Half the top US academic medical centers have no policy on ghostwriting

Half of the top 50 academic medical centres in the United States have no policies on their staff ghostwriting research on the behalf of pharmaceutical companies – including UCLA and Mayo Medical School.

Medical ghostwriting is “the practice of pharmaceutical companies secretly authoring journal articles published under the byline of academic researchers.” By getting academics at top universities to put their names to papers, often for financial reward, pharmaceutical companies aim to improve the authority of their research or even sneak dodgy methodology or fabricated findings past journal editors and readers.

Only 10 (20%) of the top 50 US academic medical centres explicitly ban their staff from ghostwriting, according to the survey published in PLoS Medicine, although three of these institutions don’t specifically use the term “ghostwriting” in their policies.

A further three (6%) have authorship policies that prohibit medical ghostwriting in practice by insisting both that staff make a substantive contribution to the paper to qualify for authorship and that all who qualify for authorship be listed.

Although all the top 10 academic research centres in the US have authorship policies, only six ban ghostwriting and the remaining four – including Duke University and Yale – don’t have policies in place.

Ghostwritten articles can be used by pharmaceutical companies to influence the prescribing – and the sales – of their top products. The authors of the study explain this practise by describing how a pharmaceutical sales representative might use such an article to influence the prescribing of a practicing clinician. “When a pharmaceutical salesperson hands a clinician an article reprint, the name of the institution on the front page of the reprint serves as a stamp of approval,” they write. “The article is not viewed as an advertisement, but as scientific research; the reprint is an effective marketing tool because peer-reviewed journal articles generated in academia are perceived to be the result of unbiased scientific inquiry.”

For example, pharmaceutical companies have used ghostwritten articles to promote sertraline – the most prescribed antidepressant in the US in 2007 – methylphenidate – also known as ritalin, the widely used, and abused, ADHD drug – and rofecoxib – otherwise known as Vioxx, the arthritis drug withdrawn in 2004 because it caused heart attacks.

Given how ghostwritten articles can be used to influence drug approval or prescribing, the authors describe the practise as “a serious threat to public health.” To try to combat ghostwriting, they recommend that participating in medical ghostwriting is defined as academic misconduct akin to plagiarism or falsifying data.

Lacasse J & Leo J (2010) Ghostwriting at Elite Academic Medical Centers in the United States. PLoS Medicine 7 (2) DOI: 10.1371/journal.pmed.1000230

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Tamiflu isn’t much good and Roche tried to stop us showing so, says the BMJ

The BMJ has just published a whole slew of papers about Tamiflu (oseltamivir) – a key drug in the public health response against swine flu (influenza A/H1N1).

The linchpin is a Cochrane review on the efficacy of neuraminidase inhibitors – namely zanamivir (Relenza; Glaxo Wellcome) and oseltamivir (Tamiflu; Roche) – for preventing and treating influenza in healthy adults.  The review found that these two drugs were only partly effective against laboratory confirmed symptomatic influenza (oseltamivir 61% effective; zanamivir 62% effective), and no good at all against asymptomatic flu or flu-like illness.

In addition, Tamiflu did not reduce the risk of influenza-related lower respiratory tract complications – bad news for the Department of Health, which recommends using the drug to prevent secondary complications in healthy adults.  The authors conclude: “Neuraminidase inhibitors might be regarded as optional for reducing the symptoms of seasonal influenza. Paucity of good data has undermined previous findings for oseltamivir’s prevention of complications from influenza.”

In an accompanying feature, Deborah Cohen retraces the steps leading to the publication of the Cochrane review and highlights all the difficulties the authors had extracting data from Roche, the makers of Tamiflu.  The review “exposed a complex interplay between politics, public health planning, availability of trial data, publishing, and drug regulation.”

Turns out that Roche’s claims that Tamiflu reduces hospital admissions and secondary complications of influenza were based on a 2003 meta-analysis that only included two proper randomised controlled trials and was authored by several Roche employees.  When the authors of the Cochrane review tried to get their hands on the data in this paper to include them in their own analysis, they came up against all sorts of obstacles thrown up by Roche.

Peter Doshi, an author of the new Cochrane review, writes in the BMJ of his struggle to get hold of the elusive data and offers a damning verdict on the use of the drug in the swine flu epidemic. “Since August 2009, our Cochrane review team has tried to obtain the data needed to verify claims that oseltamivir (Tamiflu) lowers serious complications of influenza such as pneumonia. We failed, but in failing discovered that the public evidence base for this global public health drug is fragmented, inconsistent, and contradictory. We are no longer sure that oseltamivir offers a therapeutic and public health policy advantage over cheap, over the counter drugs such as aspirin.”

In an analysis article, Nick Freemantle and Mel Calvert look over the observational studies of Tamiflu that Roche cited in defense of their claims for the drug and found that they also do not support the use of Tamiflu to treat influenza in healthy adults. In their discussion they write: “oseltamivir may reduce the risk of pneumonia in otherwise healthy people who contract flu. However, the absolute benefit is small, and side effects and safety should also be considered. None of the studies examined the role of oseltamivir in patients with H1N1 influenza, which may be associated with higher rates of pneumonitis than seasonal influenza.”

Finally, in a linked editorial, Fiona Godlee, editor of the BMJ, and Mike Clarke, director of the UK Cochrane Centre in Oxford, rail against the obstructive techniques used by Roche and call for full data from clinical trials to be made available to the scientific community.  “Why should the public have to rely on detective work by academics and journalists to patch together the evidence on such a potentially important drug?” they ask.

All this is bad news for public health planning against swine flu – the Department of Health has already stockpiled more than 30 million doses of potentially useless Tamiflu – and even worse news for Roche.

Jefferson T, Jones M, Doshi P, & Del Mar C (2009) Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ 339 DOI: 10.1136/bmj.b5106

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Drug company funded events for health professionals: the state of play in Australia

Cardiologist Jeffrey F Caren, who has a monument of over 1,200 pens gifted to him by drug companies
Cardiologist Jeffrey F Caren, who has a monument of over 1,200 pens gifted to him by drug companies

The links between the pharmaceutical industry and doctors are many and tangled. Drug companies are keen to schmooze doctors and, directly or not, persuade clinicians to prescribe their drug instead of a similar one by a competitor. One way that drug companies try to influence doctors is by sponsoring events, such as conferences or lectures.

Despite legislation, the exact extent to which the pharmaceutical industry sways doctors via this approach is not really known. To try to unravel exactly how much is being spent on sponsoring events for doctors, Robertson and colleagues investigated pharmaceutical industry funding of events in Australia, which has laws stating that details of every sponsored “do”, including the costs of any hospitality, are posted on the Medicines Australia website.

The authors found that during a six month period, the drug industry spent AUD$1 million (about £555,000 or US$900,000) a week in Australia on sponsored “educational events” for health professionals. This equates to about 600 sponsored events a week and an average annual spending of around AUD$1,000 (£555 or US$930) on each doctor.

More than a third (35%) of events were held in plush spots like restaurants, hotels or function centres, which increased the spend on the event by five-fold compared with if the event was held in a hospital (AUD$71.35 vs AUD$12.11).

Bristol-Myers Squibb was the most generous company, with an average spend per head of AUD$95.26 (£53 or US$88), although Astra Zeneca held the most events (1,310 0ver six months).

Professionals specialising in psychology or oncology were the most likely to attend sponsored events, although the biggest spend was on endocrinologists, oncologists and cardiologists.  Tellingly, specialists in these particular disciplines tend to prescribe the highest cost drugs.

Companies had some control over what was discussed at the event in 91% of cases. Where provided, topic descriptions often matched the products made by the sponsor, although there were few mentions of specific drug names.

Evidence suggests that attending a drug company sponsored event can indeed change the prescribing practices of a doctor, making the figures in this report quite disturbing.  For example, judging by the numbers in this study, as many as 13,000 Australian doctors could be under the thumb of the pharmaceutical industry.  As the authors point out, “from a company perspective, it is cheap and easy to sponsor meetings in hospitals and health centres, and the return on this ‘investment’ is likely to be high.”

In the UK, the Association of the British Pharmaceutical Industry code of conduct states that pharmaceutical companies sponsoring meetings and seminars can only provide “subsistence” for events and can only offer economy air travel to delegates sponsored to attend meetings. The code also states that lavish venues must not be used and that the costs covered “must not exceed the level which the recipients would normally adopt when paying for themselves”.

In the US, several states have mandatory disclosure laws for physician payments so that it is a bit clearer to everybody who is cosying up with drug companies and who isn’t, but these data aren’t foolproof.  For example, laws on physician reporting of industry gifts in Vermont and Minnesota exempt payments of less than US$100.

It’s worth mentioning that the system in Australia is actually more transparent than that in either the UK or the US, given that since mid-2007, there has been mandatory reporting of details of every industry-sponsored event in Oz.  On that note, the situation is probably worse in the northern hemisphere, as noted by an article last year in British newspaper The Guardian.

And although there is legislation in place these days, as the authors point out, “lavish gifts and generous travel support … have been progressively discouraged by industry and professional guidelines. It is likely that the frequent, more modest, sponsored educational events will become increasingly important and influential, and the principal form of contact between industry and health professionals.”

This research clearly outlines how endemic industry courting of doctors really is.


Robertson J, Moynihan R, Walkom E, Bero L, & Henry D. (2009) Mandatory Disclosure of Pharmaceutical Industry-Funded Events for Health Professionals. PLoS Medicine 6 (11). DOI: 10.1371/journal.pmed.1000128

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Improving communication of medication risks and benefits in direct-to-consumer ads

A new study published in Annals of Internal Medicine has shown that adding a simple fact box to adverts for prescription drugs considerably improves consumer awareness of the risks and benefits of the medication.  In this study, people who examined an advert with a drug fact box were more likely to choose the most efficacious drug than were participants who assessed an advert with an in-depth summary of the drug characteristics.

The FDA requires that direct-to-consumer adverts include a ‘brief summary’ of all the risks listed in the drug’s FDA-approved prescribing information. This summary can amount to more than a page of dense text, however, and although companies are supposed to use easy-to-understand language, the text can seem pretty impenetrable.  Writing of the current system, the study authors Schwartz et al. say that “the U.S. public currently lacks accessible and accurate information about prescription drug efficacy and side effects. Instead, people are exposed to billions of dollars in marketing designed to generate enthusiasm for new products, leaving them vulnerable to persuasive marketing techniques and selective presentations of information”.

Drugs fact box

Schwartz et al. assessed whether using a ‘drug facts box’ – a 1-page round-up of a drug’s benefits and side effects, with key information on the chance of various outcomes provided in a table – improved knowledge of the risks and benefits associated with a medication and helped patients make informed treatment choices.

This study was split into two randomised trials that assessed two types of fact box: one box on how a drug treats current symptoms and one on how a drug prevents the onset of symptoms.

In the symptom drug box trial, the authors tested adverts for a fake proton-pump inhibitor (PPI) – Maxtor – and an imaginary histamine-2 (H2) blocker – Amcid.  These two types of drug are used to treat symptoms of heartburn and have similar adverse effects, but clinical data show that PPIs clearly outperform H2 blockers. All 231 participants received the same ‘ad image page’ (the colorful front page) and then also received either the symptom fact box (drug box group) or a brief summary (control group).

In the prevention drug box trial, the authors used adverts for a statin – Concor – and clopidogrel – Pridclo – for prevention of future cardiovascular events.  Such events are relatively rare, so the drugs have small absolute effects and are, therefore, not appropriate for many individuals. The 219 study participants were randomly assigned to receive either adverts with a brief summary or adverts with a drug box.

In the symptom drug box trial, more participants in the drug box group than in the control group were able to accurately recount the risks of the two heartburn drugs.  In addition, the perceptions of individuals in the drug box group more accurately reflected the actual efficacy of the drugs.  When asked which drug they would prefer to take, 68% of the drug box group chose the PPI – objectively the more effective drug – compared with 31% of the control group.

Participants in the prevention drug box trial who received the drug box adverts were more likely to understand the side effects of the two drugs.  Also,  most of the patients in the drug box group were able to accurately quantify the small reduction in the risk of cardiovascular events provided by the two drugs, whereas more than half of the participants in the control group overestimated the benefits of the drugs by a factor of 10 or more.  Individuals in the drug box group were, therefore, more likely to conclude than the side effects associated with the drugs outweighed the small benefits provided.

The authors write: “Some may wonder whether we simply proved the obvious: one group was provided with the ‘right answers’, whereas the other was not. However, that is precisely the goal of the drug box—it provides the data needed to make informed decisions. Without these data, people can only guess, and their guesses are most likely based on the information that appears in the ads.”

Schwartz LM et al. (2009) Communicating Drug Benefits and Harms With a Drug Facts Box: Two Randomized Trials. Ann Intern Med Early-release article: 17 February 2009

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Pharmaceutical industry promotion of off-label prescribing – responsible or reckless?

fda-logoLast week the US Food and Drug Administration ruled that the pharmaceutical industry could promote drugs for uses that haven’t been cleared by the regulatory body.  The new FDA guidelines permit the “dissemination of medical journal articles and medical or scientific reference publications on unapproved uses of drugs and medical devices.”

In order to be prescribed to treat a certain disease, a drug needs to be formally assessed and approved for this use by the FDA. The practice of ‘off-label prescribing’ entails doctors using a drug to treat a particular disease regardless of whether the FDA has confirmed that the drug is a safe and effective treatment for the disease in question.  As the FDA puts it, “Once a drug or medical device has been approved or cleared by FDA, generally, healthcare professionals may lawfully use or prescribe that product for uses or treatment regimens that are not included in the product’s approved labeling”.

Off-label prescribing is reasonably common, even though you may not have heard it described this way.  An article published in Archives of Internal Medicine in 2006 reported that more than 20% of prescriptions in the US during 2001 were for off-label uses of a drug. One example of off-label prescribing is the use of the drug Avastin – approved by the FDA for the treatment of metastatic colorectal cancer and breast cancer – to treat the condition wet macular degeneration, an age-related eye disease that can lead to vision loss.

The FDA highlight the importance of off-label prescribing, stating that “These off-label uses or treatment regimens may be important and may even constitute a medically recognized standard of care”.  Such practices permit innovation and allow physicians to use their own judgment on the basis of their personal experience prescribing a drug.

The new FDA guidelines sound like good news for the pharmaceutical industry. By promoting off-label uses of already approved drugs, companies can squeeze more profit out of ‘old’ drugs and can ease off the lengthy and expensive process of investigating novel drugs.  But what’s to stop such companies ruthlessly promoting dubious off-label uses for established drugs and risking the health of patients by encouraging doctors to use drugs when there’s not adequate evidence of their efficacy for a certain disease?

Well, the new FDA guidelines include a lot of restrictions as to exactly how off-label uses can be promoted to doctors.  For starters, the guidelines discuss the use of journal articles or medical publications to promote off-label prescribing, meaning that pharmaceutical sales reps will be handing out genuine research that has been conducted by independent groups, not self-penned marketing material.

The guidelines also include lots of important limitations on what type of journal articles, or reprints, can be handed out, including that the articles must:

  • Be published in a peer-reviewed journal that has experts on the subject on the editorial board
  • Not be part of a publication or supplement that is funded in whole or in part by the company that wishes to use the article
  • Be in the form of an unabridged reprint, copy of an article, or reference publication
  • Not be marked, highlighted, summarized, or characterized by the manufacturer in any way
  • Be disseminated with a representative publication, when such information exists, that reaches contrary or different conclusions regarding the unapproved use
  • Be distributed separately from information that is promotional in nature. For example, if a sales representative delivers a reprint to a physician in his office, the reprint should not be physically attached to any promotional material the sales representative uses or delivers during the office visit and should not be the subject of discussion between the sales representative and the physician during the sales visit

So the FDA have done their best to tie up pharmaceutical companies in such a way as to ensure that doctors receive the most accurate and unbiased information possible on off-label drug uses.

Having said that, bias and conflict of interest is an important problem here – of course sales representatives are going to do their best to only hand out journal articles that show the off-label use of their drug in a positive light.  You can bet that pharmaceutical companies won’t be providing doctors with the full body of evidence when it comes to use of their drug for a particular disease, as cumulatively such research could be more ambivalent about the benefits of an off-label use.

Also, in many cases even the total body of evidence doesn’t show that an off-label use is effective.  Indeed, the aforementioned Archives of Internal Medicine paper showed that three-quarters of off-label uses were not backed up by scientific evidence.  There is an argument that the clinical trials process and the publication procedure lags behind real life, and that although there are no trials showing that an off-label use is effective, many doctors will have prescribed a drug this way and seen the beneficial results for themselves.  Fair enough, to a degree, but this undermines the whole issue of the pharmaceutical industry giving out published research on off-label uses anyway, so will be of little interest to such companies.

Finally, how on earth is the FDA going to police their restrictions?  They can insist that the pharmaceutical industry follows their rules, but there is plenty of evidence that such regulations are regularly flouted.  For example, despite the new guidelines, the straightforward marketing of a drug for uses not cleared by the FDA is still illegal.  Global pharmaceutical company Eli Lilly used catchy slogans to persuade doctors to prescribe the antipsychotic agent Zyprexa for unauthorized use in elderly patients and has this month been fined $1.5 billion for doing so.

I’m not the only one with misgivings about these well-intentioned but ultimately flawed guidelines.  California senator Henry Waxman told Medscape that the new FDA decision “fundamentally undermines the requirement that companies prove to the FDA that each new use is safe and effective” and makes it easier for drugmakers to promote potentially risky medical practices.  Over on Nature Network, research scientist Craig Rowell proclaimed that “Alarm bells should be ringing” – despite his support of off-label prescribing, Craig is still deeply skeptical that pharmaceutical companies will stick faithfully to the restrictions.

What’s the bottom line for patients here?  Many will benefit from by off-label prescribing, or at least not be harmed, and doctors will be better able to prescribe off label if they are thoroughly informed about such practices.  The sticking point is whether the pharmaceutical industry can be relied on to accurately and fairly disseminate information about off-label uses; experience suggests probably not.  Whether the FDA has made a shrewd move in getting pharmaceutical companies to do this promotion for them, or a big mistake, remains to be seen.

  • The Pharma Marketing blog has an interesting post on this issue, which discusses policing of the new guidelines and the efficacy – or not – of off-label prescribing.
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Are physician education programmes about to break free from the shackles of Big Pharma?

There’s a lot of interesting chatter around at the moment about pharmaceutical industry funding of Continuing Medical Education (CME) for physicians.

Qualified doctors are expected to keep up to date with the latest research and treatments in their field by completing educational activities, which generally take the form of quizzes that participants must complete having watched a video, read an article, attended a lecture and so on. In the US, the Accreditation Council for Continuing Medical Education awards credits for CME activities that are necessary in many states for physicians to maintain their licence to practice year on year.

CME activities are generally developed and peer reviewed by leaders in their field, and are often delivered online or in print free of charge. And this is where pharmaceutical industry funding and accusations of bias come in to the issue. It stands to reason that a pharmaceutical company wouldn’t bother funding a CME programme for a therapeutic area that they are not active in, and it’s also not unlikely that such programmes might overplay the benefits of a drug made by the sponsor over those made by their competitors.

And so to the great CME funding debacle of 2008. Earlier this year, pharmaceutical giant Pfizer declared that it would stop funding CME programs made by medical communications companies, although, interestingly, would continue to fund those run by not-for-profit groups.

Now Stanford University in California has now pledged to stop direct industry funding of CME, although Memorial Sloan Kettering Cancer Center in New York has been doing without since January last year.

All this news has got commentators sounding the death knell for industry-sponsored CME, with the British Medical Journal declaring the end of the free lunch for doctors while others more portentously state that 2008 could herald the end of CME as we know it.

So could these events be the birth pains of a new area of untainted CME? Let’s hand it to the doctors, one group who have a lot to win or lose in this argument. After all, a big feature recently published in the Journal of the American Medical Association on the long association between the pharmaceutical industry and CME programmes lays the blame for industry involvement squarely on physicians.

US physician and blogger David Toub in Pennsylvania suggests that CME might eventually become completely disentangled from the pharmaceutical industry once companies are unable to directly promote their products, although doctors may well end up having to pay for CME activities. Similarly, Dr Carlat in Massachusetts has been blogging on the issue of industry funded CME for quite some time and is firmly of the opinion that such funding “leads to many bad things, including biased education, corrupt physicians, and, ultimately, harm to our patients”.

Dr RW Donnell in Arkansas, on the other hand, states that “the inquisition against industry supported CME is knee-jerk and intellectually lazy”, and believes that CME programmes are inherently going to have some degree of bias thanks to the experiences and opinions of the doctors who develop them, whereas actual commercial bias is thin on the ground.

This issue has raged at conferences and online for a very long time and is due some sort of resolution, although whether 2008 is the year for closure depends on how pharmaceutical companies and CME providers react to all the heat. Better keep an eye on those news stories…

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Coming soon to a pharmacy near you – HELENITOL!

Pharmaceutical company drug adverts can be so cheesy or so bizarre, hence they lend themselves very well to spoofs and satire.

In the wake of the hilarious online drug name generators (Drug-O-Matic, The Prescription Drug Name Generator and The New Drug Generator to name a few), a website to generate an advert for your own imaginary drug has now been launched by CEDRA Clinical Research.

Here’s my effort:This is actually a lot of fun: you get to pick various comedy symptoms, for example “smelly feet” or “cooking deficiencies”, add a few adjectives and exclamations and hey presto, your miracle drug! The website for this enterprise – getyourdrugon.com – is pretty slick too, although I can’t say any of this marketing effort makes me want to sign up for clinical trials!

(Scienceroll actually beat me to this…)

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