Science as marketing

A new peer-reviewed study paints a disturbing picture of the use and abuse of science by pharmaceutical companies to help them sell drugs.

Published in the latest edition of the Journal of Bioethical Inquiry, the study goes through several case studies of big drug companies using questionable science to boost the apparent effectiveness and/or safety of their products. Authors Glen Spielmans and Peter Parry sifted through internal court documents released to the public through lawsuits against the drug companies in one of the first peer-reviewed studies to rely on such documents.

They outline several ways they say that companies used science improperly to market their drugs, including selective use of trial results (or "data fishing") to suppress or spin negative results, and ghostwriting -- in which a report written by or for a drug company to give a psitive review to one of its products is then published under the name of a respected academic or research who had little (if anything) to do with its preparation.

In most cases, the study says, the "authors" are not even allowed to see the raw data -- a fatal flaw, the authors say, because the raw data can sometimes point to a different conclusion that the data the company has selected to share with the outside world, or its "authors" of ghostwritten articles.

By participating in such schemes, Spielmans and Parry say, "honorary academic authors are not just padding their vitae, they are also potentially harming public health when they fail to carefully review data presented in studies on which their names appear as authors."

They outline GlaxoSmithKline's ghostwriting program for its anti-depressant Paxil, dubbed CASPPER, for "Case Study Publications for Peer Review." 

The authors also offer an example of how data fishing can work, again from GSK, but not from the CASPPER program. In the example, data from a "wash-out" period before the formal trial -- during which past medications use is washed from the participants' bodies to ensure a clean trial -- is included, which alters the study's conclusions.

Instead of showing a higher chance of suicide, the eventual study showed the opposite.

Placebo-controlled trials often include a placebo wash-out phase, in which all participants initially receive placebo prior to some participants then switching to the drug under investigation. For example, a study may use a 3-week period of placebo washout, followed by 8 weeks of patients receiving either drug or placebo. It should be obvious that the comparison of efficacy and safety between drug and placebo should begin during the fourth week, when half of the participants have started receiving active medication. Yet some manufacturers of antidepressants counted suicidal behaviour in the placebo wash-out phase against placebo in their comparisons of drug to placebo. Comparing suicidal acts on 11 weeks on placebo to 8 weeks on a drug helped to drive up apparent rates of suicidal behaviour on placebo, which made the drugs appear safe in comparison. Indeed, an article was published in 1995 allegedly showing that paroxetine reduces suicidality. The academic author admitted that he had not seen the actual raw data; rather, he had been provided data tables by the manufacturer, which he then helped to convert into an article (Glenmullen 2007). However, the data in the article included suicide attempts which occurred during the placebo washout phase, though this was not stated in the manuscript. GSK has since posted its own analysis online, in which it notes an increased risk of suicidal behaviour among patients taking paroxetine relative to placebo (GlaxoSmithKline undated). Nearly anyone reading a journal article will assume that the named authors had access to raw data rather than misleading data tables provided by a drug firm. While not technically ghost authorship, the manner in which the data were translated into final form is clearly outside of the norms of science.

The authors call for more access to raw data, and recommend that perhaps journal articles should be read with a grain of salt.

The article also provides links to several web site containing internal drug company files made public due to lawsuits: furiousseasons.com/ zyprexadocs.html, furiousseasons.com/ zip/seroqueldocs.zip and healthyskepticism.org/ documents/Antipsychotics.php. There is also the Drug Industry Document Archive at the University of California, San Francisco, which has a searchable database of company files from several court cases.

More on salami slicing -- Cymbalta ads ordered pulled

Today, I had a story in the Toronto Star about an issue I touched on in this blog last week: Salami slicing, or the re-use of clinical trial data in more than one journal study.

I spoke to Glen Spielmans, who wrote a study on the practice after looking into claims made in TV ads by Eli Lilly about its antidepressant Cymbalta.

As he went through every study he could find on Cymbalta – which is also known by its generic name, duloxetine – Spielmans began feeling as if he was reading the same study over and over again, sort of an academic déjà vu.

"There just aren't that many data to do all these secondary analyses on," Spielmans said in an interview. "That raised a flag for me."

I also spoke to a cancer researcher that while salami slicing does happen, it's worth remembering that trials are often designed so the data can be sliced up later.

"I would be careful of anything that's given a folksy name," says Dr. Ralph Meyer, director of the National Cancer Institute of Canada's Clinical Trials Group at Queen's University. ...

"Clinical trials are a lot of work. They're a lot of expense," he says.

Trials that Meyer has run, for instance, have looked at such standard questions as the safety and effectiveness of a new treatment but have also used the opportunity to examine the cost-effectiveness of the procedure or the treatment's impact on a patient's quality of life. 

Jocalyn Clark, a researcher at the University of Toronto and an editor at the journal PLoS Medicine, says top journals like hers require all authors to declare if any part of the underlying research has been – or soon will be – published elsewhere.

She said universities and hospitals need to tell their researchers that slami slicing is not acceptable, and that academics taking part in the practice risk ruining their reputations with the journals they count on to publish their studies. In a part of the stroy that had to be cut for length, she equated the practice to ghostwriting, in that academics slicing up their data are not being fully honest with readers.

Meanwhile, the Food and Drug Administration in the U.S. has sent a letter to Eli Lilly ordering to pull its "misleading" print ads for Cymbalta.

Promotional materials are misleading if they fail to reveal material facts in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials. The Print Ad is misleading because it presents various efficacy claims for Cymbalta, but fails to communicate any risk information in the main part of the ad.




 

Few actually need antidepressants, study finds

It seems that despite the efforts of big drug companies to mass market their antidepressants -- turning them into blockbuster druggs as they pitch the pills to children and pregnant women -- only the severly depressed actually benefit, a new study says.

The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

Lead researcher Robert J. DeRubeis of the University of Pennsylvania said the study, published in the Journal of the American Medical Association, showed that those with only mild depression seemed to benefit from simply the added attention given to them by doctors during the drug trials -- and points to other ways such people can fight their depression.

“The message for patients with mild to moderate depression,” Dr. DeRubeis said, “is, ‘Look, medications are always an option, but there’s little evidence that they add to other efforts to shake the depression — whether it’s exercise, seeing the doctor, reading about the disorder or going for psychotherapy.’ ”

GlaxoSmithKline, the makers of Paxil, one of the drugs in the study, questioned the findings.

”The studies used for the analysis in the JAMA paper differ methodologically from studies used to support the approval of paroxetine for major depressive disorder, so it is difficult to make direct comparisons between the study results,” Glaxo spokeswoman Claire Brough said.

”Antidepressants are an important option, in addition to counseling and lifestyle changes, for treatment of depression.”

About 70 per cent of those taking such medications have mild enough depression that the medications may be of no use, the study found. The study could change how doctors approach depression with their patients, the New York Times said.

“I think the study could dampen enthusiasm for antidepressant medications a bit, and that may be a good thing,” said Dr. Erick H. Turner, a psychiatrist at Oregon Health and Science University. “People’s expectations for the drugs won’t be so high, and doctors won’t be surprised if they’re not curing every patient they see with medications.”

But Dr. Turner added, “The findings shouldn’t dampen expectations so much that people refuse to even try medication.”

The Star's mental health blogger, Sandy Naiman, also wrote about this study today, saying it "supports the strong contention I have about quick-fix, pill-popping approaches to mental health recovery."

 

 

 

 

A thin slice of (antidepressant) salami

A new study is casting a light on the controversial practice in academic publishing of "salami slicing" -- or the publication of several studies from just one set of clinical data.

Blogger and award-winning reporter Ed Silverman defines salami slicing this way: "Simply put, this involves publishing separate, but similar articles that rely on the same set of data. Researchers may slice the salami to increase their publishing output and drugmakers may view this as a way to promote useful findings for their meds.

The study, in the journal Psychotherapy and Psychosomatics, says the practice does little to advance science, but can help boost drug sales and feed a researcher's need to publish or perish.

Salami publications may be included as part of a pharmaceutical firm’s publication plan. When supportive and highly similar points about a drug’s efficacy and/or safety from a single clinical trial are published in a variety of journals, a wide audience of potential prescribers and key opinion leaders is reached. Thus, in addition to padding the curricula vitae of researchers, salami publications may lead to the results of a successful trial being disseminated across several publications, likely helping to boost product visibility and reinforcing the product’s key marketing messages. Because various researchers and clinicians read differing journals, they may not notice that redundant findings are being presented in multiple publications.

The study found that six clinical trial were sliced thin enough to be used in 20 or more different published studies.

Medical journals act on conflicts of interest

The world's top medical journals, including the Canadian Medical Association Journal, have launched a beta version of a new financial disclosure form they will require future researchers to fill out before their studies can be published in their pages.

According to a joint editorial to be published in all the participating journals, the uniform disclosure requirements are meant to both make life simpler for researchers facing different reporting standards at each journal, and to ensure a standard measure of researchers' potential conflicts of interest.

We ask authors to disclose 4 types of information. First, their associations with commercial entities that provided support for the work reported in the submitted manuscript (the time frame for disclosure in this section of the form is the life span of the work being reported). Second, their associations with commercial entities that could be viewed as having an interest in the general area of the submitted manuscript (the time frame for disclosure in this section is the 36 months before submission of the manuscript). Third, any similar financial associations involving their spouse or their children younger than 18 years of age. Fourth, nonfinancial associations that may be relevant to the submitted manuscript.

Besides the CMAJ, the journals involved include the Journal of the American Medical Association, the New England Journal of Medicine, the Lancet and the Medical Journal of Australia.

The journals will meet in April to review the form and researchers' reaction to it, and may adjust the four-page form then.

 

Who best to regulate -- doctors or drug companies?

A move by New Jersey to become the first state in the US to regulate the relationship of doctors to drug companies is sparking a debate over the best way to counter the power of Big Pharma.

Last month, NJ Attorney General Anne Milgram released a 22-page report limiting the gifts doctors can accept from drug companies -- among other things saying they can no longer accept free lunches, gifts worth more than $200 (US) and banning them from putting their name on ghostwritten articles. It also calls for tighter controls on doctors' financial disclosure and limits on drug companies paying for doctor retraining.

All are methods used by drug companies to market their products to the doctors who write the prescriptions. New Jersey has one of the highest concentrations of drug companies in the U.S.

The Medical Society of New Jersey, however, says doctors should not be targeted.

Spokesman Daniel Klim said the task force's time could have been better spent on other issues.

"We don't believe that pharmaceutical gifts influence medical decision-making as much as, say, a patient's insurance plan," he said. Klim said that physicians follow a code of ethics and that real conflicts were rare.

"I think in any industry you could find negativity," he said.

Milgram defended the report, saying the state has greater jurisdiction over doctors. "It really is, at the end of the day, each individual doctor's conflict of interest as much as it is the industry's."

Other states, such as Massachusetts and Vermont, put the reporting onus on industry instead of physicians.

Daniel Hoffman, president of the consulting firm Pharmaceutical Business Research Associates in Glenmoore, Pa., supported the restrictions, saying small gifts lead to bigger benefits, such as free education courses.

"It's sort of the opening gambit to a one-hand-washes-the-other relationship that I think has to be broken, to which this kind of ban can be useful," he said.

Industry groups agreed with Klim, however.

Dave Knowlton, president of the nonprofit New Jersey Health Care Quality Institute, said the state should be wary of putting new regulations on doctors who already have too many hoops to jump through.

"I really think that we should be diligent about saying, 'Let's not put another hassle on them unless we really think there's a need for it,' " he said.

Knowlton was on the task force and said he was frustrated that he and other members were left out of much of the process.

He wanted proof that the regulations were needed, arguing that many of the abuses of years past had been remedied through voluntary actions by manufacturers and federal regulations controlling such things as payments to physicians during drug and product trials.

The US federal government is working on regulations governing the drug companies, but Milgram said action is needed now: "To me, the argument of 'please just wait [for a federal plan]' isn't fair to the consumer, because people go to the doctor's every day."

The report makes 22 recommendations in all.

 

 

Garden State crackdown on drug marketing

Any doctor wanting to practice medicine in New Jersey may soon have to refuse lunches from drug industry representatives and any gift worth more than $200 (US), if new rules proposed by the state's attorney general are adopted.

The proposals were among 22 recommendations included in a Dec. 3 report to Attorney General Anne Milgram

While a handful of states have fought financial conflicts in medicine by regulating drugmakers and threatening hefty fines, the proposals would make New Jersey the first to make doctors the targets of enforcement.

The proposed regulations "are designed to ensure that patient care is guided by the unbiased exercise of doctors' best judgments," Milgram said in endorsing the report's proposals. "It is critical to minimize the potential for conflicts, and it is critical that patients are made aware of any financial relationship between a physician and a pharmaceutical company or medical device manufacturer. Such relationships could bias medical decision-making."

The report calls on the state medical board to require that 25 per cent of continuing medical education credits come from "evidence-based educational programs" that refuse industry grants. The report also targets ghostwriting, a widespread practice in the drug industry, by recommending that doctors be barred from claiming authorship for articles they did not write. The report also aims to stop doctors from misrepresenting their financial interests on disclosure forms.

On the industry side, the report recommends tight controls on what is known in the pharmaceutical industry as “data mining,” or tracking physician prescription information. All physicians would have to be notified when renewing their licenses that they can opt out of having information about their prescriptions sold by pharmacists to healthcare information organizations, which collect information on prescriptions for pharmaceutical company marketing.

As well, the report recommends that pharmacies be required to maintain documentation that doctors have consented to the sale of their prescribing information. The report calls for legislation to restrict the use and sale of prescriber information for commercial purposes.