October 26

Published Clinical Trials Contradict Claimed Benefits – Front Page Pill Pushers

Published Clinical Trials Contradict Claimed Benefits – Front Page Pill Pushers

Tue Aug 16, 2005

Two items from the BMJ

A systemic review of 22 randomized clinical trials of Alzheimer’s disease treatments in the BMJ found the studies to have suffered from flawed methodology and to have revealed that commonly prescribed treatments had neglible clinical use. [1] The study adds evidence in yet another area of medicine whose clinical practice is misguided by fraudulent clinical trial reports.

A commentary by Stefan Kruszeuski, M.D. and Jeffrey Brown, MD, JD, MPH, below, cites the dubious “off-label” use of gabapentin (Neurontin), a drug approved for adjunctive use in partial seizure disorders and post-herpetic neuralgia, which is widely prescribed for a variety of chronic pain and psychiatric syndromes. Pfizer had pleaded guilty to criminal marketing practices and fined $430 million. But clearly fines don’t have much of an impact on companies that make billions through fraud and deception.

Those flawed trials–i.e., designed to mislead–were conducted and reported in the literature by physicians. Those physicians are collaborators of drug manufacturers. Therefore, they bear no less responsibility for misrepresenting the drugs’ benefits and concealing the hazardous effects. Doctors who pitch drugs for manufacturers are largely responsible for those unsupportable “off label” prescriptions for drugs such as Neurontin, whose adverse effects–including the highest drug-related suicide rate–more than outweigh the undocumented benefits.

A commentary by Naomi Marks about an excellent appraisal of the media’s role in hyping drugs in the Columbia Journalism Review by Trudi Lieberman (See: http://cjr.org/issues/2005/4/lieberman.asp or https://ahrp.org/infomail/05/07/27.php ).

When will the science reporters show demonstrate healthy skepticism and stop disseminating false and misleading information about drugs and medicine provided by those with substantial financial stakes in the products they praise?

The drug industry has secured powerful friends who help pitch misleading information about drugs. The drug industry’s influence is boght and paid for: the media which has come to depend upon income from drug advertisements colors much of the reporting about medicine. And public officials whose campaigns this industry finances turn a blind eye and deaf ear to the death toll from harmful drugs.

1. Hanna Kaduszkiewicz, Thomas Zimmermann, Hans-Peter Beck-Bornholdt, and Hendrik van den Bussche
Cholinesterase inhibitors for patients with Alzheimer’s disease: systematic review of randomised clinical trials
BMJ 2005; 331: 321-327

Contact: Vera Hassner Sharav

BMJ 16 August 2005 Rapid Responses published: http://bmj.bmjjournals.com/cgi/eletters/331/7512/321 The Timing of Published Non-Confirmatory Data Re-Analysis Deserves Attention Stefan P Kruszewski , M.D., & Jeffrey A Brown, M.D., J.D., M.P.H., Clinical Associate Professor of Psychiatry, University of Medicine and Dentistry of New Jersey (16 August 2005)

BMJ published an important paper by Kaduszkiewicz, Zimmermann, Beck- Bornholdt and van den Bussche in their 06 August edition. (1) The paper, “Cholinesterase inhibitors for patients with Alzheimer’s disease: Systematic review of randomised clinical trials”, is a meta-analysis of 22 trials. It demonstrated that flawed methodology and negligible clinical benefits undermine previously asserted recommendations for some of the commonly prescribed anticholinesterase inhibitors for Alzheimer’s disease.

Separately, an important 2002 study by Ann Hamer and her associates published in the Journal of Managed Care Pharmacy (JMCP) revealed similar findings of flawed methodology and limited clinical benefits. The subject of that investigation was the “off-label” use of gabapentin, a drug approved for adjunctive use in partial seizure disorders and post-herpetic neuralgia but not for the wider variety of chronic pain and psychiatric syndromes which accounted for much of its off-label prescribing.

In that study, the authors retrospectively reviewed medical records from 105 patients who were treated with gabapentin, prescriptions reimbursed by Oregon Medicaid. (2) 95% of the gabapentin prescriptions were off-label. More significantly, 88% of patients receiving gabapentin did not demonstrate a positive response.

Unfortunately for those who paid the bills for gabapentin therapy and for those consumers who reported no benefit and/or unpleasant side- effects, these published negative results came almost 9 years after the successful release and marketing of gabapentin. [Gabapentin (Neurontin- Parke-Davis) was approved by the US FDA on 30 December 1993. In 2001, according to Hamer et al, gabapentin was in the top-10 drug products by total costs paid by Oregon Medicaid fee-for-service. ]

One of the likely sources of over-enthusiastic off-label prescribing and lack of documented off-label benefits has been the uncritical adoption of claims of benefits based upon open-label trials or inadequately populated cohorts. Another occurs when research scientists are not expected to compare their original findings with those of longer term studies which contradict their original conclusions.

Some of these problems were recently described in an investigative report by John Ioannidis that appeared in the 13 July 2005 edition of the Journal of the American Medical Association (JAMA.) (3) He reviewed 49 highly cited original clinical research studies to determine whether subsequent analysis could reiterate or replicate original positive findings. Although some studies (24%) went unchallenged, about 32% of studies—-or nearly one-third of preliminary highly touted research findings involving various medicines and therapeutics—did not have the reliability and validity of their findings confirmed by follow-up research, with some outcomes specifically contradicted by subsequent studies.

Kudos to BMJ, JAMA, and JMCP (and other comparably reputable peer- reviewed journals) for identifying research whose original findings have subsequently been seriously qualified or invalidated. We believe ethical journals have an obligation to expose research making claims of efficacy– -especially for off-label use of medications—when these claims do not withstand subsequent prospective scrutiny. Pharmaceutical journals have a particularly strong obligation to do this since they hold a special trust in the provider community, often being the first place where new drugs are introduced and off-label use is promoted. Furthermore, we maintain that, in order to repair public and provider trust in academic and pharmaceutically-sponsored research, journals must expand their exposure of data analyses that are later found to have been biased and/or predicated upon misstatements regarding the reliability and validity of prior published results.

Even more carefully considered research and publishing criteria still fall short of protecting the patient and provider communities when publication is too-long delayed. Timing is keenly important.

Indeed, even after the publication of spurious data collection or misrepresented results, multi-year lapses routinely occur between non- confirmatory re-analysis and bogus preliminary findings. Therefore, if journal and media scrutiny are effectively to minimize the ramifications (morbidity, mortality and added healthcare costs) of questionable data, published re-analysis must occur, if at all possible, in close temporal relationship to the original publications.

Stefan P. Kruszewski, M.D.
Jeffrey A. Brown, M.D., J.D., M.P.H.
Clinical Associate Professor of Psychiatry
University of Medicine and Dentistry of New Jersey

1 Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer’s disease: systematic review of randomised clinical trials BMJ. 2005 Aug 6; 331(7512): 321-327

2 Hamer, AN M, Haxby, DG, McFarland, BH and Ketchum, K. Gabapentin Use in a Managed Medicaid Population. JMCP 2002; 8(4): 266-271

3 Ioannidis, JP. Contradicted and Initially Stronger Effects in Highly Cited Clinical Research. JAMA. 2005; 294 (2): 218-228

Competing interests: None declared


British Medical Journal
August 13, 2005
BMJ 2005;331:410 (13 August), doi:10.1136/bmj.331.7513.410
Front page pill pushers
How the media are complicit in drug marketing

The lay media have long come under attack for not adequately scrutinising the information emerging from Big Pharma about new prescription drugs, but now they stand accused of helping to publicise and promote drug company products. In a hardhitting article in the current issue of the prestigious US periodical the Columbia Journalism Review, the press is criticised, in its coverage of drug industry matters, for failing as a public watchdog.

“Americans have always been obsessed with all things health-related,” says the article, “but today a drug can move almost instantaneously from medical research to miracle cure through news media that too often seem more interested in hype and hope than in critically appraising new drugs on behalf of the public” (www.cjr.org/issues/2005/4/lieberman.asp).

The article’s author, Trudy Lieberman, who is health policy editor of US watchdog organisation Consumers Union, blames various factors. In short, she says, journalists all too often fail to:

* find information sources and case studies other than those offered by drug companies and their public relations people

* disclose the financial or other interests of those they quote

* seek out and evaluate research data.

Other factors exacerbate the situation, she says: there is the increasingly sophisticated way that drug companies hide aggressive marketing activities; there is the growth in direct to consumer advertising leading to conflict between advertising and editorial in media organisations; and there is the hard to break culture of newsrooms in which simplistic black and white stories are seen as so much sexier than reports painted in more realistic shades of grey. Ms Lieberman also points a finger at the US Food and Drug Administration and its “somewhat cozy relationship with the companies it regulates,” which sees those reporters asking tough questions being “frozen out.”

Overall, she says, such a mix finds the press caught up in a drug industry marketing web that leaves the public without a reliable watchdog.

Ms Lieberman-whose article analyses coverage of various drugs that have since been withdrawn, such as rofecoxib (Vioxx)-is writing about the United States, but the scenario she outlines is recognised all too clearly by Dr Ike Iheanacho, editor of the UK based Drug and Therapeutics Bulletin. “These themes of how the drug industry interacts with the public involving the media are universal and perennial,” he says.

Dr Iheanacho points to the standard health reporting formula: “There’s a `break-through,’ an interview or quotes from somebody who has benefited, and maybe a quote from the manufacturer. You don’t get a sense of balance, that there might be side effects, or that the drug might not even be available for a few years.” He adds: “It takes time to be truly critical. Either you have to look at the studies yourself or talk to someone or several people in detail. Having done all that you may end up with a very confused picture and that doesn’t make easy journalism.”

Indeed, for journalists not content to settle for “easy journalism,” reporting can be more than just time consuming. Jo Revill, health editor of the UK Sunday broadsheet the Observer, believes that UK journalists do at least display a greater scepticism toward the drug industry than their US counterparts-but you need more than scepticism to cover the health beat critically and effectively. The big drug companies, she says, are reluctant to talk to journalists outside of the trade press, and while invitations to press conferences about drug launches are forthcoming, “when you want to ask more detailed questions about a drug it can be really difficult getting information. The PRs won’t deal with these questions and people in-house don’t want to deal with you either.”

On the other hand, when drug companies are keen to speak to journalists, they can be incredibly forthcoming-from offering trips abroad to attend launches to paying “honorariums” to attend evening “think tanks.”

According to Dr Iheanacho, however, there are glimmers of hope for a better informed public. There are growing demands for clinical trial information to be made public and patients are exhibiting a new enthusiasm for asking questions about their health care. In addition, uncritical reporting often has a fixed lifespan: as in the case of Vioxx, today’s miracle cure can turn out to be tomorrow’s disaster. “The public will become more sceptical,” he says.

Naomi Marks, freelance journalist

FAIR USE NOTICE: This may contain copyrighted (© ) material the use of which has not always been specifically authorized by the copyright owner. Such material is made available for educational purposes, to advance understanding of human rights, democracy, scientific, moral, ethical, and social justice issues, etc. It is believed that this constitutes a ‘fair use’ of any such copyrighted material as provided for in Title 17 U.S.C. section 107 of the US Copyright Law. This material is distributed without profit.

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