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Neurology Today:
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ON FDA POLICY ON ANTIPSYCHOTICS AND OTHER DRUGS, EXPERTS SAY ‘SHOW US THE DATA’

Valeo, Tom

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Editor's Note: The Jan. 3 Neurology Today reported on several timely studies on atypical antipsychotics. See “Increased Risk of Death with Antipsychotics for Demented Elderly,” page 18.)

H. Christian Schumacher, MD, a Neurology resident at Columbia University's Neurological Institute, treats stroke patients who, because of their brain injury, occasionally develop psychotic symptoms. To quell their agitation and behavioral disorders, Dr. Schumacher, like many other physicians, prescribes atypical antipsychotics, such as olanzapine (Zyprexa) and quetiapine (Seroquel) – drugs approved by the US Food and Drug Administration (FDA) to treat the symptoms of schizophrenia, but also widely used “off-label” to treat behavioral problems associated with Alzheimer disease and other forms of brain injury.

So when Dr. Schumacher learned about the black-box label from the FDA in April 2005 warning that atypical antipsychotic drugs increase the risk of death among elderly patients by 60 percent to 70 percent, he decided to review the research data that prompted the warning label.

“I thought, why not look up these 14 trials and make the judgment for myself,” he said. “But I could not find most of the trials published that led to the FDA decision. There are no real data out there to explain this mortality increase.” When he asked for the data, he was told it was not available to him.

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PROPRIETARY DATA NOT USEABLE

That denial came because the drug companies paid for most of the clinical studies that the FDA used to determine the need for the warning label. “The data are proprietary and not releasable by the FDA,” Christine S. Parker, Public Affairs Specialist with the FDA, explained via e-mail. “Some of the studies are published, and in fact, a meta-analysis of published data was published recently.”

That meta-analysis, however, did not rely entirely on published data because there was not enough available. Instead, Lon S. Schneider, MD, the lead author of the paper published in JAMA last October (2005;294:1934–1943), gleaned much of the data indirectly – by studying posters about the drugs that the manufacturers put up at medical conventions and meetings. The poster presentations, mainly describing efficacy, might contain, for example, information about “serious adverse events,” which include death, hospitalization, and other significant changes in a patient's status. Dr. Schneider also asked companies for additional information.

“That's how the data for our paper were pieced together,” said Dr. Schneider, Professor of Psychiatry, Neurology, and Gerontology at the Keck School of Medicine of the University of Southern California. “When a company does a clinical trial, and pays for it, it owns the data, so it can decide whether, how, and when to release it. Then, if someone like me asks for the actual internal study report, or the data in question, the company might agree or, more likely, say, ‘No, it's ours, wait until we publish it.’ They may be concerned that the information will be analyzed wrong, or presented to their disadvantage.”

Figure. In the past ...
Figure. In the past ...
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USE OF GHOSTWRITERS

Drug companies sometimes even hire ghost writers to ensure that scientific articles bearing the names of respected researchers are written in a way that puts the drug in their best possible light.

On December 13, The Wall Street Journal reported that one ghostwriter, Susanna Dodgson, was hired by Johnson & Johnson to write an article about the company's anemia drug erythropoietin (Eprex). She was told to follow an instruction sheet provided by the company that emphasized the “main message of the study,” which Johnson & Johnson determined to be that 79.3 percent of people with anemia did well taking the drug just once a week, just like a competitor's drug.

“In fact, only 63.2 percent of patients responded well as defined by the original study protocol, according to a report she was provided,” the Wall Street Journal reported. “That report said the study's goal ‘could not be reached.’ The higher figure Dr. Dodgson was asked to highlight used a broader definition of success and excluded patients who dropped out of the trial or didn't adhere to all its rules.”

Nevertheless, the study written by Ms. Dodgson appeared in the Journal of Clinical Nephrology under the name of lead author Paul Barre, MD, of McGill University in Montreal. The study cited only the 79.3 percent figure, not the lower one.

Such practices corrupt the scientific method, according to John Abramson, MD, a physician and author of Overdo$ed America: The Broken Promise of American Medicine (Harper Collins, 2004). “Medical knowledge is now in the hands of the drug companies, and produced primarily as a commodity,” Dr. Abramson said in an interview. “Facts are deemed medical knowledge when published in respected medical journals. This is what drives the beliefs of doctors. But the medical journals can no longer guarantee the integrity of the research data printed in its pages because of the lack of transparency.”

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MANIPULATING STUDY REPORTS

Dr. Abramson and a growing number of critics accuse drug companies of drawing a curtain around the process of testing drugs. Behind that curtain they manipulate test results, sometimes even eliminating negative data.

Once drugs get to market, drug companies spend lavishly to promote them as major improvements over existing medications. With the raw clinical data concealed as proprietary information, challenging such claims becomes very difficult. It took years, for example, to recognize that the painkiller rofecoxib (Vioxx) increases the incidence of heart attacks among users, and that certain antidepressants seem to promote suicidal thoughts in adolescents. The companies that produce these drugs found evidence of these problems during clinical trials, but concealed the data. The New England Journal of Medicine has publicly accused Merck of withholding data about heart attack risk from a paper about rofecoxib that was published in the NEJM. (See “Can You Trust the Data? What Neurology Journal Editors Do to Ensure Research Integrity,” page TK.)

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FINDINGS ON ATYPICAL ANTIPSYCHOTICS

In September the NEJM reported that atypical antipsychotics, which drug companies claim have fewer side effects than older drugs such as thorazine, may be no more effective at treating chronic schizophrenia (N Engl J Med 2005;353:1209–1223). Patients on the atypicals stopped taking the drugs due to side-effects at about the same rate as patients on perphenazine, an older drug. In addition, the atypicals cause tremors and other movement disorders at about the same rate as the older drugs, according to the study.

Another study in the February 2 issue of JAMA (2005:293:596–608) concluded that except for the atypical antipsychotics risperidone and olanzapine, which provide slight benefit, “pharmacological therapies are not particularly effective for management of neuropsychiatric symptoms of dementia.” Yet, drug companies have been expanding their market for atypicals by promoting them vigorously for the treatment of the behavioral disorders associated with brain disease among the elderly.

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FORMER NEJM EDITORS SPEAK OUT

Two former editors of the NEJM have written books on the influence of drug companies on journal articles. Jerome P. Kassirer, MD, of Tufts University School of Medicine denounces drug companies for spending an average of $30,000 a year on each of this country's 600,000 physicians, wooing them with dinners in fine restaurants, “educational” junkets, generous fees for lectures and fees for providing patients for drug trials.

“Financial conflicts of interest threaten patient care, taint medical information, and raise costs,” he writes in his book, On the Take: How Medicine's Complicity With Big Business Can Endanger Your Health (Oxford University Press, 2004). “They create deception, impair physicians' judgment, and reduce their willingness to be their patients' advocates. They reduce professional dignity and integrity, denigrate the profession, and erode trust in the profession's practitioners, researchers, and institutions.”

When asked specifically about drug companies withholding data on atypical antipsychotics, Dr. Kassirer wondered, “Why aren't the authors of those studies out there saying, ‘We'll give you the data?’ One possibility is, they have stock in the company, or they want to do more studies for the company. The authors may be concerned that if they try to go against the companies they will no longer be able to do the studies that keep their research programs alive.”

In The Truth About the Drug Companies: How They Deceive Us and What to Do About it (Random House, 2004), Marcia Angell, MD, another former NEJM editor, argues that the drug industry “has moved very far from its original high purpose of discovering and producing useful new drugs. Now primarily a marketing machine to sell drugs of dubious benefit, this industry uses its wealth and power to co-opt every institution that might stand in its way, including the U.S. Congress, the Food and Drug Administration, academic medical centers, and the medical profession itself.”

That is why she opposes the law that forces the FDA to withhold the results of clinical trials. “I think that is putting proprietary interest of drug companies ahead of public health, and it's simply wrong,” she told Neurology Today.

[At press time, Dr. Angell did not identify the particular law that “forces the FDA to withhold results of clinical trials,” but a public affairs representative of the FDA forwarded regulations that revealed that the agency denies requests for data on the grounds that they are exempt from public disclosure as trade secrets or confidential commercial or financial data and information.]

Dr. Angell continued: “I would say that as a condition of enrolling human subjects, any company should have to register trials, and they should be required to add the results afterward to a publicly-administered database. When you use human subjects you acquire a public responsibility. Human subjects think they are volunteering for the good of science. If you said you're volunteering for the good of our bottom line, they probably wouldn't do it.”

She contends that the drug companies, which have the largest lobby in Washington, have been able to sway legislation so drastically that the public good has been compromised. “They give generously to political campaigns,” she said of the drug companies. “You can look at legislation for past 20 years and see that Congress never passes a law against the proprietary interests of the drug industry.”

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WILL A DRUG REGISTRY HELP?

Given the wealth and influence of the drug companies, passing legislation to require greater disclosure of clinical trial results would be a daunting challenge, so some medical journal editors have adopted a different strategy. They have agreed to reject any articles submitted for publication unless all the clinical data is available.

The members of the International Committee of Medical Journal Editors announced in 2004 that they will accept articles for publication only if the trials on which they are based have been registered (N Eng J Med 2004:351:1250–1251). In that announcement, the editors called for www.clinicaltrials.gov to become the repository of all trial data.

Deborah A. Zarin, MD, who oversees a database posted at www.clinicaltrials.gov – developed by the NIH through the National Library of Medicine with input from the FDA and other agencies – reported last month that between May and October of 2005, drug companies did indeed register more of their clinical trials – at a 73 percent increase – but she criticized some drug companies for providing only vague descriptions of studies.

“In our opinion, it is unacceptable for a trial sponsor not to register its trial in a complete, meaningful, and timely fashion,” Dr. Zarin wrote in the December 29 issue of NEJM (2005:353:2811–2812). “If a company continues to register trials using meaningless data, with no respect for the registration process and the patients who participate in those trials, investigators and patients should refuse to participate. If a company realizes that secrecy and failure to register mean that it cannot meet its recruitment goals, it will quickly recognize that the consequence of that secrecy is commercial failure, not competitive success.”

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ARTICLE IN BRIEF

✓ Physicians question why data from trials by drug companies – which often form the basis for FDA policies – should be kept confidential.

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SEEKING SUBMISSIONS FOR CASE IN POINT

We welcome your submissions to Case in Point, a periodic feature that provides a window into the process of solving challenging clinical problems. In 250 words or less, each case should include a brief description of clinical symptoms, a patient history, and the pathway to solving the case. Please send your cases for consideration to John Corboy, MD, at john.corboy@uchsc.edu.

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REFERENCES

• Zarin DA, Ide NC. Trial registration at clinicaltrials.gov between May and October 2005. N Engl J Med 2005:353:2779–2787.

• Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antpsychotic drug treatment for dementia: Meta-analysis of randomized placebo-controlled trials. JAMA 2005: 294: 1934–1943.

• Leiberman JA, Stroup TS, Hsiao JK, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005: 353: 1209–1223.

• Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: A review of the evidence. JAMA 2005:293:596–608.

©2006 American Academy of Neurology

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