In Latest Drug Scandal, Ketek’s Safety and FDA Approval Are Strongly Challenged

By Steven DiJoseph

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The most striking portion of Dr. Graham’s testimony involved his carefully formulated opinion that (even using Merck’s own VIGOR and APPROVe trials) some 88,000 to 139,000 Americans alone have already suffered heart attacks as a result of taking Vioxx and of that number, “30-40% probably died.” (Note that another respected expert, Dr. Eric Topol, estimated the heart attack figure to be up to 160,000).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The panel did recommend all COX-2 inhibitors carry “black box” warnings. Serious? Yes. Fatal? No.

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

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

· “FDA Drug Oversight Fails Patients” (AP 5/23/01)

· “FDA Failing in Drug Safety, Official Asserts” (The New York Times, 11/19/04)

· “Are Too Many Unproven Drugs Receiving FDA Early Approval?” (The Wall Street Journal, 3/1/05)

· “A Rudderless, Leaderless FDA” (Los Angeles Times, 1/18/05)

· A broken agency that needs to be “fixed” (Forbes, 1/13/05)

· “Study Faults Drug Approval Mechanism” (Yahoo! News, 5/7/02)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The current law states that all new drugs need proof that they are effective, as well as safe, before they can be approved for marketing. The problem with the current approval process, however, is that even when the answer to this question turns out to be “no,” many dangerous drugs have either been approved or permitted to remain on the market for considerable lengths of time.

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

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

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

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

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

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

Dr. Solomon Sobel, director of the FDA’s metabolic endocrine drugs division throughout the 1990s, said that there was extreme pressure to meet deadlines and complete reviews. “The basic message,” he said, “is to approve.”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

At this point, the manufacturer was eager to gain approval so it embarked on a study (labeled “3014”) that was contracted out to Pharmaceutical Product Development Inc. (PPD).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

When asked to comment on the FDA’s role as a public watchdog in the Ketek and other similar prescription drug scandals, a seasoned litigation attorney simply stated; “With friends like that you don’t need enemies.”

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