CANADA: Is medical science for sale?

Are medical researchers and journals too close to the pharmaceutical industry for comfort - or patient safety? Sergio Sismondo, a professor of philosophy at Queen's University, interrogates this pertinent and controversial issue in an article titled "Medical Publishing and the Drug Industry: Is medical science for sale?" in the current edition of the Canadian journal Academic Matters.

Observation #1

I recently looked at the cv of a distinguished professor of medicine and saw that he had authored (most usually had co-authored) about 800 articles in peer-reviewed journals, an average of nearly 30 per year over his career. His publication rate has accelerated over the years, reaching 40 articles per year in the past decade. How can a scientist author and publish 40 articles in a year? Year after year? In my fields - science and technology studies, philosophy, sociology - five peer-reviewed articles in a year is a lot, and most researchers would be happy to write one truly good article each year.

Observation #2

I recently looked at the articles published about one blockbuster drug (that is, with sales over $1 billion per year). The PubMed database contained over 700 articles in the "core clinical journals" that showed the drug's generic name as a keyword. There were more than 3,200 articles on the drug in medical journals as a whole. Other blockbuster drugs have similar profiles. Why do these drugs merit such attention?

This double mystery has a single solution, albeit a partial one.

Pharmaceutical companies sponsor a considerable amount of research, typically performed by for-profit contract research organisations (CROs). On the basis of that data and the publicly available medical research, drug companies and their agents produce a significant percentage of the manuscripts on major current drugs. These manuscripts are then "authored" by academic researchers, whose contribution ranges from having supplied some of the patients for a clinical trial, to editing the manuscript, to simply signing off on the final draft.

The companies submit these manuscripts to medical journals, where they fare quite well and are published. The published articles contribute to accepted scientific opinions, but the circumstances of their production remain largely invisible. When the articles are useful, the marketing departments of the drug companies involved will buy thousands of reprints, which sales representatives (reps) can give to physicians.

I call this whole process the "ghost management" of pharmaceutical research and publication.(1)

Some of the process is difficult to observe. A study of industry-sponsored research showed that statistician contributors were usually unacknowledged in the publications that flowed from that research, as were the creators of trial designs and protocols.(2) Although we know that pharmaceutical company statisticians and medical directors do work, there are no obvious ways of investigating their activities.

Yet some of this process is quite open. The manuscripts are produced under the guidance of publication planners, who tend to work for independent agencies rather than for pharmaceutical companies. More than 50 agencies advertise publication planning on the internet. Many of these are straightforward about what they do. Publication planning, says the director of one agency, is "gaining product adoption and usage through the systematic, planned dissemination of key messages and data to appropriate target audiences at the optimum time using the most effective communication channels."(3) These channels are such things as: "publications, journal reviews, symposia, workshops, advisory boards, abstracts, educational materials/PR." That is, the industry markets products via the core scientific media.

How much of the literature is ghost-managed? From the few cases where we have hard data, it appears that roughly 40% of medical journal articles on major in-patent drugs are parts of individual publication plans on the drugs.(4) (It is possible that additional articles are also sponsored by the pharmaceutical companies but are handled differently.) Forty percent is a very substantial amount, certainly allowing a company to attract interest in a drug and shape the perception of it, under the names of apparently independent authors.

The 40% figure might seem at first to be implausibly large, but upon closer examination, it is reasonable. First, pharmaceutical companies sponsor some 70% of all clinical trials, and 70% of those are run by CROs that have no interest in publishing the results under their own names - they produce data that is wholly owned by their sponsors. Thus, pharmaceutical companies have complete control over roughly half of all clinical trial data. Second, the publication planning industry is substantial. Some of those 50 agencies visibly advertising planning services boast of having hundreds of employees and handling many hundreds of manuscripts per year. The industry is large enough that there are two competing international associations of publication planners that organise meetings and seminars; there are other associations of medical writers. There are also for-profit organisations that organise similar meetings and seminars.

I attended one of the society meetings, the 2007 annual meeting of the International Society of Medical Planning Professionals (ISMPP) and learned much. The 2007 annual meeting of the main competing organisation, the International Publication Planning Association, looked similar, and the line-up of speakers overlapped slightly. About 400 people attended the ISMPP meeting, most of them publication planners who, from my conversations with them, were handling dozens of manuscripts per year. One planner told me that she was in charge of a campaign involving more than 100 manuscripts and conference presentations! Thus, the 40% figure is plausible.

Generating bulk research

A common complaint in scientific publishing is the division of research into "least publishable units" and the publication of overlapping or redundant analyses. These practices fill journals with articles that have the advantage and disadvantage of making only one point each. Academic authors are well versed in the art of multiplying papers and, also, with complaining about it. However, in the pharmaceutical industry each publication is part of a marketing campaign and has an expected return. The professionalisation and commercialisation of publishing makes a science out of the multiplication of papers.

At the ISMPP meeting, the director of medical publishing for one of the world's largest academic publishing companies chided his audience: "You don't help when you take your research and you do your primary publication and then you follow it with 20, 30, 40 secondary analyses. This is alarming publication and it is actually contributing to the whole peer review process grinding to a halt." He was probably exaggerating for effect. However, the salami slicing to which he pointed was promptly corroborated by another speaker, a pharmaceutical company employee who explained how to better multiply articles:

"There are more publication ideas coming from my medical team than we can handle even if we had 15 agencies and 20 people focused solely on publication for this one area. That's one of the bigger challenges, 'cause it adds more analyses. And now I need more statisticians, I need more investigators, I need more authors. I need more writers, whether they're agency writers or external physicians doing the writing."

Her eventual point was that it is important to winnow ideas early, to optimise production. She didn't object to multiple publications but wanted to make sure that they are all merited. There comes a point when another article is not cost-effective.

Medical journals participate

It is unsurprising that a publisher was on the list of speakers at ISMPP, as several publishing companies own publication planning agencies. The agencies advertise that the connections create synergies by increasing access to journals and networks of key opinion leaders (KOLs). For example, Carus Clinical Communications offers "world class innovation and experience supported by the unmatched depth and breadth of Elsevier's worldwide medical publication resources."(5) Such connections may also benefit the journals, by providing high quality papers, by providing papers that will be sold as reprints, and by generating advertising.

Also addressing the conference were four editors of highly respected medical journals, one of whom was representing an association of journal editors. The publisher and one of the editors took the opportunity when at the podium to promote their journals, soliciting manuscripts from the audience; the others merely mentioned their journals frequently. None of the editors were critical of publication planning, and one thanked planners for producing better manuscripts than academics do on their own: "We appreciate it as editors because we have to read a lot of papers and we can tell which ones have had expert writers participate in their development."

All the editors framed misconduct as either an abstract problem or a problem for authors, not the pharmaceutical industry and its agents: "An academic researcher needs to insist on early active involvement in the research project. They should decline any offers to sign off on already-written manuscripts, particularly in review articles. They should insist that the article reflects their own interpretation of the evidence. They have to be adamant about full disclosure...."

These editors are well aware that many manuscripts are funnelled to them via publication planners. A document obtained by the clinical psychiatrist and scholar David Healy in a court case made it clear that planners, not authors, are the journals' primary contacts on many manuscripts.(6) In addition, journal editors recognise that the publications have a market value. One said: "The way to get an article published easily, which is what our goal is and yours, is to avoid practices that are going to...slow the period of time before you can start enjoying the acclaim and the revenue that comes with successful publication in a big journal." Publication earns money for the industry.

It also earns money for the journals, through advertising and reprint fees. Although some editors have taken strong stances against the pharmaceutical industry's research and publication practices, they are too dependent on the industry for material and revenue to refuse industry manuscripts.

Those industry manuscripts are very successful, probably reflecting the resources behind them. Medical journals have high rejection rates, as high as 94% in the case of such journals as the Journal of the American Medical Association and the British Medical Journal. Meanwhile, publication planners claim to have very high acceptance rates; for example, an "acceptance rate on first submission of 94% for abstracts and 78% for manuscripts."(7)

Authors and plagiarism

Key opinion leaders (KOLs), as one speaker defines them, are well-known specialists who "can influence other physicians". In practice, the term is applied to a specialist with existing relations to the industry, not simply to a prominent expert. Publication planners make KOLs their authors on articles and their speakers at conferences and other events. Actually, in the process they make KOLs themselves, by making some specialists more prominent as experts.

Undoubtedly, authors of industry manuscripts perform amounts of work that vary considerably. However, it is clear that they typically play very limited roles. One ISMPP speaker objected to the practice of only showing authors the penultimate draft, which he claimed was the most common practice. (His complaint concerned efficiency rather than ethics: When authors make substantial changes to completed manuscripts, work has to be done a second time.)

This fits well the individual cases that have come to light, either because of litigation or because approached authors have stepped forward. To take only one example from among many, Dr Adriane Fugh-Berman describes being asked by a medical communications firm to author a paper on the negative interactions of dietary supplements and warfarin (a blood thinner). The sponsor had developed a competitor to warfarin and wanted to set the stage for its eventual arrival on the market. After Fugh-Berman declined the offer, the same article was submitted to a journal under the name of another author.(8)

At the ISMPP meeting, there was a serious debate about whether authors should be allowed to see data. The debate was occasioned by the discussion of a scandal involving Dr Aubrey Blumsohn, a researcher who became a whistle-blower when he suspected that the conference presentations and articles he was authoring were distorting data, data that he had helped to generate but to which he was not given access.(9) A pharmaceutical company scientific director, speaking carefully, reminded the audience of how complicated the analysis of data is, and how individuals might misinterpret it.

"I'm aware of cases where amateurs have tried to analyse databases and failed to match up IDs, or for example, when they are merging variables from different places and you end up with complete garbage. You wouldn't be able to identify that if you weren't already familiar with the database. It puts the sponsor in a position where they have to go back and verify any analysis that is done outside, which is time-consuming and can result in disputes that are very, very hard to resolve."

Thus, pharmaceutical companies commit themselves only to showing authors a "summary" of the results.

Among themselves, planners portray authors as lazy, greedy and prone to miss deadlines. Planners would like authors to make some contributions to manuscripts, for the sake of legitimacy. However, authors need to be coaxed and coached. One speaker recommended very specific questions as a way of eliciting a contribution, a sound pedagogical technique: "You can actually guide them to where you want feedback. So don't just say: 'Here's a first draft, and can I have your comment.' Say: 'Here's a first draft, and I've tried to figure out the methodology, to fit within the word requirement. However, I feel, could you pay some attention to this, and have I picked up the right point?'"

In these circumstances authors are unlikely to make major contributions to the analysis or writing of an article. They are shown well-crafted manuscripts that have been reviewed by many scientists, writers, and marketers. They are not given access to the data. They are asked their views on very specific points. They are given short deadlines. Thus, authors of industry manuscripts are largely sidelined from the process of analysing, writing and publishing research.

Conclusions

Among the standard ethical problems associated with academic publishing, the most generally discussed are plagiarism and the mis-allocation of credit. For as long as there has been academic publishing, some authors have found it convenient to copy work of others, and some authors have taken credit for work done by their students and juniors.

For the most part, concern about plagiarism is about fairness, as some people's work is exploited while other people gain unearned credit. The pharmaceutical industry, always an innovator, has developed a different form of plagiarism, involving only willing participants. Moreover, it has created new reasons for concern: the hiding of interests that drive research and publication and the possible harm to patients that this may create. When sales reps bring reprints of articles to the offices of physicians, prescribing nurses, hospital staff in charge of formularies and other drug gatekeepers, those articles may look like independent confirmation of the reps' pitches. Plagiarising KOLs lend their good names to the pitches.

Another much-discussed issue in the ethics of publishing is over-publication. We are buried in masses of literature, making it difficult to find what is valuable. Publication hides as much as it reveals. Every year, library budgets increase at well above the overall rate of inflation. This is caused in part by publishers increasing the prices of journals, and in part by the increasing number of journals. The ghost management of pharmaceutical research and publication plays a role within the medical sciences, as industry planners calculate how many new articles bearing key messages they need to affect perceptions and sway those who prescribe drugs.

What can be done? The solutions involve pulling apart research and marketing.

Physicians and others who prescribe drugs should not read scientific articles provided by sales reps, because they are apt to become confused about the roles of those reps. In fact, no one should read sponsored research, because no one can tell, in general, the difference between commercially-driven and merely sponsored research.

Would-be KOLs should refuse to be authors on manuscripts unless they have made genuine and substantial contributions to the analysis and writing and, of course, have worked with the data. Medical journals already have clear guidelines for authorship, which are routinely ignored by authors.

So far, I am simply moralising, because there is little hope of convincing huge numbers of physicians to change their habits and their desires, just as there is little hope of the pharmaceutical industry changing its practices unless it is compelled to. Elsewhere in the system there is some potential.

Medical schools should punish plagiarists severely, for the usual reasons plus the fact that plagiarists put patients' health at increased risk. They should also stop valuing pharmaceutical company sponsorship of research.

Medical journals should require authors to describe in detail their contributions to articles and should scrutinise those descriptions. They should stop dealing with publication planners or anybody other than authors. They should also stop pandering to the industry for important manuscripts. More controversially, they should stop publishing sponsored research altogether: the 10 or so most important medical journals have such a lock on prestige that together they could step away from the pharmaceutical industry and show off their clean hands.

Finally, governments should sequester drug research and marketing.(10) We cannot assume that drug companies will end the use of research for marketing on their own. Governments could take clinical trials out of the hands of drug companies, funding necessary ones through taxes on those companies. Or they could redefine the allowable scope of drug companies, dividing them into research entities and marketing entities. Such solutions would take enormous political will, but might solve many problems.

Until such measures are taken, we might ask, with a widely circulating joke, is medical science for sale? No, its current owners are perfectly happy with it.

* Sergio Sismondo is a professor of philosophy at Queen's University.

* "Medical Publishing and the Drug Industry: Is medical science for sale?" is re-published with permission from Academic Matters.

* The original article in Academic Matters can be found here.


References

1 Sismondo S (2007) "Ghost management: How much of the medical literature is shaped behind the scenes by the pharmaceutical industry?"
PLoS Med 4(9): e286.
2 Gøtzsche PC, Hróbjartsson A, Johansen HK, Haahr MT, Altman DG, et al. (2007) "Ghost authorship in industry-initiated randomized trials." PLoS Med 4: e19. doi:10.1371.
3 Bohdanowicz H (2005) "A guide to strategic communication planning." Pharmaceutical Executive Europe. Available at: www.pharmexeceurope.com. Accessed 22 August 2007.
4 Healy D, Cattell D (2003) "Interface between authorship, industry and science in the domain of therapeutics." Br J Psychiatry 183: 22-27; Ross JS, Hill KP, Egilman DS et al. "Documents From Rofecoxib Litigation Related to Rofecoxib: A Case Study of Industry Guest Authorship and Ghostwriting in Publications." JAMA 299(15): 1800-12
5 Carus Clinical Communications (2007) www.carusclinical.com (accessed 29 November 2007).
6 See Healy D, Cattell D (2003) Op. cit.
7 Gardiner-Caldwell Group (2007) www.thgc-group.com (accessed
29 November 2007).
8 Fugh-Berman A. (2005) "The Corporate Coauthor." Journal of General Internal Medicine 20:546-548.
9 Blumsohn A. (2006) "Authorship, ghost-science, access to data and control of the pharmaceutical scientific literature: Who stands behind the word?" AAAS Professional Ethics Report 29(3):1-4.
10 E.g. Schafer A (2004) "Biomedical conflicts of interest: A defence of the sequestration thesis--Learning from the cases of Nancy Olivieri and David Healy." J Med Ethics 30: 8-24

Comment:
My primary source of income is presenting CME on the topic of warfarin. The seminars are entirely financed by the registration fees. I have no ties to the pharmaceutical industry. Thus I must review the literature continually on my own. The paucity of negative articles has led me to speculate the the term "evidence-based medicine" is a concept developed by commercial journal publishers.

Al Lodwick