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Natrecor: Another Deadly Off-Label Con Job by a Drug Industry Driven By the Bottom LineJan 1, 2006
When a pharmaceutical company believes it has a potential “blockbuster” drug on its hands, many of the ethical considerations by that the drug industry should be governed quickly fall by the wayside.
Blockbuster is not a term to be thrown around loosely when it comes to a prescription drug. It is usually reserved for only those medications with annual sales of a billion dollars or more. While annual sales in the $500 million range are significant, the drugs that attain that level of success are looked upon as revenue producers. The blockbusters are looked upon as king-makers.
Thus, when any drug has the potential to attain the elusive “10-figure” status, some very questionable marketing strategies often begin to take place. These include:
Failing to disclose or report negative test or clinical trial results;
Failing to report adverse reactions;
Failing to finalize post-approval testing or reporting;
Spending more on “glitzy” advertising campaigns than it cost to develop and test the drug itself;
Withholding negative information from doctors or using questionable incentives to encourage the writing of prescriptions for a specific drug;
Indirectly engineering a campaign to stimulate (while not actually promoting) one or more “off-label” uses of a drug that may actually generate more income for that drug than the approved uses. (The “off-label” market will be described below.)
These revenue-driven strategies do not make a drug better or safer. In fact, every case is little more than marketing winning out over science, safety, and even ethical considerations.
In the case of Natrecor, nothing good can be said concerning the manner in which the drug has been promoted and marketed and the failure to report at least two product-related additional deaths during its clinical testing.
Natrecor, or nesiritide, was approved by the FDA in 2001 to treat congestive heart failure or acute decompensating heart failure in which patients experience shortness of breath and the heart fails to adequately pump blood to other organs in the body.
The drug works by mimicking a hormone-like molecule that dilates vessels to prevent blood from gathering in the heart and lungs thereby allowing the patient to breathe.
Natrecor is manufactured by Scios, a company which was bought by Johnson & Johnson in 2003. As many as 600,000 patients have been treated with the drug since its approval.
Natrecor was, and still is, supposed to be used for the sole purpose of treating hospitalized patients with the aforementioned heart conditions.
Despite this express limitation on its approved use; Natrecor became an increasingly popular option in outpatient clinics nationwide where it is used for far longer periods than it was originally approved for.
Some outpatient clinics even established programs to administer Natrecor twice weekly for up to 12 weeks. This type of use is considered to be extremely dangerous as no study has been conducted to confirm whether long-term use is either safe or effective.
This “off-label” use of Natrecor has lead to the discovery of severe side-effects and a subsequent push from medical experts and consumer advocates for the manufacturer to conduct further large-scale, longitudinal studies of the drug.
The off-label prescribing of drugs beyond the scope of their approval by the FDA has become a serious concern in recent years. Dosage levels, medical conditions, and treatment durations for which drugs were never intended or tested make the entire area of off-label use problematic at best. At its worst, the practice can be downright deadly.
It is for this reason that the FDA regularly discourages and even warns against such uses of drugs. This has been especially true in the case of powerful drugs like antipsychotics, heart medications, and antidepressants.
The incredibly strange thing about off-label use, however, is that doctors may prescribe drugs to treat conditions for which the FDA has even denied approval. Thus, while a manufacturer cannot market a drug for an unapproved off-label use, a doctor may prescribe the drug for that use.
Thus, if a pharmaceutical company is able to subtly (or, even not so subtly) stimulate off-label use of one of its drugs, the return in unanticipated profits can be quite significant. In fact, a clever marketing scheme can turn a restricted approval drug with limited sales potential into one of those prized billion-dollar blockbusters.
Many times, off-label use of a drug is stimulated by doctors themselves who are acting more like marketing agents than as responsible health professionals. One doctor may get a favorable result in an off-label situation and begin touting that use of the drug to colleagues or even other patients.
These “anecdotal” stories of a drug’s success in an area it was never approved for often create an inflated demand for that drug well beyond its true market potential.
Dr. Jonathan Sackner-Bernstein, a cardiologist at North Shore University Hospital in New York and an avid opponent of the overuse of Natrecor, co-wrote several journal articles that provide data which links Natrecor to kidney problems and elevated death rates.
Sackner-Bernstein’s patients taking Natrecor were 80% more likely to die within the next 30 days than patients who had received other treatments such as diuretics or vasodilators.
The issues relating to kidney safety were known prior to and during the process of FDA approval of the drug and are specifically noted in the drug’s labeling. Yet the increased risk of mortality was not entirely known or appreciated until the drug became widely used in outpatient clinics for extended periods of time.
This particular problem would take on added significance when, as discussed below, it was revealed that Scios had failed to disclose data on at least two additional Natrecor-related deaths that took place during clinical testing.
Although Scios argued that the Sackner-Bernstein paper included studies done at higher doses than are advised on the drug’s label, those higher (unapproved and risky) doses are precisely what patients are being exposed to when they receive the treatment outside of hospitals.
Natrecor was never approved to be used as frequently as was (and may still be) being used in outpatient clinics. Sackner-Bernstien and other experts, including fellow cardiologist Keith Aaronson, have attempted to show that Natrecor should not be administered in outpatient settings and that the drug’s label should indicate the serious problems associated with unrestricted off-label usage.
In the July 14, 2005 edition of the New England Journal of Medicine, Dr. Eric Topol of the Cleveland Clinic (and also an outspoken critic of Vioxx) was highly critical of the way in which Scios was marketing Natrecor. He even went so far as to state that the drug should be off the market because the FDA was never given sufficient data upon which to have based its approval.
Natrecor has been aggressively marketed with sales of the drug now reaching almost $700 million this year. This is because Natrecor is an expensive option, costing nearly 50 times (yes, 5,000%) more than standard therapy options. That’s like paying $10,000 for a $200 iPod or $19.50 for a 39-cent postage stamp.
Natrecor is billed to insurance companies at up to $700 per session. When used in hospitals for emergency situations, as intended, the cost, while high, is somewhat controllable. When patients receive this treatment dozens of times in outpatient clinics, however, the cost quickly spirals out of control.
In addition to other questionable marketing strategies, Scios provided doctors with promotional materials advising them on how to bill Medicare for Natrecor uses that are clearly not approved by the FDA.
The Scios reimbursement guide, also available through a toll-free number, told doctors to use Medicare codes that treat Natrecor like chemotherapy allowing them to bill for larger Medicare reimbursements.
As a result, Medicare managers became concerned that reimbursements for Natrecor treatments in outpatient clinics would skyrocket as a result of the information that Scios was supplying to medical professionals.
In May 2005, Johnson & Johnson announced that in compliance with the FDA, it would revise the labeling for Natrecor to include data indicating an increased risk of mortality within 30 days for Natrecor patients compared with patients taking a placebo or other treatments.
While that was a good start, doctors and other medical professionals were still advocating further studies of Natrecor to determine the health risks associated with the drug.
Milton Packer, a cardiologist at the University of Texas, Southwestern, is concerned that Scios, like Vioxx maker Merck, had not done adequate studies to make sure that its drug is safe. Although the FDA approved the drug in 2001, many doctors argue that today the vote might be closer and Natrecor would probably wind up with a tougher label.
Then, in May 2005, an independent expert panel, convened by Johnson & Johnson itself, recommended that Natrecor be restricted to severely ill hospitalized patients. Most experts also agreed that a large-scale clinical trial is needed in order to determine the risks of Natrecor.
Although a spokesperson for Scios argued that the company could not control how doctors prescribe the drug, Scios itself greatly contributed (or even created) the problem by affirmatively providing doctors with information on how to maximize their billing of Natrecor for off-label uses. Once again, it’s all about the money.
Many experts consider it ethically irresponsible for a pharmaceutical company to promote an off-label (and potentially harmful) use of a medication for no other apparent reason than financial gain.
Such questionable conduct could ultimately turn into a significant problem for Scios and Johnson & Johnson if the drug continues to prove to be as dangerous as it appears to be and it continued to be prescribed in outpatient settings as opposed to hospital situations where it is a life-or-death situation.
In June 2005, the panel of cardiologists convened by Johnson & Johnson and headed by the highly respected heart researcher, Harvard’s Dr. Eugene Braunwald, recommended strict limitations on Natrecor, including not using it for scheduled “tune-ups” or even administering it outside the hospital.
The panel specifically recommended that Natrecor only be used in cases of an acute type of heart failure when the patient actually shows up at the hospital; that it should not be used in place of diuretics, the first-line treatment for heart failure; and never used for outpatients, scheduled appointments, or to improve kidney function.
Furthermore, the panel believed that: “Scios should immediately undertake a proactive educational program to inform physicians regarding the conditions and circumstances in which [Natrecor] should and should not be used.”
A member of the panel, Barry Massie (professor of medicine at University of California in San Francisco) also expressed disapproval of the manner in which doctors flagrantly engage in the off-label prescribing of drugs.
Dr. Massie believes it is important for doctors to take responsibility for their actions and only prescribe drugs for their approved uses. “It shouldn’t all be blamed on the pharmaceutical companies, no matter what they do to encourage unproven indications.”
On July 20, 2005, Johnson & Johnson acknowledged it had received a subpoena from the United States Attorney’s office in Boston requesting documents related to the sales and marketing of Natrecor.
As a result of this virtual tidal wave of disapproval concerning the questionable tactics associated with the marketing of Natrecor, Johnson & Johnson added a clear disclaimer to its hotline used by doctors seeking information on how to charge Medicare and insurance carriers for the drug. The disclaimer clearly seeks to discourage the heretofore rampant off-label use of Natrecor.
The disclaimer warns of the “lack of clinical data” regarding off-label use of the drug and that Scios “does not recommend Natrecor for this use.” Johnson & Johnson now plans to follow up on the panel’s suggestions.
Unfortunately, the story did not end there as revealed by the recent disclosure of data relating to previously unreported deaths that occurred during the clinical testing of Natrecor.
In the wake of the Vioxx and numerous other scandals, it has become clear that what consumers, and even the FDA, are told in order to get a drug approved and to keep it on the market sometimes falls far short of full and honest disclosure.
As recently reported in newsinferno.com (12/25/05), with respect to the falsification of data by Dr. Hwang Woo Suk, a highly respected stem cell researcher at Seoul National University, that rendered his entire project worthless since at least nine of 11 colonies of stem cells described in a high-profile report last spring either never existed or were never proved to be stem cells “ Although this type of inexcusable conduct in scientific research is difficult to imagine especially in situations where people’s lives may depend on the results, it is far from isolated. In fact, it is becoming disturbingly common. Thus, the fact that this project involved “front page” research only made the scandal more visible, not more surprising.”
“Professional egos, pressure exerted by pharmaceutical and medical device companies (with hundreds of millions of dollars at stake), and conflicts of interest have all resulted in a marked deterioration of the ethical standards that once defined the world of medical and scientific research.”
In addition, those who should be closely monitoring the accuracy and truthfulness of such important scientific research have, themselves, slipped into an area where their own credibility and allegiances are open to question.
In the case of the stem cell deception, many critics blamed the stiff competition between scientific journals to be the first to publish breakthrough findings. The review process at Science, which claims to involve sending out manuscripts for expert analysis, appears to have missed obvious problems with the research.
For example, Dr. Hwang and co-author Dr. Schatten (University of Pittsburgh) submitted their 2005 paper only seven weeks after winning ethics approval to collect human eggs. According to expert’s like Jeanne Loring, a stem-cell biologist at California's Burhnam Institute, that isn't even enough time to have created and tested the 11 stem-cell supplies reported in that paper.
In an article titled “Drug profits infect medical studies” published January 7, in the Los Angeles Times , John Abramson, a clinical instructor at Harvard Medical School and author of "Overdosed America" (HarperCollins, 2004) wrote: “This week brings the news that a Johnson & Johnson subsidiary failed to include the deaths of two patients in a clinical trial of its new drug for heart failure, Natrecor, in an article published in the Journal of Emergency Medicine.
Why shouldn't we be surprised? Because over the last 25 years, clinical research has been largely privatized. Three-quarters of the clinical studies published in the three most respected medical journals (the New England Journal of Medicine, the Journal of the American Medical Assn. and the Lancet) are now commercially funded. As a result, our medical knowledge grows not in the direction that best improves our health but toward corporate profits, the way that plants grow toward sunlight.
This wasn't always so. Before 1980, most medical studies were publicly funded, and most academic researchers scorned industry support. Now, however, the vast majority of clinical trials are commercially funded, and with the financial stakes so high, there is mounting evidence of individual scientists and corporations manipulating their findings.
Even our most trusted journals are dependent on drug-company money. Drug makers don't just buy advertising in their pages. According to Richard Horton, editor of the Lancet, they also pay up to $1.75 million for reprints of articles favorable to their drugs, which sales reps then hand out to doctors.
And many journal articles are biased in favor of their sponsors' products. A 2003 report in the Journal of the American Medical Assn. found that clinical studies funded by drug companies are three times more likely to conclude that the sponsor's drug is the treatment of choice, compared to studies of the same drug that were not commercially funded. (This study of the effects of commercial bias, by the way, was funded by Danish research institutions.) The disturbing conclusion is that most of the evidence in what doctors believe to be "evidence-based medicine" is more infomercial than dispassionate science.
It's vital to protect the integrity of our medical knowledge. But the current peer review system alone can't do the job. The journals, and the peer reviewers they rely on, are in the untenable position of having to trust that corporate sponsors have accurately and completely reported their findings. At present, journal editors and peer reviewers typically are not allowed unrestricted access to the data from commercially sponsored research. Amazingly, many drug company-funded researchers who write the articles are also not allowed access to all of the data the company has collected.
There is no better cautionary tale than the unwarranted success of Vioxx. Greater safety was the only reason for doctors to have prescribed Vioxx, given that it provided no better relief of arthritis symptoms or pain and cost up to 10 times more than the older anti-inflammatory drug, naproxen (sold without a prescription as Aleve). But Merck's own study clearly showed that Vioxx was more dangerous than naproxen overall and caused significantly more heart attacks, blood clots and strokes — whether or not the patient had a previous history of cardiovascular disease.
SO WHY DID American doctors prescribe $7 billion worth of Vioxx after Merck and the Food and Drug Administration knew all this?
Because the New England Journal article that ostensibly reported the results of Merck's study didn't even mention either the cardiovascular or the overall dangers of Vioxx. Instead, it reported only selective data on heart attacks and strokes, allowing Merck to claim that Vioxx wasn't a risk to people without a history of these problems.
The Journal's editors are now accusing Merck of withholding critical data. Shame on Merck. But shame on the Journal too for not insisting that the article include a discussion of the most important complications. Doctors were left with the impression that Vioxx was safer than naproxen when exactly the opposite was true.
The Journal again misled its readers in 2001, when one of its influential review articles dismissed the dangers of Vioxx as perhaps reflecting "the play of chance." This article was published seven months after FDA reviewers' concerns and Merck's own research data, which documented the dangers, had been posted on the FDA's website. Worse, the Journal violated its own policy prohibiting scientists with conflicts of interest from writing review articles. (Both authors had financial ties to Merck.) That the Journal disclosed those ties mitigates neither its ethical breach nor the consequences of its repeated understatement of the risks of Vioxx.
This is hardly an academic argument. According to an article in the Lancet, based on Merck's own data Vioxx probably caused between 88,000 and 144,000 cases of serious heart disease.
The stem cell and Natrecor debacles offer further evidence that the problem is not just individual bad actors or occasional lapses of scientific integrity by drug makers. It's that even the most prestigious journals are unable to perform the quality control that doctors take for granted.
Sadly, the evidence shows that it's time for the journals to change their policies from trust to "trust, but verify." They should introduce a new standard requiring an independent audit of the accuracy and completeness of research reports before they are sent out for peer review. These scientific auditors should be statisticians and medical experts who are completely free of conflicts of interest and are given unfettered access to the data.
The journals will rightfully claim they cannot afford to pay for such scientific oversight. But the lack of oversight is even more costly. Americans waste billions each year on drugs of dubious value. Until we find a way to fund quality controls on published research, the cost of our medical care will continue to soar and our health will suffer.”The Abramson article, while right on point, was actually somewhat conservative in its indictment of a system in which the search for scientific truth has been largely replaced by an unwavering obsession with corporate profits.
So, when the New Year brought the revelation regarding two deaths associated with Natrecor that had not bee reported to federal regulators, should anyone have been surprised? Not unless they had been vacationing for the past several years on Mars.
When the report of the clinical trial was published in October of 2005 in the Journal of Emergency Medicine, the information about the two deaths was not included. The report stated that there had been 6 deaths within 30 days among a test group of 237 patients who had been given Natrecor or other treatments in emergency rooms only between 2001 and 2002. Five of those deaths were attributed to Natrecor, but the two unreported deaths brings that total to seven, which represents a significant statistical difference.
While Scios claims that the additional two deaths do not alter safety assumptions about the drug, medical professionals argue that in clinical trials, every death counts and mistakes are not supposed to be covered up.
The additional two deaths were discovered when Scios reviewed their original study. As soon as the company learned of the deaths, they notified the FDA. While the results have already been published, Scios plans to update the article with this new information.
Some of the more egregious recent examples of this type of objectionable behavior include a study published in the Journal of the American Medical Association (JAMA) in 2004 that found 65% of findings of harmful effects were not fully reported in medical-journal articles. Results are often “cherry-picked” so that only the positive data is published.
The JAMA study also found that 62% of trials had at least one piece of data or one result that was changed, added, or omitted to make the drug appear better.
The controversy surrounding Natrecor is only one example of the debates surrounding drug safety that take place all the time in the medical arena. Drug safety will essentially always be suspect until this behavior is stopped.
Recently, while the third Vioxx trial was in progress, a shocking accusation was made by Dr. Gregory Curfman, executive editor of the New England Journal of Medicine (NEJM) that data linking Vioxx to increased cardiovascular risk was deleted (apparently by Merck researchers) from the VIGOR study two days before it was submitted to the NEJM for publication.
Dr. Curfman did not find out until November 21, 2005, that by July 5, 2000, two Merck authors on the VIGOR study knew of three additional fatal heart attacks among Vioxx patients in the study, which had not been disclosed to the NEJM.
The heart attacks occurred in the final five weeks of the trial and in patients at low risk for heart problems. Curfman also learned that a prior version of the manuscript revealed more cardiovascular problems potentially connected to Vioxx than those discussed in the published study.
The Journal now contends that "at least two" of the study's three authors knew of the additional heart attacks for some 4 1/2 months prior to publication. "There was ample time to include the data on these three additional infarctions in the article."
The accusation by the NEJM that Merck knowingly withheld data on three fatal heart attacks and more, if true, significantly undermines the VIGOR study results as well as the entire premise upon which Merck has built its entire defense.
Recently, Eli Lilly came under scrutiny for suppressing reports relating to the potential increased risk of suicide risk suspected during early clinical trials. Current clinical trial data that has confirmed this elevated suicide risk.
One trial showed that 3.7% of Prozac users attempted suicide while less than 1% of participants on non-SSRI depressants exhibited the same behavior. Thus, it is reasonable to assume that had there been full disclosure of the early trial data and reports, lives could have been saved.
Johnson and Johnson’s heartburn drug Propulsid has been linked to 80 heart-related deaths and 341 injuries. Despite the adverse effects associated with the drug, Johnson and Johnson did not conduct safety studies and pushed to keep Propulsid on the market. Even with strong black-box warnings on the drugs label, Propulsid was prescribed inappropriately to both adults and children.
After five years of reported problems, Propulsid was pulled from the market in 2000. In 2004, Johnson and Johnson agreed to pay up to $90 million to settle pending claims relating to deaths and injuries from Propulsid.
On May 19, 2005, Able Laboratories, the largest manufacturer of generic drugs, stopped all shipments of its products. Four days later Able recalled its entire product line, suspended all manufacturing and withdrew seven approved applications to market various medications. The massive recall was based on what the FDA itself stated were “serious concerns that they (all of Able’s products) were not produced according to quality assurance standards.”
The FDA eventually revealed that its drastic enforcement action was the result of agency inspectors having found massive record falsification and mismanagement by Able in order to elude FDA detection of several defective medications. Some of the violations included alteration and falsification of test data and covering up deficiencies by changing results.
Medical device manufacturers are no more credible or trustworthy than their drug manufacturing counterparts and have been caught engaging in similar bad acts.
On July 13, 2005, the FDA issued an extensive warning to Hitachi Medical Systems America, Inc. for serious reporting violations and problems with respect to its MRI and PET equipment. The warning followed inspections of Hitachi’s medical device manufacturing facilities by an FDA investigator with respect to the magnetic resonance imaging (MRI) systems manufactured by Hitachi Medical, Tokyo, Japan which are medical devices as defined in section 201(h) of the Federal Food, Drug and Cosmetic Act (the Act).
The above inspection revealed that Hitachi’s devices were misbranded in that the company failed to furnish material or information required under the Act and the Medical Device Reporting (MDR) Regulation. Specifically, Hitachi had received complaints relating to four separate events for which it failed to submit an MDR to the FDA within 30 days of receiving information that the devices may have caused or contributed to a death or serious injury.
On May 24, 2005, Guidant Corporation disclosed for the first time that it had waited three years before disclosing it had been aware of the electrical problem that had caused some 28 of these defibrillators to malfunction. The revelation came in the form of an alert to physicians which was not issued until Guidant learned that The New York Times was about to publish a story on the defibrillator. There is no doubt among experts that the delay probably caused unnecessary deaths.
Now, however, additional internal documents from Guidant show that the company had projected in an internal report that some patients might die as a result of short circuits in one of its defibrillators yet it did not publicize the defect because it appears Guidant viewed the overall failure rate as acceptable. Guidant had also determined in a mid-2002 company report that the consequences of the defibrillator’s electrical problem could be "life threatening." Nonetheless, Guidant continued to sell tens of thousands of the potentially defective devices and did not even notify doctors about the problem until May 2004.
Chester Douglass, a professor at the Harvard School of Dental Medicine was accused of covering up data that suggested a link between fluoridated tap water and osteosarcoma, a rare form of bone cancer, in adolescent boys. He is currently being investigated for claiming that there is no correlation between fluoride and osteosarcoma when previous research and data suggests otherwise.
In fact, his own doctoral student came forward with data from Douglass’s study which concluded that: “Among males, exposure to fluoride at or above the target level was associated with an increased risk of developing osteosarcoma. The association was most apparent between ages 5-10 with a peak at six to eight years of age.” Douglass’ attempt to falsify and cover-up his data is an incredible breach of the public trust.
In addition, Douglass was editing a newsletter funded by Colgate-Palmolive Co. which creates a serious conflict of interest since Colgate-Palmolive manufactures toothpaste with fluoride.
In 1996, Dr. Andrew Friedman was caught faking data in some of his studies that had been published in medical journals. Investigators found that he had been making up information relating to hormonal treatment for gynecological conditions and this information had passed through peer reviews to become published data. He agreed to be excluded from working on federally funded research for three years.
Last year, Eric Poehlman, a professor at the University Of Vermont College Of Medicine, was charged with falsifying research data on issues like menopause, aging, and hormone supplements in order to receive millions of dollars in grant money from the federal government.
In November 2004, Dr. Ali Sultan was discovered to have plagiarized tests and data in his malaria study but substituting results from one type of malaria for another. When charged, he placed all the blame on a postdoctoral student. He later resigned and became a faculty member at the Cornell Medical College in Qatar.
Anne Butkovitz, a coordinator at a pediatric practice involved in an FDA approved clinical study, has been charged with falsifying data with respect to follow up contact information she was supposed to obtain directly from the parents of children vaccinated with an experimental rotavirus vaccine.
Rotavirus causes severe diarrhea in infants. The purpose of the follow-ups was to determine if there had been any serious adverse experiences (SAEs). It is alleged that Ms. Butkovitz did not make the required contacts and yet claimed that she had on report forms. In one case, she is accused of having actually falsified information with respect to the SAEs of a patient enrolled in the clinical study.
As a result of Ms. Butkovitz’s actions, the pharmaceutical company involved removed the pediatric practice she was employed by from the study and disregarded the data it had generated.
When the FDA held hearings in February of 2005 supposedly to determine if the COX-2 inhibitors were safe enough to remain on the market, more signs of a system with widespread conflicts of interest became disturbingly clear.
Of the 32 government drug advisers who would vote on the issue, 10 had consulted for Merck (Vioxx) or Pfizer (Celebrex and Bextra) in recent years.While the committee voted unanimously that all of the drugs significantly increased the risk of heart attack and stroke, Vioxx, a drug pulled from the market by its own manufacturer (Merck) only 3 months before miraculously 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 which had even more serious risks associated with it than Vioxx, 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). Bextra was pulled from the market less than two months later.
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.”
In 1997 Rezulin was approved to treat Type 2 diabetes. The drug was made and marketed by Parke-Davis, a division of Warner-Lambert Company. Rezulin was removed from the market by the FDA in March of 2000 as a result of having been linked to a mounting number of cases of serious liver damage and death.
Shortly after Rezulin was approved by the FDA, the agency announced the drug had been linked to illness and death from liver failure. Significantly, these problems had been apparent while the drug was being tested.
By the beginning of 2000, four senior FDA physicians as well as Dr. Robert I. Mishbin, the FDA Medical Officer most closely involved with the government's approval and continued support of Rezulin, were strongly urging its withdrawal from the market.
In fact, in a January 24, 2000 e-mail to his superiors, Dr Mishbin stated: "I see no reason why any well-informed physician would continue to prescribe [Rezulin]." In warning that "additional cases of preventable liver failure" may occur, Dr. Mishbin also stated that he did not see "any reason why FDA should delay in taking steps to remove [Rezulin] from the market."
The FDA's response was to threaten Dr. Mishbin with disciplinary action or dismissal from federal service. Even before Dr. Mishbin's change of position, two other FDA physicians had raised serious questions concerning Rezulin.
In October, 1996, FDA Medical Officer, Dr. John L. Gueriguian recommended Rezulin not be approved because of potential liver and heart toxicity. Dr. Gueriguian was the FDA Medical Officer initially in charge of reviewing the Rezulin New Drug Application (NDA).
He was a twenty year veteran of the FDA, but 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. That same month, Dr. Gueriguian was stripped of further involvement in reviewing Rezulin and his negative review purged from agency files.
The National Institutes of Health (NIH) conducted an internal review with respect to consulting payments from pharmaceutical companies to scientists employed by the agency. Of the initial sample, more than half (44 of 81) admitted to conduct which violated one or more NIH rules.
Of those, 36 were still employed by the agency and were referred for possible disciplinary action. Nine of those 36 were also referred to the HHS Office of Inspector general for further investigation. The 8 who left the agency are not subject to administrative action.
The House Energy and Commerce Committee requested the review after comparing NIH records to consulting agreements maintained by 20 pharmaceutical companies. The Committee found 81 cases between 1999 and 2004 where the agreements were not listed in the NIH records provided to the committee.
Excerpts from the findings of the investigation, provided by NIH Director Elias A. Zerhouni to three members of Congress included the following statement: "We discovered cases of employees who consulted with research entities without seeking required approval, consulted in areas that appeared to conflict with their official duties, or consulted in situations where the main benefit was the ability of the employer to invoke the name of NIH as an affiliation.” Although Zerhouni requested the release to Congress to be treated as confidential, Committee leaders released it as a matter of compelling public interest.
On August 5, 2001, the Washington Post reported “Missing Data on Celebrex,” a charge that sounds eerily similar to the recent revelation by the New England Journal of Medicine (NEJM) with respect to Merck’s conduct involving Vioxx study data. That article stated: “When editors of the Journal of the American Medical Association sent medical expert M. Michael Wolfe an unpublished study on the blockbuster arthritis drug Celebrex last summer, he was impressed by what he read. JAMA's editors wanted to rush the findings into print, and Wolfe and a colleague provided a cautiously favorable editorial to accompany it. But in February, when Wolfe was shown the complete data from the same study as a member of the Food and Drug Administration's arthritis advisory committee, he said he saw a different picture. ‘We were flabbergasted,’ he said. The study -- already completed at the time he wrote the editorial - - had lasted a year, not six months as he had thought, Wolfe learned. Almost all of the ulcer complications that occurred during the second half of the study were in Celebrex users. When all of the data were considered, most of Celebrex's apparent safety advantage disappeared. ‘I am furious. . . . I wrote the editorial. I looked like a fool," said Wolfe, a Boston University gastroenterologist. "But . . . all I had available to me was the data presented in the article.’ JAMA's editor, Catherine D. DeAngelis, said the journal's editors were not informed about the missing data. ‘I am disheartened to hear that they had those data at the time that they submitted [the manuscript] to us," she said. "We are functioning on a level of trust that was, perhaps, broken.’ The study's 16 authors included faculty members of eight medical schools. All authors were either employees of Pharmacia, Celebrex's manufacturer, or paid consultants of the company.*** James Wright, a professor of clinical pharmacology at the University of British Columbia, said he complained to JAMA after noticing differences between the published report and the data presented to the FDA. He praised the Public Citizen's Health Research Group, a consumer organization, for filing a lawsuit that led to the agency's putting all drug studies presented to its advisory committees on its public Web site. ‘Otherwise, we still wouldn't know this,’ Wright said. ‘We would still be in the dark.’”
On December 23, 2005, The Wall Street Journal presented an extensive article entitled “Study Tied Pollutant to Cancer, Then Consultants Got Hold of It – ‘Clarification’ of Chinese Study Absolved Chromium-6; Did Author Really Write It? Echo of Erin Brockovich Case.”
In essence, the story details the circumstances surrounding a highly questionable 1997 “clarification” of a widely accepted 1987 Chinese study showing a link between chromium-polluted water and cancer that amounted to a complete retraction of that finding.
It turns out, however, that the study author had nothing to do with the so-called clarification which was apparently “conceived, drafted, edited, and submitted to medical journals by scientific consultants working for the lawsuit’s defendant, a utility company being sued for alleged chromium pollution.”
A survey involving 3,247 scientists who were based in the United States and who had received funding from the National Institutes of Health revealed that about 33% of the participants stated that, within the previous three years, they had engaged in at least one practice that could get them into trouble.
The types of questionable conduct included circumventing minor aspect of rules for doing research on people (8%) and ignoring another researcher’s use of flawed data or questionable interpretation of data (about 13%). Less than 2% admitted falsifying data, plagiarism, or ignoring major aspects of rules governing studies with human subjects. Surprisingly (or maybe not so surprisingly), almost 16% admitted they had changed the designs, methods, or results of a study “in response to pressure from a funding source.”
Thus, can anyone really look at the Natrecor revelation as some sort of innocent or inconsequential error on the part of Scion or Johnson & Johnson? Hardly.
The pharmaceutical industry is in the business of providing whatever data is necessary in order to get the sales that they need to make a profit on their drugs. Once a drug is approved, it appears that accountability is lost and patients are left to fend for themselves once side effects start surfacing.
If you think that the off-label scam engaged in with respect to Natrecor was somehow a “fluke” or not the same as the other examples of calculated deceit, consider the following Associated Press article that appeared on January 11 on boston.com; “ Former worker sues Genentech over drug marketing”
“A former Genentech Inc. employee has accused the biotechnology company and marketing partner Biogen Idec Inc. of illegally promoting cancer drug Rituxan as a treatment for arthritis, a use not yet approved by regulators.
Paul McDermott, who worked for Genentech in Falmouth, Maine, from March 2004 until April 2005, filed a whistleblower lawsuit in July 2005 in U.S. District Court in Maine alleging the companies' marketing of Rituxan defrauded government health-care programs.
The suit also says Genentech fired McDermott in retaliation for bringing the matter to the attention of Genentech executives…McDermott's lawsuit is the latest legal challenge facing Genentech over Rituxan's marketing. In October 2004, Genentech received a subpoena from the U.S. Attorney's Office in Philadelphia seeking documents related to the promotion of Rituxan. Genentech is cooperating with that investigation, which it said was both civil and criminal in nature.
The promotion of off-label uses of pharmaceuticals has gotten other drug companies in trouble. In 2004, Warner-Lambert pleaded guilty to federal charges that it promoted epilepsy drug Neurontin for off-label uses beginning in the 1990s. Pfizer Inc., which acquired Warner-Lambert in 2000, agreed to pay $430 million to resolve criminal charges and civil liabilities in the case.
The U.S. Food and Drug Administration approved Rituxan in 1997 as a treatment for a type of non-Hodgkin's lymphoma. U.S. sales of the drug grew to $1.8 billion last year. Studies have shown Rituxan also potential to treat rheumatoid arthritis.
Biogen and Genentech have applied for FDA approval to market Rituxan as such a treatment and a decision is expected by late February.
It's generally legal for doctors to prescribe FDA-approved drugs in ways that haven't yet been approved by the FDA, and so-called ‘off-label’ prescriptions are common. But drug companies are generally barred from actively promoting off-label uses of their drugs.
McDermott worked as a ‘professional educational liaison’ for Genentech, according to the lawsuit, a job that involved recruiting doctors to promote the use of Rituxan as a treatment for rheumatoid arthritis.
He alleges Genentech sent sales representatives to the offices of rheumatologists, even though Genentech had no products approved by the FDA for such treatments.
Also, McDermott alleges Genentech and Biogen used ‘sham’ consulting agreements to pay rheumatologists whom the companies identified as being ‘key opinion leaders,’ who were expected to influence other doctors to begin prescribing Rituxan for arthritis.
The lawsuit alleges that Biogen, the company that discovered Rituxan, had similar marketing practices for the drug.”
Thus, it matters little whether the fault lies with the pharmaceutical industry, the FDA, journals which publish the results of clinical studies, or some combination of the three, the real bottom line is, the public loses. When lives (and lots of them) are at stake, anything short of complete honesty is unacceptable and inexcusable.
In order to eliminate the risk of “bad drugs” dominating the prescription drug market, there needs to be a sea-change in the procedures by which drugs are approved, marketed, and prescribed. Patients have a right to receive the best treatment possible, not a potential death sentence meted out as a result of laziness, inaccuracy, deceit, and greed.