Threats to science-based medicine: Pharma ghostwriting (revisited)

Here and elsewhere in the blogosphere, over the last several years, what started out as a more general interest in skepticism and science with a natural focus on medicine and a side interest in combatting Holocaust denial became more focused on promoting science-based medicine. As the saying goes, “Science, it works, bitches,” and I make no apologies for promoting science-based medicine as the best medicine and applying skepticism and science to claims of purveyors of unscientific so-called “alternative” medicine advocates and anti-vaccine loons. However, I am not blind to the shortcomings of SBM, the claims otherwise of those who really, really don’t like me notwithstanding. I’ve even written about them right here on this very blog (and elsewhere). However, I continue to steal ruthlessly from Winston Churchill when he said, “Many forms of Government have been tried and will be tried in this world of sin and woe. No one pretends that democracy is perfect or all-wise. Indeed, it has been said that democracy is the worst form of government except all those other forms that have been tried from time to time.”

The same thing goes for SBM. It’s the worst form of medicine–except for all those other forms that have been tried before. (Look for some enterprising woo-meister to quote mine that passage.)

One of the most important aspects of SBM–actually all of science–is the peer-reviewed scientific literature. There, scientists report their findings, after they have been subjected to peer review, for other scientists to examine, replicate and expand on, and, quite often, attack ruthlessly. It is through a ruthless, Darwinian selection process that poor science is either overturned or forgotten and good science is confirmed and expanded upon to use as a basis to improve upon. This process is incredibly messy, particularly in medicine and particularly to lay people who are not used to the rather nasty testing to which scientists naturally subject each other’s work to, which is perhaps one reason why alt-med advocates often have a hard time handling scientific criticism that is actually not even particularly harsh. Be that as it may, SBM can be quite frustrating in that it may take much longer than one would expect to change in response to new evidence, but if there’s one thing that distinguishes SBM from woo is that it actually does change in response to evidence, casting aside therapies that do not work or do not work as well in favor of therapies that work better. The peer-reviewed scientific literature is how that new scientific information is distributed to physicians. If the peer-reviewed scientific literature is corrupted, then the information that physicians receive is corrupted.

Yesterday, I was depressed to see Steve Novella take on a Policy Forum article in PLoS Medicine by Adriane J. Fugh-Berma of the Department of Physiology and Biophysics at Georgetown University entitled The Haunting of Medical Journals: How Ghostwriting Sold “HRT”. Steve did his usual fantastic job of looking at the article and the practice of pharma ghostwriting, but I decided that I needed to comment on the article as well, mainly because of how related to my area of specialty it is. Hormone replacement therapy (HRT) is a textbook example of how medicine can at times embrace a therapy before its’ ready for prime time to the point that the therapy can even become the standard of care. It’s also a topic I have discussed before in the context of HRT. Basically, the first time around I expressed my outrage at a particularly egregious example of allowing pharma ghostwriting on the topic of HRT. In particular, I could not understand how Dr. Gloria Bachman, professor of obstetrics and gynecology at the Robert Wood Johnson Medical School in New Brunswick, NJ, in essence allowed a minion of Wyeth Pharmaceuticals working through a company contracted by the pharmaceutical company to write a 14 page review article that Bachman published almost unchanged in The Journal of Reproductive Medicine in 2005.

In his PLoS Medicine article, Fugh-Berman tells the tale of how a company hired by Wyeth called DesignWrite did far more than just publish one ghostwritten review article upon which it pasted just one academic physician’s name.In reality, Dr. Bachman’s betrayal of her academic position was but a small part of DesignWrite’s scheme. The scheme, which was designed as a way of getting around FDA regulations on advertising claims for pharmaceuticals:

It is illegal for pharmaceutical companies to promote a marketed drug for off-label use, i.e., for uses other than those approved by the U.S. Food and Drug Administration (FDA) or equivalent national agencies. Articles in medical journals, newsletters, and magazines, however, are not considered promotional. As an industry article states, “Peer-reviewed publications offer pharma companies shelter from often-stormy regulatory waters. FDA views published articles as protected commercial speech so doesn’t regulate their content” [29].

In the absence of data (or in the presence of data adverse to marketing goals), review articles in medical journals are crucial vehicles for encouraging off-label uses, promoting unproven benefits, and for downplaying harms. Narrative reviews summarize and analyze prevailing literature and often offer clinical recommendations [30]. Commentaries and other opinion pieces are also highly valued because they provide clinical direction, and are usually not peer-reviewed. Presentations at medical meetings are important for the same reason [30].

Of course, besides the First Amendment, one reason why speech in peer-reviewed journals is generally considered not to be on the same level of advertising is because it is peer-reviewed. The peer review is supposed to make sure that the factual information in articles is, well, factual. However, one thing peer review can’t necessarily do–or at least can’t do as well– is to comment on the conclusions authors of review articles draw from the evidence they present. After all, by their very nature, most review articles are in essence commentary. Most reviewers will therefore concentrate on the facts and only intervene if the conclusions being drawn from those facts are egregiously out of line with the facts presented or if well-known contradictory information and data are not acknowledged and discussed. Commentaries can get away with even more because they are often not peer reviewed. On the surface, none of this is necessarily wrong or deceptive. Rather, it’s just how scientists and physicians publicly debate the data and the clinical recommendations that flow from that data.

There are, however, three assumptions behind these reviews, editorials, and commentaries, and those assumption are (1) that the authors of these articles are honest brokers; (2) that the authors actually wrote the review articles; and (3) that what the authors write represents their opinion. Indeed, that is the same assumption that goes into the peer review of these articles as well. In other words, no matter how extreme or strongly argued the opinion, there is the assumption that it is an honest opinion presented by the academics holding it. Moreover, it is quite common for academics to argue for the off-label use of various drugs, and there is nothing wrong with that. Off-label use is not necessarily non-science-based, nor is it illegal or even against the standard of care.. Sometimes off-label use can be quite science-based in that it is simply ahead of its time, with some clinical trials having been done but not enough (yet) for an application to the FDA. However, the FDA quite correctly does not allow pharmaceutical companies to advertise their drugs for off-label indications for the simple reason that, if such advertising were allowed, then drug companies would have no incentive to do the clinical trials to get their drugs approved for additional indications. All they’d have to do is to get approval for one indication and then advertise for any other indication they want. In contrast, physicians are perfectly free to advocate for off-label uses.

To take advantage of this DesignWrite designed a comprehensive plan, which Fugh-Berman describes:

As Table 1 shows, DesignWrite helped to produce numerous ghostwritten reviews and commentaries, including articles designed to promote the off-label use of Prempro for preventing Alzheimer’s disease, Parkinson’s disease, age-related macular degeneration, and wrinkles. The scope of these articles is summarized in Box 1. The DesignWrite documents avoid discussing off-label marketing, but noted that reviews can “Disseminate messages that fill the gaps not addressed by current studies” [31]. Another document noted that the “Strategic Publications Team” should “Identify data gaps” and “Fill the gap with review papers” [32].

This even went so far as DesignWrite “managing” a stable of authors:

An important part of DesignWrite’s work for Wyeth was to manage “authors” and journals. There is evidence in unsealed DesignWrite documents that although some authors signed off on ghostwritten articles, others insisted on contributing to their articles. One co-author seemed puzzled by the concept that she was to author, but not write, an article [34]: “From what you have written, I would be more of an ‘editor’ rather than the major writer–that is, you guys would be writing the versions–with me ‘altering, editing, etc.? Is that correct?'” This query was in response to an e-mail from Karen Mittleman (a DesignWrite employee who supervised medical writers) that stated: “The beauty of this process is that we become your postdocs! … We provide you with an outline that you review and suggest changes to. We then develop a draft from the final outline. You have complete editorial control of the paper, but we provide you with the materials to review/critique” [34].

So what’s wrong with this? A lot. The biggest problem with this is that there are an uncredited co-authors (the ghostwriters from DesignWrite) who are employed by the pharmaceutical company making the drug that is the topic of the review article. In the case of HRT, these articles were designed to be marketing materials, not objective (or even not-so-objective) commentaries or review articles. The “authors” (who don’t deserve the appellation, given that they in essence just put their names on articles to which they contributed relatively little) could suggest changes, and DesignWrite would even incorporate them–as long as the changes didn’t compromise the marketing message.

There were many marketing messages, too. In the case of HRT, the marketing messages were many. They included promoting the cardiovascular benefits of HRT (which, as later studies showed), were vastly overblown and in fact nonexistent; sliming the competition (generics); and, most relevant to my specialty, trying to downplay the connection between HRT and increased risk of breast cancer, complete with a number of “talking points”:

  • Cast doubt on the link between HT and breast cancer
  • Questioned whether HT-induced changes in mammographic density were related to increased breast cancer risk
  • Implied that use of estrogen after breast cancer was safe
  • Promoted the concept that HT-associated breast cancers were less aggressive cancers

Regarding point number one, the Women’s Health Initiative (WHI) study, whose results were published in 2002, was the final nail in the coffin of claims by promoters of HRT for cardiovascular benefits. Even more alarming, the WHI found an increased risk of breast cancer. Indeed, since the WHI study was published and HRT use plummeted, the incidence of breast cancer has decreased. As for the other points, mammographic density is related to breast cancer risk; that is becoming more and more clear, not to mention an increasing area of research interest among investigators whom I know. In any case, the DesignWrite campaign, undertaken on behalf of Wyeth, has all the classic earmarks of a denialist campaign every bit as deceptive as that undertaken by tobacco companies.

And, as was the case with tobacco, academic physicians were complicit in the campaign.

I have to agree with Fugh-Berman when she asserts that “medicine, as a profession, must take responsibility for this situation,” and that “naïveté is no longer an excuse.” It’s true. Five or ten years ago it may have been possible for an academic physician to plead naïveté, but no more after this incident and other prominent examples of pharma ghostwriting. I do feel obligated to point out, though, that Fugh-Berman does have an agenda. She is an Associate Professor of Complementary and Alternative Medicine at Georgetown University, which earned my wrath years ago for requiring the teaching of non-science-based quackery “alternative medicine.” That she is correct to castigate the practice of pharma ghostwriting now does not mean I don’t keep in mind that she clearly has a bug up her behind about pharma that appears to be at least in part based on her belief in the glories of CAM. (I know through the grapevine that Fugh-Berman has a rather credulous attitude towards, for example, homeopathy.)

Be that as it may, like Steve Novella, I have never personally encountered an example of ghostwriting, but, also like Steve, I don’t think that necessarily means anything. For one thing, as much as I’d like to pretend otherwise, I am not a “thought leader” highly sought out by ghostwriters to spread their message, and the true thought leaders that I’ve worked with during my career are so well-published as to be virtually immune to the need for just one more publication. I don’t have any data to confirm this, but it appears to me that DesignWrite tended to target early mid-career academics who had made a name for themselves may have been up for promotion or tenure and could use every paper they could get. Those are the most vulnerable of academics, and, having recently been in a position where I really, really needed some papers, I can fully understand how it would be very tempting if a pharma minion from DesignWrite came up to me with a prewritten article that I could publish under my own name. However, I would resist, and we as academics have the duty to resist.

SBM works best in the light of day, where there is full disclosure, and I don’t view pharmaceutical companies as inherently evil, as some do. They are, however, profit-making companies with every right to market their legal products, but competing against that is medical profession’s need to know what is science, what is opinion, and what is advertising. The reason ghostwriting is so disturbing to me is not so much that a pharmaceutical company helped academics write their review articles but rather that not all the coauthors’ identities and affiliations were revealed. I rather suspect that, if they knew that multiple authors of an article were employees of a commercial company hired by a pharmaceutical company, editors would be less likely to publish the article and physicians would be less likely to read it or take its recommendations to heart. That’s why the light of day needs ot be shone on the entire process, so that the cockroaches will go scuttling back under their rocks. SBM demands it.