, was found to be enrolling patients when the clinic was closed, and patient consent forms had date modifications and signature inconsistencies.

Dr Campbell had a practice in Alabama, that attracted patients by advertising weight-control treatments. “By the middle of January 2002,” according to the May 1, 2006 Wall Street Journal, “she had signed up 287 patients and was receiving enough of the drugs to enroll 30 new people a day, according to emails sent by a PPD employee on Jan. 15 and 17.”

On February 27, 2002, Nadine Grethe, an Aventis manager overseeing the study, got an email from PPD warning that there were possible problems with Campbell including the lack of “proper diagnosis of an appropriate medical condition,” medical charts described as “very limited,” and lab test results that were “suspiciously similar” for multiple patients. PPD also found that many patients signed up during a lunch break when the office was supposed to be closed.

The suspicions were validated on August 29, 2003, in the case of Maria “Anne” Kirkman, MD, aka Maria “Anne” Kirkman-Campbell, DOH Case No 2004-20974, when Campbell was charged in a 21 count indictment in the US District Court for the Northern District of Alabama with 10 counts of using a scheme or fraud to obtain money and property by means of false pretenses and documentation, and 11 counts of knowingly and willingly making and using, and causing to be made and used false writing and document knowing it to contain a materially false, fictitious and fraudulent statement and entry.

The information alleged that Campbell falsified documentation released to a study to establish the safety and effectiveness of Ketek before it could be a approved by the FDA.

Despite all this, when Aventis submitted the results of Study 3014 to the FDA, they included 407 of Campbell’s patients, and “did not alert the Agency to any problems” with Campbell, according to a review of Ketek’s history, safety and efficacy by FDA official, Dr David Ross, on the FDA web site.

Campbell was eventually sentenced to 57 months in prison and was given an additional 3 years of supervised release after the prison term is completed. She was also fined $557,251 and ordered to make restitution to Aventis to the tune of $925,774.

An FDA inspector ended up at Campbell’s office in late 2002, simply by chance because she had enrolled so many patients. The investigator found patients who said they had not received any medication, even though their records said they had, according to Dr Ross. Others patients were being treated for weight loss and not respiratory infections, and some subjects were friends and members of Campbell’s family.

Dr Egisto Salerno was a study investigator in San Diego whose 214 patient recruitment made him the 3rd largest recruiter. Here is part of what was known about Salerno at the time he was conducting the study, according to a report by the Medical Board of California, Department of Consumer Affairs, on March 6, 2006

Petitioner started using cocaine in 1994 on an occasional, recreational basis. His use gradually escalated from occasional use in the mid-1990s to using cocaine every weekend by 2001. He “extended” his weekends to use cocaine by taking time off from his practice on Fridays, and sometimes on Thursdays or Mondays as well. He did not use cocaine before seeing any patients. Petitioner testified his denial of his addictions was so intense he was unaware he was dependent. The use of cocaine became an essential part of petitioner and his wife’s lives.

Petitioner admitted ingested cocaine and drank alcohol Monday morning, April 22, 2002, after which he thought four or five people were inside his home. He armed himself with a loaded .45 caliber handgun. He threatened to kill his wife if she called the police. His mother in law found out what was going on and contracted the police, who responded to petitioner’s home. Petitioner was armed and other weapons n the home, but most of them were antiques. Petitioner was under the influence of drugs and was arrested.

Dr Jeffrey McLeod was another quack who participated in the study from Virginia. On August 24, 2005, the FDA recommended that he be disqualified as a trial investigator and sent him a letter outlining his fraudulent conduct in the Ketek study and said in part:

The FDA’s Center for Drug Evaluation and Research believes that you have repeatedly or deliberately violated regulations governing the proper conduct of clinical studies involving investigational new drugs as published under Title 21, Code of Federal Regulations (CFR, Part 312, and that you submitted false information in a required report to FDA or the sponsor.

The FDA told McLeod: (1) You failed to obtain informed consent from seven subjects; (2) For six subjects you provided consent documents that were signed and dated after they had completed the study; and (3) For 17 subjects you provided documents in which the signatures were backdated to make it appear that informed consents were obtained prior to their enrollment in the study.

The investigation even found that consent forms for 22 of the 23 patients contained a date that preceded the date McLeod received the informed consent templates on March 4, 2002, including 13 documents with his own signature. A member of his staff also told the FDA investigator that McLeod instructed her to backdate the consent signatures.

In addition, the study protocol required clinical lab tests on subjects at visit 1 and 2, but there was no documentation to show that such tests were conducted on 11 subjects.

The protocol required that women of childbearing age have a urine pregnancy test before taking the study medication, but there was no documentation to show that the tests were done on 6 subjects.

The protocol also required McLeod to document adverse events and determine whether any events were of “special interest” as that term was defined in the protocol. The investigator said, that even though records showed that 2 subjects had lab tests to evaluate what was identified on the lab report as a “Cardiac Adverse Event,” the case report submitted by McLeod states that these subjects experienced no adverse events.

For some subjects, McLeod failed to remove the tear-off labels and place them in the Case Report Form so it could not be determined which medication the subjects were given.

Finally, one subject was enrolled despite a documented allergy to the penicillin antibiotic.

Another ace investigator was Dr William Terpstra, of Indiana who had more than 150 patients enrolled in the study. However, an investigation found that he had over 20 violations of the study instructions.

All that said, in April 2006, the results of Study 3014 were cited in an article in the New England Journal of Medicine that claimed Ketek was as safe as other antibiotics. However, five of the 6 six authors had to disclose that they had received consulting fees from Aventis, and that at the time of the study, the 6th author was an employee of Aventis.

In his June 8, 2006, letter, Senator Grassley asked the agency to explain what it is doing to inform parents about the safety issues surrounding pediatric trials of Ketek and pointed out that he had posed the same question to the agency 6 weeks earlier but had not yet gotten an answer.

Filed under: 2006, FDA, Ketek, Sanofi-Aventis

Lawmakers Demand Answers About Ketek From FDA

Evelyn Pringle June 13, 2006

The FDA has continued to cite a fraudulent study in information released to the public about the safety of the antibiotic Ketek. On January 20, 2006, the agency issued a Public Health Announcement, in response to an article in the Annals of Internal Medicine, where researchers reported three cases of severe liver problems in patients taking Ketek.

The article reported one patient at the Carolinas Medical Center in Charlotte, NC, had died after taking Ketek, another required a liver transplant, and a third patient recovered from drug-induced hepatitis after treatment with Ketek was stopped. The Annal’s report also said that Sanofi-Aventis reported 7 cases of hepatitis or hepatocellular damage in patients taking Ketek in data from Phase III trials.

On June 9, 2006, drug maker Sanofi-Aventis made the announcement that it had stopped enrolling children in clinical trials for Ketek and said it halted tests to ensure that clinical trials complied with FDA requirements. The company did not mention the heat coming from two powerful Congressional Committees.

As it turns out, the cases above are not the only serious Ketek related adverse events that have been reported to the FDA. According to a review by the staff of the Senate Finance Committee, of reports in the Adverse Event Reporting System between July 2005 and September 2005, the most recent 3 month period available, two deaths, 35 liver adverse events, 44 cardiac adverse events, and 80 visual adverse events have been recorded.

Because it is well-known that only between 1% and 10% of adverse events are ever reported to the FDA, the numbers above would have to be multiplied many times over to establish a true accounting of the adverse events associated with Ketek.

Along with the January 20, Public Announcement, the FDA posted a document titled, “Questions and Answers on Telithromycin (marketed as Ketek),” on its web site, that asked, “What information was known about liver problems related to telithromycin prior to approval?”

In response, the FDA said, “Based on the pre-marketing clinical data it appeared that the risk of liver injury with telithromycin was similar to that of other marketed antibiotics.”

Prior to the approval of Ketek, the agency said, the FDA looked extensively at the potential for hepatic toxicity in patients treated with Ketek. The data examined included a 25,000 patient controlled study, as well as information in nearly 4 million postmarketing prescriptions outside the United States.

The release of this public announcement is what initially sent Senator Charles Grassley (R-Iowa), chairman of the Senate Finance Committee, on the warpath. He demanded an explanation as to why the FDA continued to cite Study 3014 without disclosing that the Anti-Effective Drugs Advisory Committee voted to recommend the approval of Ketek, without knowledge that the study was fraudulent.

In a press release on May 1, 2006, Senator Grassley said he was concerned about the FDA’s complicity with the drug maker and subsequent failure to ensure the integrity of a pivotal study about the benefits and risks of Ketek.

On May 16, 2006, he called it “mystifying” that the FDA continued to provide information the agency knew was fraudulent, and said that he’s keeping the pressure on the FDA for more information about the drug’s approval and post-market surveillance. He continues to seek a face-to-face interview with the FDA investigator who discovered the fraud and misconduct in Study 3014.

The study began in October 2001, when doctors began enrolling subjects and were paid $100 for each patient they signed up, and another $150 when they submitted study results, as well as a final $150 after all questions were resolved, according to the May 1, 2006 Wall Street Journal.

On July 24, 2002, drug maker Aventis submitted the results of the study to the FDA, but without disclosing the study’s integrity problems.

When the AIDAC reviewed the study, the FDA did not disclose that the agency’s Division of Scientific Investigation and Office of Criminal Investigation were investigating the integrity of the study.

A memorandum dated March 25, 2004, by the FDA’s Division of Scientific Investigations titled, “DSI Recommendations on Data Integrity,” states that Study 3014 involved “multiple instances of fraud” and that “the integrity of data from all sites involved in [the] study … cannot be assured with any degree of confidence.”

The infractions discovered were not minor. The doctor with the highest number of patients, Dr Anne Campbell, was subsequently charged in a 21 count indictment related to her fraudulent conduct during the study, and in March 2004, she was sentenced to 57 months in prison.

The doctor with the 3rd most patients was in the chronic stage of cocaine addiction and was arrested the same month the study was submitted to the FDA with cocaine in his underwear while holding his wife hostage with a gun.

Another doctor engaged in such blatant misconduct that he was disqualified as an investigator and barred from participating in future clinical studies. Still another investigator with 150 patients was cited with 20 violations of the studies instructions.

“It looks like the FDA caught the drug company red handed,” Senator said in a press release, “and let them get away with it.”

“On top of that,” he said, “the FDA failed to set the record straight and, in fact, continues to cite a discredited safety study as a principal reason to feel okay about using this drug.”

The power struggle between the top dogs at FDA and Senator Grassley has been ongoing for nearly 2 months. In a letter to the FDA on April 26, 2006, Senator Grassley asked the FDA to: “Please explain in detail why the FDA has continued to cite Study 3014 in its safety information for Ketek.”

Senator Grassley said the stakes continued to grow when it comes to overseeing Ketek, because it was being tested in children as young as 6-months-old, and the Senate Committee has received equally serious allegations related to the post-market surveillance of the drug.

For example, in the FDA-approved pediatric clinical trial, known as “TELI COM – Telithromycin in Children With Otitis Media,” despite the known toxicities of Ketek, including evidence of hepatic, visual, cardiovascular adverse events, the FDA was allowing Aventis to experiment on children as young as six-months old.

The Senate panel reviewed a report from the Adverse Event Reporting System that details a suspected visual adverse event in a 15-month old girl participating in the study. According to the report, on 3 occasions the mother observed the girl having staring spells one day after taking Ketek, and one spell lasted for 60 seconds.

The investigator-doctor initially listed the event as related to Ketek and “serious.” However, in addendums to the report, dated months later, the investigator downgraded the event and assessed it to be “non-serious,” not interpreted as a “visual event,” and that a “staring spell is considered unexpected.”

“Given that the Ketek label warns of severe cases of visual problems,” Senator Grassley wrote in the letter to the FDA, “please advise the Committee what action has been taken to fully inform the parents of infants and children enrolled in this study about the risks and benefits of Ketek, including its known liver and visual toxicities.”

In addition, the Senator said he wants FDA staff to make “immediate arrangements” for his staff to review documents and information related to Ketek and Study 3014, including, but not limited to, the administrative files within DSI, OCI, and the Office of Compliance.

“Given the gravity of the Ketek allegations,” the Senator wrote, “I respectfully request that your staff contact my Committee staff by no later than Friday, April 28, 2006, so that my Committee staff may travel to your offices as soon as possible to review the requested administrative files.”

“As Chairman of the Committee,” he added, “I also respectfully request that senior FDA management officials be prepared to brief my Committee staff within three weeks of the date of this letter.”

The FDA’s approval of Ketek is also under investigation by the House of Representative’s Energy and Commerce Committee. On May 1, 2006, Representatives Edward Markey (D-MA), and Henry Waxman (D-CA), the senior Democrats on the Committee, sent a letter to the FDA questioning the approval process for Ketek and the potential dangers involved in conducting clinical trials on children.

In announcing the investigation, the Congressmen issued a press release saying, “public documents obtained and examined by Reps. Markey and Waxman’s staff indicate that the approval process for this drug was seriously flawed.”

Rep Markey said, “I am very concerned that the FDA approved Ketek even though it may be neither safe nor effective, and that FDA has allowed the sponsor to give this drug to children in clinical trials.”

“Recently,” he said, “the GAO found that the FDA does not have a good enough system in place to protect the public from drugs once they are on the market.”

However, he continued, “the Ketek case shows that the FDA may also not be doing a good enough job deciding which drugs should or should not be approved in the first place.”

“We need to look more closely at the Ketek case,” Rep Markey advised, “to determine whether this approval was made in error, and we need to assess whether the Ketek approval process reflects broader systemic problems within the FDA.”

“We cannot allow this critical public health watch dog agency,” he warned, “to become a lapdog for the pharmaceutical industry.”

Congressman Waxman is equally disturbed. “The Ketek case demonstrates the urgent need for reform at the FDA and in the pharmaceutical industry,” he said.  

“FDA approved the drug on flimsy data without resolving the safety issues, and it failed to penalize Aventis,” Rep Waxman noted. “Americans deserve more vigilance from FDA and from the companies that make critical medical treatments.”

“We know drug companies manipulate published studies on their drugs, hiding negative information from physicians,” he added. But here, Aventis went even further he said, by “failing to disclose to FDA grave flaws in a key safety study.”

The Markey-Waxman letter, requests numerous documents and responses to questions on the approval process for Ketek, and other drugs, and states: “The public has a right to know how the FDA reached its decision to approve Ketek and whether they can rely on those conclusions.”

The battle between the FDA and Senator Grassley intensified on June 8, 2006, when he once again wrote to the agency and pointed out that he had asked the exact same questions 6 weeks earlier in a letter but had received no answers.

The Senator said he was repeating his request for answers based on a New York Times article that revealed FDA experts’ concerns about trials involving children and infants.

“The adverse events identified with Ketek are serious ones and the possibility that any six-month old child is being exposed to these kinds of risks unnecessarily is unconscionable,” he wrote to Acting Commissioner, Andrew von Eschenbach.

The New York Times article titled, “Halt Is Urged for Trials of Antibiotic in Children,” reported that this recommendation was made by FDA officials in the Office of Drug Safety and Dr Danny Benjamin, an infectious disease specialist at Duke University, who consulted on the pediatric trials.

According to the Times, an internal review of reports by ODS officials found 110 cases of liver failure or serious liver injury associated with Ketek, since the drug was approved, and most of the events occurred in otherwise healthy people. Twelve adult patients suffered liver failure, including four who died, and 23 others suffered serious liver injury.

A leaked internal FDA memo dated May 16, 2006, says Ketek patients have a higher rate of acute liver failure and deaths than those using other antibiotics.

Based on their review, these agency officials recommended that the FDA “consider forcing Sanofi-Aventis to withdraw Ketek from the market, severely restrict its uses, even in adults, or add a prominent warning to its label about potentially fatal side effects.”

The NYTs also reported that in light of the risk of fatal liver failure, blurred vision and loss of consciousness, FDA official, Dr Rosemary Johann-Liang, questioned the agency’s decision to allow pediatric trials to continue and whether it was even possible to assess blurred vision and loss of consciousness in very young children.

The article said that Dr Benjamin also “concluded that the pediatric trials with Ketek were a cause for concern and ‘hard to support.'”

In a memorandum, Dr Benjamin noted that in up to 87% of the cases, ear infections resolve themselves within a few days without treatment and that tests of an unusually risky antibiotic in infants might only be justified if the infants had already been treated unsuccessfully with safer a antibiotics first.

In his letter, Senator Grassley said: “Now my concerns are even further heightened by the New York Times article on ODS’s assessment of adverse events associated with Ketek and Dr. Johann-Liang’s and Dr. Benjamin’s conclusions regarding the pediatric trials.”

“Let me reiterate,” he wrote, “that more than 6 weeks ago I asked you to advise the Committee of “what action has been taken to fully inform the parents of infants and children enrolled in this study about the risks and benefits of Ketek.”

“Unfortunately,” he said, “I have not received a response to this important question, and I presume that parents who have enrolled their children in the trials have not been advised of anything either.”

“If there are no plans to update consent forms and patient brochures at this time,” he wrote, “please provide a rationale for the FDA’s decision.”

Senator Grassley also wants an interview set up with Dr Rosemary Johann-Liang no later than June 28, 2006 and instructed the FDA to make the arrangements no later than June 12, 2006.

“The adverse events identified with Ketek are serious ones,” Senator Grassley wrote, “and the possibility that any six-month old child is being exposed to these kinds of risks unnecessarily is unconscionable.”

Sanofi-Aventis is the world’s third-largest pharmaceutical company with revenue in 2005 of $34 billion. 3.35 million prescriptions for Ketek were written in the US in 2005 amounting to $193 million in sales, according to IMS Health.

No doubt in response to all the bad publicity, sales of Ketek are in a freefall. According to Verispan LLC, a drug tracking firm, in the 22 weeks ending June 2, 2006, the number of prescription written for Ketek dropped 69%.

Filed under: 2006, FDA, Ketek, Sanofi-Aventis

FDA Still Dodging Bullets Over Ketek

Evelyn Pringle September 26, 2006

In recent months Senator Charles Grassley (R-IA), is like a dog with a bone when it comes to investigating why FDA officials approved the antibiotic, Ketek, despite its knowledge that the main pre-approval study on the drug was riddled with fraud.

Ketek first sought approval in 2000, but approval was denied due to indications of side effects such as liver damage, blurred vision, and others found in a review of the clinical trials submitted by Aventis.

The FDA requested more information so the drug maker hired Pharmaceutical Product Development to conduct a study known as 3014. Senator Grassley became alarmed after he learned that the FDA approved the drug knowing that some of the clinical trials involved in study 3014 were fraudulent.

And the allegations of fraud involved serious misconduct and they were confirmed. For example, the trial with the largest number of subjects was conducted at a weight loss clinic in Gadsden, Alabama, and Dr Maria Kirkman-Campbell, the doctor involved, is currently sitting in a federal prison serving a 5-year sentence for submitting falsified data to Aventis.

While enrolling patients at record speed she used relatives and friends, and subjects who did not have respiratory infections, and subjects who never received the drug. A former nurse at the clinic, Michelle Snedeker, told ABC News on June 14, 2006, that she was ordered to forge documents and report data on people who had never been given Ketek.

According to the ABC report, Dr Kirkman-Campbell was paid $400 for each of the 407 subjects enrolled which comes to $162,800.

Internal Aventis documents obtained and made public by the Wall Street Journal in May 2006, show that Aventis was worried about Dr Kirkman-Campbell early on but the drug maker did not inform the FDA about the fraud and an agency inspector subsequently discovered it during her own investigation.

Ketek was finally approved in April 2004 for the adult treatment of acute bacterial infections from chronic bronchitis, acute bacterial sinusitis and community-acquired pneumonia. The drug has since been linked to extremely serious adverse reactions.

In a January 27, 2006 statement, the European Medicines Agency said that it had asked Ketek maker, Sanofi-Aventis SA, to add stronger warnings about potential liver problems to the Ketek label. The EMEA statement included the following:

“Cases of serious acute hepatitis, including liver failure, some of which were fatal, have been reported to and assessed by the EMEA in the context of the continuous monitoring of the safety of Ketek.

“The reported serious liver reactions started during or immediately after treatment with Ketek and were, in most cases, reversible after use of this product was discontinued.”

In this country, an article first published online in January 2006, and then in the print edition of the March 21, 2006, Annals of Internal Medicine, described three cases of liver damage in patients taking Ketek at a Medical Center in Charlotte, North Carolina.

One patient took the drug for only five days and died from liver failure two weeks later, another patient with liver failure required a liver transplant, and the third patient developed hepatitis.

To counter the bad publicity caused by reports of liver damage, an April 2006 article in the New England Journal of Medicine claimed that Ketek was as safe as other antibiotics. But in an all-too-common scenario these days, it turns out that all six authors of the article had financial ties to Sanofi-Aventis. Five authors earned consulting fees and one was an employee.

A little over 2 years after Ketek was approved, in May 2006, the FDA recommended that a black box warning be added to the Ketek label, stating that “severe, life-threatening, and in some cases fatal” liver toxicity has been reported in patients taking Ketek

In mid-June 2006, after months of trying to set up a meeting to obtain information from the FDA inspector involved in the investigation of the fraudulent Ketek study, which Senator Grassley described as, “key to understanding what the FDA did when it became clear that the safety study required by the FDA in order to approve the drug was fraudulent and faulty,” he marched over to the Department of Health and Human Services insisting that he had a right to interview the investigator and obtain the information.

After a brief conversation with senior officials from the HHS and FDA, and no luck in setting up the meeting, the Senator left the agency furious. “I’m tired of the runaround,” he said outside the HHS headquarter.

He said he told the officials, “I know it’s probably not your intent to protect companies, to cover for companies.” But every time “you stand in the way of information getting out that ought to be public, that’s the impression you give the American people.”

He is “committed to getting to the bottom of the matter,” he told the Wall Street Journal on June 13, 2006.

About two week after his visit to the FDA, on June 30, 2006, the agency issued a warning that Ketek could cause acute liver failure after only a few doses and advised physicians to monitor patients on Ketek closely.

In the two years that Ketek was on the market through April 2006, the FDA said it received reports of 12 cases of acute liver failure, and 23 cases of serious liver injury. Of those cases, four people died and one patient required a liver transplant.

The debacle involving the FDA approval of Ketek has now become a bi-partisan battle against senior FDA officials by members of Congress from both sides of the isle.

On September 5, 2006, US Representatives, Edward Markey (D-MA), John Dingell (D-MI), Henry Waxman (D-CA), and Bart Stupak (D-MI), of the House Energy and Commerce Committee, and Chairman of the Senate Finance Committee, Senator Grassley, sent a letter asking the Government Accountability Office (GAO) to investigate the FDA’s reliance on non-inferiority studies, which experts say are not appropriate for approving drugs like Ketek that have serious, even lethal side effects.

According to Rep Markey, who organized the group that sent the letter, “The Bush Administration’s FDA has been working hand in glove with the drug industry for six years, leaving Americans vulnerable to dangerous drugs and insufficient information about the side effects of those drugs.”

“This practice,” he stated, “has lead to growing bipartisan concerns about the direction the FDA has been taking.”

The most common way of establishing the effectiveness of a drug is to compare the outcome of a patient taking the test drug to the outcome of a patient taking a placebo. However, if the likely outcome of taking a placebo might be death or other serious health conditions, then the effectiveness of the drug must be established by some other method.

One method used involves the use of a “non-inferiority” study, in which one group of test subjects is given a drug of known effectiveness and a second group is given the drug for which effectiveness needs to be established.

The new drug’s effectiveness is considered established if it performs in a similar manner, within some statistical range, to the known medication. Over the years, many concerns have been raised about the use of non-inferiority trials. So the letter from members of Congress asks the GAO to evaluate the FDA’s reliance on these studies.

“A comprehensive GAO study of the FDA’s use of these controversial studies and questionable approval processes,” Rep Markey said in a statement, “is essential if we are to ensure that the FDA is not abandoning it’s commitment to safeguarding public health.”

Senator Grassley said, “These studies which were used to approve the antibiotic Ketek – are dubious because they don’t provide any evidence that a particular drug is any better than nothing at all.”

According to Rep Waxman, “An antibiotic that is no better than a placebo can’t fight off an infection.”

“Worse,” he added, “it can subject you to serious, even life-threatening side effects without any compensating benefit.”

“Americans deserve to have confidence that an FDA-approved drug will be both safe and effective,” Rep Waxman noted.

The dispute over the approval of Ketek follows in a line of similar disputes between the FDA and Senator Grassley over the agency’s interest in protecting industry profits instead of alerting the public to the risks of adverse events associated with dangerous drugs, that began with SSRI antidepressants and Vioxx.

The benefits of the pharmaceutical industry’s influence on senior Bush appointed officials within the FDA cannot be understated. These officials have the power to: (1) control billions of dollars in drug profits; (2) effect drug company stock value; (3) influence litigation; and (4) drive a company out of business.

For the past three years, Senator Grassley has pressured the agency to sever its alliance with drug companies and to act with more independence and transparency. He has also sponsored legislation to mandate a clinical trials registry and a stronger post-market surveillance process within the FDA.

In a September 20, 2006, letter to FDA acting commissioner, Dr von Eschenbach, Senator Grassley called on the FDA to address “persistent” problems at the agency, especially the “too-cozy” relationship with the industry and the inclination of agency leaders to suppress scientific dissent and drug-safety recommendations.

“I am writing this letter,” he advised, “to encourage you to establish and implement a resuscitation plan to restore the FDA’s credibility in the mind of its own employees and the American public.”

“I have frequently criticized the FDA for its relationship with the industry, which I believe is far too cozy,” he wrote. “The FDA needs to distance itself from the industry and return to its role as regulator, not a facilitator,” Senator Grassley told the acting Commissioner.

He said the most powerful message coming from increasing numbers of current and former FDA personnel is that the FDA has “sold out” to the industries it is charged to regulate.

“FDA’s handling of the antibiotic Ketek,” Senator Grassley said, “is another example where the FDA appears to have accommodated a drug company despite the fact that the company submitted fraudulent data from a safety study to the FDA and repeatedly provided incomplete safety information.”

“What baffles me even more,” he continued, “is the fact that the FDA continued to cite Study 3014 in publicly released safety information for Ketek even after its Division of Scientific Investigations concluded that Study 3014 involved “multiple instances of fraud” and that “the integrity of data from all sites involved in [the] study…cannot be assured with any degree of confidence.”

Your recent meeting with FDA staff involved in the review of Ketek is a disturbing example that FDA’s internal dispute resolution processes are not working, he told the acting commissioner. “Instead of reassuring FDA employees that they can raise concerns without being subjected to retaliation or intimidation,” he wrote, “the meeting itself appears to be an act of intimidation.”

It is beyond dispute that FDA employees are being intimidated and muzzled. A survey released by the Union of Concerned Scientists (UCS) and the Public Employees for Environmental Responsibility (PEER) on July 20, 2006, found that approximately one-fifth of the nearly 1,000 FDA scientists surveyed said that they had been asked, for nonscientific reasons, to inappropriately exclude or alter technical information or their conclusions.

One-fifth of those responding said that they have been explicitly asked by FDA decision-makers to provide incomplete, inaccurate or misleading information to the public, industry, the media and government officials, and over one-third said they could not openly express any concerns about public health within the FDA without fear of retaliation.

Experts agree that all new drugs come with possible adverse reactions, and that the list of side effects on the label of a new drug is never complete because there are always cases where certain people may have an unpredicted adverse reaction to a new drug.

However, unfortunately nowadays, once a new drug is approved, mass-marketing campaigns result in millions of people being exposed to the drug long before the serious side effects and problems with long-term use are known.

Filed under: 2006, FDA, Ketek

Ketek Investigation Derails Confirmation of New FDA Commissioner

Evelyn Pringle December 6, 2006

When the Democrats won control of Congress, Senator Charles Grassley may have lost the chairmanship of the Senate Finance Committee, but the current acting FDA commissioner had better not get too settled in because the Senator is apparently not ready to throw in the towel in the on-going battle with him.

In a recent press release accompanying a letter to acting commissioner, Andrew von Eschenbach, Senator Grassley (R-Iowa) said his investigations of the FDA have “shed sunlight on how frequently differences of scientific opinion are quashed, the nature of the cozy relationship between the FDA and the industries it is supposed to regulate, and the failure of the agency to be adequately transparent and accountable to the public.”

For months, the Senator has been requesting specific information from von Eschenbach, related to the FDA’s approval of Ketek (telithromycin), on April 1, 2004, for the treatment of adults with community-acquired pneumonia, sinusitis, and acute exacerbation of chronic bronchitis. Ketek is made by French drug maker, Sanofi-Aventis, and is the first drug in a new class of antibiotics known as ketolides.

“FDA’s handling of the antibiotic Ketek,” Senator Grassley stated in the September 26, 2006 letter, “is another example where the FDA appears to have accommodated a drug company despite the fact that the company submitted fraudulent data from a safety study to the FDA and repeatedly provided incomplete safety information.”

“One of the most troubling allegations,” Senator Grassley told von Eschenbach, “is that the FDA approved Ketek with full knowledge that some of the clinical safety data supporting its approval was beset by systemic data integrity problems.”

Specifically, Senator Grassley is asking the FDA to allow one of its special agents who investigated and assisted in the prosecution of a doctor in a fraud case involving a Ketek study to meet with him. He is also seeking access to FDA documents, including emails about drug.

“As Chairman of the Committee,” he wrote, “I also respectfully request that your staff make immediate arrangements for my Committee staff to interview Special Agent, who successfully investigated and participated in the prosecution and sentencing of Dr. Maria Anne Kirkman Cambpell to nearly five years in prison for her fraud in Ketek Study 3014.”

“In addition,” he instructed von Eschenbach, “provide a copy of all documents and communications related to Ketek and Study 3014 in the possession of Special Agent, including, but not limited to, all emails related to Ketek and/or the Committee’s investigation of Ketek.”

The Senator says the FDA has an obligation to be “forthcoming and open” about its actions. “Serious allegations have been made about misconduct with the drug Ketek,” he states, “and the public should not be mislead with statements about the safety of Ketek that cite a fraudulent study.”

Senator Grassley has gone so far as to issue subpoenas in attempt to interview the FDA investigator and the acting commissioner has simply refused to comply. One day last summer the Senator showed up at the FDA unannounced and requested a meeting with the agent, and that request was turned down flat.

Due to his knowledge of the FDA’s practice of muzzling, intimidating and retaliating against agency employees who cooperate with his investigations, and most specifically Dr Andrew Mosholder and Dr David Graham, during the investigation of the FDA’s handling of the SSRI antidepressants and Vioxx matters, Senator Grassley has taken measures to prohibit such behavior in the Ketek investigation.

In a letter, dated April 27, 2006, he told von Eschenbach to inform FDA employees of their right to speak with Congress and that no records, data or information related to Ketek should be destroyed, removed or otherwise made inaccessible to the Committee.

Furthermore, he said, if any FDA employee believes that he or she has been subject to retaliation for meeting with Committee staff for anything associated with the ongoing investigation of Ketek, the employee should contact the Committee immediately.

At one point, the Senator even hinted that he might cut off von Eschenbach’s salary if he refused to cooperate or retaliated against any employee who does, citing a law that enunciates a prohibition on the use of federal funds to pay the salary of any official who prohibits or prevents or threatens to prevent or prohibit an employee from contacting Congress, and “any punishment or threat of punishment because of any contact or communication by an officer or employee with a Member, committee or subcommittee.”

Dr Graham apparently feels protected because on November 23, 2006, the New England Journal of Medicine published his letter to the editor titled, “Telithromycin and Acute Liver Failure,” in which he criticizes the FDA for failing to follow the recommendation of a 2001 FDA advisory committee which he said had “voted against the approval of [Ketek] primarily because of concern about hepatotoxicity.”

According to Dr Graham, the FDA’s decision to approve Ketek, “was made in the absence of reliable data disproving the concern expressed in 2001 by the advisory committee.”

He reports that an analysis of the FDA’s post-marketing database showed that the rate of reporting of acute liver failure was 3.5 to 11 times as high for Ketek as for other antibiotics on the market, with a reporting rate of 167 cases of acute liver failure per 1 million person-years of use, as compared with the expected rate of 1 case per 1 million.

In the NEJM letter, Dr Graham points out that without accounting for underreporting, which could be 10 times higher, this rate is greater than that of three other drugs previously removed from the market by the FDA because of the risk of acute liver failure.

For many months, Dr Graham has been unsuccessfully calling for the removal of Ketek from the market and in his NEJM letter, he offers some free advice “Given that telithromycin is neither clinically superior to other drugs prescribed for respiratory tract infections nor uniquely life-saving,” he wrote, “physicians, patients, and third-party payers might wish to reconsider their choice of antibiotic for such infections.”

In a recent statement refusing to fully respond to the latest round of questions from Senator Grassley, von Eschenbach said full disclosure of the information could not be released because it “poses an inherent threat to the integrity of the executive branch’s enforcement and litigation functions,” and there would be a “chilling effect” on employees.

That may be true, but Senator Grassley disagrees and that non-responsive comment is instead have a chilling effect on von Eschenbach’s changes of becoming a full-time FDA commissioner because Senator Grassley has officially placed a “hold” on his nomination for commissioner.

The Senator announced his intention to block a Senate vote on the nomination in a November 16, 2006, letter to Senate Majority Leader Bill Frist, (R-TN), because of what he called von Eschenbach’s “continued failure to comply with the Committee’s subpoenas over the past six months.”

In a November 29, 2006, letter to Health and Human Services Secretary Mike Leavitt, Senator Grassley said, “Selectively providing documents and access to executive agency officials pursuant to a congressional subpoena cannot constitute compliance.”

According to the Senator, the questions he wants answered are proper as part of his oversight duties. “Congress has a constitutional responsibility,” he said, “to oversee the executive branch of government, and the FDA as a public agency has a responsibility to be responsive.”

The Senate Finance Committee, he says, has jurisdiction over the Medicare and Medicaid programs and a responsibility to the more than 80 million Americans who receive health care coverage and prescription drugs under those programs.

Among the most serious Ketek related charges under investigation are that top FDA officials: (1) knowingly accepted the resubmission of a new drug approval application which included fraudulent data; (2) instructed FDA scientists that they should present fraudulent data to an advisory committee because discussing issues regarding data integrity and the conduct of the safety study would not be “productive”; (3) approved a Ketek pediatric trial with infants as young as 6-months old, despite concerns about known toxicities, including hepatic, visual, cardiovascular, and vasculitic adverse events; and (4) continued to cite fraudulent study data in publicly released safety information on Ketek.

In mid-May 2006, the FDA’s drug safety office recommended that a Black Box warning be added to the Ketek label, stating that “severe, life-threatening, and in some cases fatal” liver toxicity has been reported in patients taking Ketek.

An internal FDA memo dated May 16, 2006, by FDA safety reviewers said that Ketek was linked to 12 reported liver failures including 4 deaths, 23 reports of serious liver injury, and a higher rate of adverse reaction reports than other antibiotics on the market.

On June 29, 2006, Sanofi-Aventis, issued a press release saying the company was sending out a “Dear Doctor” letter to alert healthcare providers about new bolded text in the Warnings section of the Ketek label that stated:

“Acute hepatic failure and severe liver injury, in some cases fatal, have been reported in patients treated with KETEK. These 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.”

The same day, the FDA also issued an alert for both medical professionals and patients, with Dr Steven Galson, Director for FDA’s Center for Drug Evaluation and Research, stating: “We are advising both patients taking Ketek and their doctors to be on the alert for signs and symptoms of liver problems.”

The signs and symptoms of liver failure, the FDA said, include fatigue, malaise, loss of appetite, nausea, yellow skin and dark-colored urine. “Patients experiencing such signs or symptoms,” Dr Galson warned in the alert, “should discontinue Ketek and seek medical evaluation, which may include tests for liver function.”

An FDA advisory committee is scheduled to meet on December 14-15, 2006, to discuss the risks and benefits of Ketek and is expected to make a recommendation as to whether the drug should stay on the market.

Filed under: 2006, FDA, Ketek

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