Study 329: 50 Shades of Gray

David Healy, MD
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(Author’s Note:  None of these posts about Study 329 should be taken as representative of a RIAT (Restoring Invisible and Abandoned Trials) view, especially this one. Also: See Study 329: Conflicting Interests for a prequel to this post and to make sense of the last comment.)

Fiona Godlee to RIAT July 6 2015
Re: Study 329

Dear Dr Jureidini,

“Many thanks for your letter. I quite understand you concerns. You are right to say that there are few or no precedents against which to compare this article. We ourselves are feeling our way, both with the RIAT process since this is the first full RIAT research paper we will publish, and with the specific challenges posed by this particular study and you as the paper’s authors. I want to stress that we are proceeding in good faith with the clear aim of publishing the article as soon as possible provided we can do so safely”. …

All best wishes

Fiona Godlee FRCP
Editor-in-Chief The BMJ

In Utero

The editor dealing with Study 329 through its year-long gestation in the belly of the BMJ was Elizabeth Loder. The paper improved considerably during this time, but there was almost nothing constructive from BMJ that led to any of these improvements. Readers can examine for themselves the various letters, reviews and revisions, bearing in mind that from our side the correspondence is written under constraint. Indeed, almost all inputs from BMJ produced outcomes that likely made the editorial staff ever more uncomfortable.

As the features of Study 329 took shape in the BMJ womb, the New England Journal of Medicine (NEJM) had a series of articles suggesting that concerns about Conflict of Interest had gone too far.  The NEJM said that some journals were in a state of moral panic; that they were hunting for witches. They should have run their articles at Halloween.

The BMJ, in an editorial by Elizabeth Loder and Fiona Godlee, led the way in responding with outrage to the NEJM, suggesting that this was not the time to step back from seeking transparency on conflicting interests.  Ideally we would go further and find ways to bring non-financial conflicts of interest into the frame.  The medical literature is clearly still a mess, and this can only be because we have not been zealous enough about conflicting interests.

The alternate view — not popular with some “progressives” who don’t do science — is that access to data is more important than access to information about conflicts of interest.  It is only when there is access to the data that we can see if interests are conflicting and take that into account.  Science needs conflicting interests – financial and non-financial. Problems don’t get solved unless someone is motivated for some reason. We need the bias that pharmaceutical companies bring to bear in their defense of a product, along with the bias of those who might have been injured by a treatment.  Both of these biases can distort the picture but it’s when people with differing points of view agree on what is right in front of their noses that we can begin to have some confidence about what we have.

Outsiders Have Conflicts; Insiders Don’t

Sixteen years ago I sent a paper to BMJ based on Lilly documents that had come into the public domain because of a Court Case.  BMJ’s initial response was that they should perhaps publish, given that they had published a Lilly article; the Beasley et al 1991 article, that had done a good deal to create the antidepressant and suicide problem. But Richard Smith resiled from this position. In later correspondence, he stated BMJ would never publish anything from me on this topic.

The real issue was that BMJ were lily-livered and were prepared to cite my supposed conflicts as their escape route, even though the data was fully in the public domain and publishing would have laid bare whether my judgments were unduly conflicted.  Another journal took the paper promptly.

At the time of the July 6 email above, BMJ stated they were thinking about sending parts of our material out to a third party to review. In fact they had already sent the material out for review when they told us they were thinking about doing so.  We objected and made it clear that this was unacceptable and when the reviews came back, we paid little heed to them.

On July 8,  we emailed BMJ raising issues covered below.

A Headache

Some of the drama in Restoring Study 329 centered on headaches. GSK coded headaches and dizziness one way in the original Study Report and a different way in the Keller et al paper.  Headaches and dizziness were so common that moving them from Body as a Whole to Nervous System laundered out the evidence not just from suicide events (coded as emotional lability) but from pretty well all psychiatric events.

We were less interested in the question of where exactly headaches and dizziness should be placed, and much more interested to make sure readers of the article were aware that it was possible to move them around and in so doing to “re-author” (re-interpret) the findings.  Our concern wasn’t to show that deception had happened, but rather to show how people might be misled – perhaps inadvertently.

Elizabeth Loder was upset.  She might have regarded our approach as cavalier or she might have missed the point because of a conflicting interest.

EL is a professor of neurology and a migraine expert based in Boston. She has several books on headaches – something we hadn’t thought to check before July 6.

She has been the President of and serves on the Board of the American Headache Society, which runs an influential journal. She serves on the Executive Council of the International Headache Society, and the Board of the Headache Cooperative of New England. She has helped write all manner of guidelines for treatment of migraines, and has chaired the “Choosing Wisely” committee of neurologists.

Knowing this might have affected how we worded things.

Dr Loder has been with BMJ since 2006 and declares that she has no links to pharmaceutical companies since then. She declares she has previously been a speaker, received grant support, or been a consultant for: OrthoMcNeil, Endo, AstraZeneca, GlaxoSmithKline, Pfizer, and Allergan – a list of companies that overlaps with one that formed part of my conflict of interest statement as of that point in time.

Before moving to BMJ, in a 2003 paper she co-wrote about how we don’t need to be so afraid of using triptans, it says both authors have gotten research grants and done speaking on behalf of various migraine medicine manufacturers including GSK.

Imitrex – sumatriptan – is GlaxoSmithKline’s triptan. With Imitrex off patent, GSK turned to Treximet, a combination of sumatriptan and an NSAID that was approved for migraine in children over 12 in May this year.

Sumatriptan comes with a suicide problem.  Robert Gibbons has been enlisted to pooh-pooh this.

In a recent Washington Post article Dr Loder answers readers’ questions about migraine. She says:

“You haven’t failed sumatriptan till you’ve failed to respond to a full dose of injectable sumatriptan given early in the migraine. That’s my mantra!”

She squeezes in that “there’s evidence it’s more effective when taken with an NSAID” – just before Treximet came out.

While Dr Loder’s name is not listed in OpenPayments or Dollars for Docs, a regular partner on much of her work is Stephen Silberstein.  They are on all the same Influential Committees.  Dr. Silberstein comes close to being the KOL’s KOL in the headache field.  Here is a recent Disclosure Statement.

Meanwhile, her hospital, Brigham & Women’s, got $15-20 million from GSK in 2014.

50 Shades of Gray

Meanwhile in addition to helping articulate BMJ’s position on conflicts of interest, Dr Loder was involved in a Lown Institute Twitter Chat in July on conflicts of interest, where she makes clear we need to find out more about non-financial COI’s.

Her BMJ COI statement refers to her husband’s position in a law firm but she states that he does not have a healthcare involvement.

His law firm is the Boston-based Ropes and Gray.

John M Loder is not in the Healthcare division of Ropes and Gray.  He is in Hedge Funds, Investment Advisors, SEC compliance.  Attorneys from Mergers & Acquisitions, Government Enforcement, and White-Collar Defense divisions likely work with GSK every day of the week.

Central to the work Ropes and Gray does is a First Amendment commitment that horrifies those who are usually most vocal about conflict of interest.  This company is one of the main supporters of off-label marketing, on the basis that to prohibit it would be an interference with free speech.  They have achieved some success in these areas. Their position makes a certain amount of sense to me.

The irony was that BMJ were using a close-to-monopoly position to abuse our First Amendment rights in respect to Restoring Study 329. If we had the money, the perfect people to have hired to fight our case against BMJ would have been Ropes and Gray.

But more to the point, Ropes and Gray are currently GSK’s lead attorneys on company fraud matters in China. Their ties to GSK are close enough that journalists describe them as “GSK’s law firm in Hong Kong.”

And for several years they were also central to defending GSK in the Department of Justice and related investigations that led to a $3 billion fine against GSK in 2012.  A key element to the charge against GSK lay in their handling of Study 329.

Colleen Conry and Brien O’Connor, co-leaders of the Ropes & Gray government enforcement practice, were successful in winning an acquittal for former GlaxoSmithKline associate general counsel Lauren Stevens in the U.S. District Court for the District of Maryland back in 2011.

As they say on their website:

Companies and individuals worldwide turn to Ropes & Gray’s leading government enforcement practice to guide them through all manner of investigations, enforcement actions, and compliance issues. Our attorneys understand business and regulation and help our clients pre-empt, resolve or mitigate the impact of government investigations and enforcement actions.

A Radical Suggestion

Around the time of Fiona Godlee’s July 6 email, BMJ suggested that the entire data from the study be re-analyzed by a third party who had no prior contact with the issues. This would likely have taken a further year at the very least.

This was plain bizarre.

Intriguingly, Elizabeth Loder and I had both attended a Selling Sickness conference in Washington in February 2013, and in her account of the meeting in BMJ a few weeks later she floated a very similar proposal:

How Medical Journals can Help Stop Disease Mongering

“It would be hard to collect a more fascinating bunch of topics or people in a hotel conference room. The 2013 Selling Sickness conference recently held in Washington, DC was among the most thought provoking and just plain interesting conferences I’ve been to in a long while, and I go to a lot of conferences. This third conference in a string of international conferences was characterised by its organizers as part of “a global reform movement” against the “marketization of health, the corporatization of healthcare, and the hijacking of patient and consumer language to disguise market interests.” Opening speaker Shannon Brownlee identified “the different heads of the hydra” as “disease-mongering, conflict of interest, and overdiagnosis.” In her view, the challenge of this meeting was to identify these aspects of selling sickness and “weave them together in a systemic movement that promotes systemic changes.

“I participated in a roundtable discussion charged with examining the news and communication perspective on disease-mongering, and was joined on the journal side by Jocalyn Clark of PLoS MedicineModerator Gary Schwitzer of HealthNews Review and panelist Nancy Shute considered the problem from the vantage of medical journalists. When it came time to examine how medical journals might address their role in selling sickness and disease mongering, I suggested two possible strategies.

“First, why not quarantine apparently ground breaking studies about new treatments or interventions in a special journal until the findings are replicated and long term consequences explored? Print copies of the journal would arrive in plain brown wrappers which undone would show the journal’s cover logo of a skull and crossbones. During quarantine, any news stories or summaries of research from this journal would travel with a sternly worded disclaimer, along the lines of those that accompany investment company advertisements. Something like the following would do nicely:

Warning! Taking any action on the basis of this research could result in injury or death. The results described in this study have not been replicated and the long term effects of this treatment are unknown. Past performance is no guarantee of future results. When subjected to further investigation, most published research findings turn out to be false.

“To fill the void, medical journals deprived of these sensational research studies could instead devote themselves to the promotion and prioritization of the less glamorous medical research that really matters: replication studies, comparative effectiveness trials, and long term pharmacosurveillance and safety studies.

“My second suggestion was that several parts of a typical research paper are too important to be written by the researchers or anyone else with a vested interest in the outcome of the research. These include the portions where “spin” is mostly likely to enter into the paper, namely the title, abstract, results, and conclusion sections, and any summary or “what this study adds” statements that authors are now sometimes asked to supply. These portions of research papers should instead be written by disinterested parties with subject matter expertise.

“I have no illusion that these things will come to pass but I can dream, can’t I?

“During the question and answer session fellow panelist Nancy Shute turned to me and said “I’m impressed by your radicalism.” I’ll take that as a compliment!”

****

One can wonder if Dr Loder ever suggested anything like this for any of Dr Silberstein’s articles, or GSK linked articles involving treatments for migraine.

While a suggestion like this didn’t appear formally in the correspondence between RIAT and BMJ, it was raised in behind the scenes negotiations.

Access to the Data

On July 8, RIAT sent an email to Fiona Godlee outlining some of the points made above.  There was no response.

Have conflicting interests had an effect in this case?  There are data that can be consulted.

When finally published, Restoring Study 329 came with a number of tabs, one of which is labeled Reviews.  As of this year it is BMJ’s policy to publish the reviews of articles along with the article.

One of the first Rapid Responses to the article was from Elizabeth Wager, a medical writer who has previously had close links with BMJ and who had reviewed previous articles about Study 329 submitted to BMJ that did not get published.  She asked where the Reviews were.  There was no response from BMJ.  I submitted a response to her letter indicating that the reviews were available in their entirety on Study329.org.  BMJ did not publish my response.

RIAT re-sent the July 8 letter to Fiona Godlee on September 30.  We have had no response.

My impression is that most people reading the entire correspondence on Study329.org between RIAT and BMJ (mostly Elizabeth Loder) will agree that it shows an extraordinary level of difficulty. At several points the RIAT team came close to reaching the end of the line. The correspondence makes clear that some of us seriously entertained the view that BMJ did not want to publish.  By July 6 we were exploring publication options with other journals.

In my opinion very few people will think BMJ were not biased by something. You don’t have to trust me – you can access the data and make your own mind up. Against this background, Elizabeth Loder’s competing interests will raise eyebrows for some.

Not Tonight: I Have a Headache

Did John Loder’s involvement with Ropes and Gray cause our problems?  In my opinion, no.

Did Elizabeth Loder’s prior links to GSK cause our problems?  In my opinion, no.

Did Elizabeth Loder’s headache expertise cause our problems?  In my opinion, no.  She was finicky but could have been a lot more finicky than she was.

The strongest evidence I have as to why there was such an unconscionable delay is that BMJ have been and still are scared close to shitless about publishing anything that might make a pharmaceutical company uncomfortable.

They have no problem publishing a Beasley et al paper whose data show an increased risk of suicidal behavior on Prozac, but claims there is no risk and that the data exonerates Prozac.  They have no problem publishing Lu et al, 2014 that claims to show warnings on antidepressants cause suicide – a shoddy piece of work if ever there was one.

Ironically, providing access to the data seems to have increased BMJ’s difficulties. A key message from Restoring Study 329 is that when data is made available all authorship (interpretation) becomes provisional.  Despite apparent support for access to data, The BMJ want science to be authoritative – Biblical – rather than provisional.  If an article offers the indisputable Word of God, they can’t get sued.  If there is scope to read the matter in another way, as David Linden’s Response to Restoring Stud 329 indicates there is and always will be, the BMJ and their lawyers have a problem.

In my experience journals run by ex-pharmaceutical company employees have been much more courageous than BMJ on matters like this.  However, while they appear to have lied at least twice in the process, BMJ are a long way from being the worst in terms of courage and integrity – they do, though, take some beating in terms of prissiness.

What was galling about the exercise was that BMJ (and everyone else who colludes to put BMJ and other journals in this position) see fit to turn their lack of guts around and blame our conflicting interests.

This is to be expected from people who have themselves been abused or are living in an abusive situation.

It’s Medication Time.

* * * * *

This blog is adapted from a post
 on David Healy’s website.

3 COMMENTS

  1. Thank you for clarifying and sharing more in depth what transpired in the name of ” conflicts of interest” , indeed we all have them, it’s the lack of transparency that so often is missing in these human “negotiations”, or in your exchange here with BMJ, the lack of response which only catered to more subliminal conflicts….sure would be nice if one day we might expect the dialogue, the sharing of our opins and conflicts so we might have a full conversation, which doesn’t mean we will all agree but at least multiple truths might be heard for all .

    • Yana,

      I think there is something greater than *transparency* that is lacking — . Integrity is a better term, I think., to describe what is glaringly absent in each of the “human negotiations” described by Dr. Healy.

      I am not sure “conflicts of interest” is the right term either. Whatever causes there may be for the manipulation of scientific literature, there is surely no interest shown in the purpose for scientific literature by those who edit and contribute in some way to the publishing of professional journals. Doctors misinformed or ill-informed– patients suffer over what is only being called COI–? This is trivializing a scourge of epic proportions–.

      Speaking of trivializing, it seems that is your tone in response to this and the previous post by David Healy. I think that a more substantial response from you is warranted– or rather, if you have evidence to refute these instances of obstruction to publishing crucial information for the medical professionals who depend on their journals for scientific literature, I suggest you supply it. Otherwise you come off as a flippant critic, trying to cast doubt on the credibility of the messenger and bypassing the message all together.

  2. “Shannon Brownlee identified “the different heads of the hydra” as “disease-mongering, conflict of interest, and overdiagnosis.” In her view, the challenge of this meeting was to identify these aspects of selling sickness …”

    Hallelujah! The monstrosity is coming into view.

    “BMJ suggested that the entire data from the study be re-analyzed by a third party who had no prior contact with the issues.”

    Just let it all loose into the public domain. What greater third party could there be? It could be a international televised event, like a Scrabble championship. I joke.

    “The BMJ want science to be authoritative – Biblical – rather than provisional. If an article offers the indisputable Word of God, they can’t get sued.”

    God would want you to focus on the heart of the matter, which is that people have been harmed by the neurotoxic drug.

    We’re not talking about innocent mistakes or accidents. This is the case of profiteering by injuring, harming, sickening and even killing people, in the name of health. It’s murderous, desecration. A synonym of desecration is blasphemy. I’ve just attributed blasphemy to the head of your hydra, which is now written on it and cannot be undone.

    antagonist is today’s Word of The Day.