The Avandia Spin Cycle Continues Even After the FDA Safety Hearings

We have posted multiple times about Avandia (rosiglitazone), GlaxoSmithKline's star-crossed glucose-lowering drug.  While Avandia has received considerable media coverage, we focused on two questions: 1 - what are the benefits and harms of rosiglitazone as a treatment of type 2 diabetes, and therefore for which patients under what circumstances should this drug be used? 2 - what barriers have prevented physicians and patients from getting the best possible answer to the first question, and what can be done about them?  (See recent post here.) 

In particular, the Avandia case has illustrated how those with vested interests in the success of a health care product have done their best to obscure information that might threaten its success, even when doing so obscures the information that physicians and patients need to make the best possible decisions.  At one point, (in 2007, no less) we called this the "Avandia spin cycle."

Avandia once again has been in the news after the US Food and Drug Administration's hearings on the safety of the drug.  These hearings were so well covered in the media that a lengthy summary would be superfluous.  However, their main points demonstrated the persistence of the Avandia spin cycle:
- An FDA reviewer felt that "the company's misreadings of the ... Record trial ... were so profound, he concluded, that they 'suggest serious flaws with trial conduct.'" (per Gardiner Harris writing in the New York Times)
-A former FDA reviewer "withheld from regulators a study showing its Avandia diabetes drug may cause heart attacks." (per Bloomberg News)
- GlaxoSmithKline's forerunner SmithKline Beecham "secretly began a study to find out if its diabetes medicine, Avandia, was safer for the heart than a competing pill, Actos, made by Takeda."  However, "the study also provided clear signs that it [Avandia] was riskier to the heart.  But instead of publishing the results, the company spent the next 11 years trying to cover them up." (per Gardiner Harris writing in the New York Times.
- "Government experts and a panel of medical advisers repeatedly voiced skepticism on Tuesday about the trustworthiness of GlaxoSmithKline, which makes the controversial diabetes drug Avandia." (per Gardiner Harris again writing in the New York Times.)

So the Avandia saga has brought to the front pages the concerns we have had with suppression and manipulation of clinical research, especially when pursued by health care organizations with vested interests in the results of specific research projects coming out a certain way, and how they have been enabled by those with conflicts of interest.  Doctors thus should be worried whether those of us who try to practice evidence-based medicine have been fooled into practicing pseudo-evidence-based-medicine.

Those commenting on the story focused on the need for transparency when clinical research is funded and run by the corporations whose products are being evaluated.
-  "GlaxoSmithKline, the maker of Avandia, can't be trusted to report adverse clinical results fairly.  The company must be watched like a hawk as additional trials that it sponsors go forward."  (NY Times editorial)
-  "What America should demand in return for ... [generous patent] protection is that the FDA be able to make an honest evaluation of the efficacy of drugs.  When drug companies make this impossible by suppressing test results, not only do they violate their fundamental obligation of honesty with the public, their customers and their regulator, but they also break the bargain they have struck in return for the protection of their intellectual capital."  (Former NY Attorney General Eliot Spitzer in Slate.)

Instead, as I have written before, maybe we ought to consider whether those with vested interests in drugs or devices ought to be running clinical research meant to evaluate their own products.

 Ironically, while this discussion of how the Avandia spin cycle first began to revolve were going on, others were still trying to add revolutions (per minute).  In particular, a Reuters story noted:

Three influential groups of doctors who treat diabetes urged patients not to stop taking Avandia, saying on Thursday that while news about the controversial drug may be frightening, it would be worse to suddenly stop taking it.

That is odd, given that Avandia has never been shown to improve clinical outcomes for patients with diabetes, and that there are many other drugs that control blood sugar which appear to be safer. But wait, there is more,

The Endocrine Society, American Diabetes Association and the American Association of Clinical Endocrinologists worried that patients may be afraid to take Avandia.

'Patients should continue taking all currently prescribed medications unless instructed otherwise by their health care provider,' Dr. Robert Vigersky of the Endocrine Society said in a statement.

'Stopping diabetes medications can cause significant harm and result in higher levels of blood glucose that may cause severe short term health problems and could increase the risk of diabetes-related complications in the long term.'

Would not it make more sense to advise patients still on Avandia to consult with their doctors urgently about possible alternatives?  Meanwhile, it does not seem irrational to be afraid of taking Avandia, given the increasing evidence about its harms, and increasing evidence that what we know about its harms may be an under-estimate.

So I wondered why these august medical societies seemed so unaffected about the doubts about Avandia's safety, and about the evidence offered to support its use that the latest news ought to generate. It turns out that all three of the medical societies get financial support from, -- wait for it --, GlaxoSmithKline.

The Endocrine Society lists GSK as one of its Corporate Liaison Board Members. The American Diabetes Association lists GSK as one of its Banting Circle Supporters, that is, those that give at least $1,000,000 a year. The American Association of Clinical Endocrinologists lists GSK as a member of its Corporate AACE Partnership. (I was not able to find out the total amount contributed by GSK to either the Endocrine Society or the AACE.)

So once again, the loudest voices in support of the product come from those used to, and perhaps dependent on financial support from its manufacturer. As a physician, I have been particularly disappointed that our medical societies, whose missions are ostensibly to support our professional values, seem to act more and more like marketers for the companies whose contributions, rather than members' dues increasingly support them.

The cycle keeps spinning.

For further thoughts on the latest in the Avandia case, see this post by Howard Brody on the Hooked: Ethics, Medicine and Pharma blog, and this by Alison Bass on the Alison Bass Blog.

Study: Researchers with Glaxo ties favored Avandia

As mentioned in my previous post on the MIT controversy surrounding an economist's testifying to Congress on healthcare policy without revealing possible economic conflicts of interest that could affect his views, frequently expressed on this blog are concerns about undisclosed conflicts of interest and their corrosive effects upon healthcare (query link).

One major question that arises is the degree to which conflicts of interest can affect the integrity of the scientific literature. Answering this question is more a matter of social science research rather than biomedical inquiry.

One internal medicine resident at the Mayo Clinic took on this challenge and published such a study, a systematic review, in the British Medical Journal. It is entitled "Association between industry affiliation and position on cardiovascular risk with rosiglitazone: cross sectional systematic review" (BMJ 2010;340:c1344).

Mayo Clinical researchers led by the resident, Amy Wang, examined more than 200 articles that appeared after an analysis in the NEJM linked Avandia to a 43 percent increased risk of heart attacks, and a subsequent clinical trial found no greater danger of heart disease. The results are fascinating. From a summary in the Philadelphia Inquirer:

"We aimed to determine whether financial conflicts of interest with pharmaceutical manufacturers could be fueling this fire," wrote the researchers, led by Amy Wang, a resident in internal medicine at the Mayo Clinic in Rochester, Minn. "From our findings, it appears that the answer is yes.

From the BMJ article itself, free full text available as of this writing at link above:

For each article, we sought information about the authors’ financial conflicts of interest in the report itself and elsewhere (that is, in all publications within two years of the original publication and online). Two reviewers blinded to the authors’ financial relationships independently classified each article as presenting a favourable (that is, rosiglitazone does not increase the risk of myocardial infarction), neutral, or unfavourable view on the risk of myocardial infarction with rosiglitazone and on recommendations on the use of the drug.

The "and elsewhere" can be a valuable addition to the capabilities of today's researchers, often enabled via the internet (e.g., non-literature based resources such as conference brochures, personal web pages, corporate and other financial disclosures. etc.) when articles themselves prove unrevealing.

Overall, this is a straightforward methodology, and while potentially subject to bias and expertise issues, nonetheless seems an excellent new contribution to the needed social research on undisclosed COI's.

As to results (see the full article for statistical details I am omitting here):

Of the 202 included articles, 108 (53%) had a conflict of interest statement. Ninety authors (45%) had financial conflicts of interest. Authors who had a favourable view of the risk of myocardial infarction with rosiglitazone were more likely to have financial conflicts of interest with manufacturers of antihyperglycaemic agents in general, and with rosiglitazone manufacturers in particular, than authors who had an unfavourable view. There was likewise a strong association between favourable recommendations on the use of rosiglitazone and financial conflicts of interest. These links persisted when articles rather than authors were used as the unit of analysis, when the analysis was restricted to opinion articles or to articles in which the rosiglitazone controversy was the main focus, and both in articles published before and after the Food and Drug Administration issued a safety warning for rosiglitazone.

While causality is not proven, these results are still stunning. Per the Inquirer's summary:

... Almost 90 percent of scientists who wrote positive articles, reviews, or commentaries about Avandia had financial ties to London-based Glaxo, the study published in the British Medical Journal found.

Almost three of every four authors who expressed negative views of the drug had no financial ties to manufacturers of diabetes medicines, while just 6 percent of those with positive opinions of the drug received no funding or fees from industry.

The authors cite prior literature also demonstrating an associations of COI with pro-industry views (references 2-6; #2 is regarding the mid 1990's calcium channel blocker controversy).

The authors observe that:

In the past decade, research and policy has focused on this association [between COI and pro-industry views - ed.], leading to important progress in policies to manage and encourage disclosure of such financial conflicts of interest.

Their findings about the effects of this "progress" was particularly disappointing, that only about half of the articles carried conflict-of-interest statements:

Of the 202 eligible studies (10 reported original research, 91 were letters, editorials, or commentaries, and 101 were reviews, meta-analyses, or guidelines), 108 articles (53%) included a conflict of interest statement. [The other 47% did not - ed.]

One wonders about the publishers of the articles themselves omitting COI statements, either acknowledging possible COI's or confirming that no COI's exist.

... A total of 90 (45%) of the 202 articles were authored by individuals who had financial conflicts of interest. Of the 90 studies with conflicts of interest, 69 (77%) had a statement disclosing the conflict of interest in the article itself. The other 21 studies with financial conflicts of interest (23%) did not disclose these relationships, which were discovered through searching other publications by the same author or the internet. Three (14%) of these 21 studies published a statement declaring no conflicts of interest. [Oops - ed.]

So, almost one quarter of articles with author COI did not disclose that fact, and several misrepresented the issue.

Finally, the pharmaceutical company's view, also published in the Inquirer article cited above:

A Glaxo spokeswoman said the company posted information and results from all its clinical trials on its Web site.

"It's vital that people have trust in the way we do research and the way it's made public," Jo Revill, Glaxo spokeswoman, said yesterday. "Part of that is sharing data. What we have done is develop policies that will have disclosure and encourage disclosure."

"Encouraging" disclosure of COI's is far too weak a stand for a pharmaceutical company to take on such a critical issue, in my view.

The Mayo researchers wisely conclude:

Disclosure rates for financial conflicts of interest were unexpectedly low, and there was a clear and strong link between the orientation of authors’ expressed views on the rosiglitazone controversy and their financial conflicts of interest with pharmaceutical companies. Although these findings do not necessarily indicate a causal link between the position taken on the cardiac risk of rosiglitazone in patients with diabetes and the authors’ financial conflicts of interest, they underscore the need for further changes in disclosure procedures in order for the scientific record to be trusted.

Finally, I add that these findings are not too surprising. It's human nature not to bite the hand that feeds you. Money is also a powerful stimulant to the brain's rationalization (as opposed to rational) centers.

We as a culture do truly need to understand the potential corrosive effects on the scientific literature of dysfunctions such as ghostwriting, financial and other conflicts of interest, publish-or-perish pressures of academia, and other such social issues.

These practices also simply need to be abolished, for as I have written before on these pages ("Has Ghostwriting Infected The Experts With Tainted Knowledge, Creating Vectors for Further Spread and Mutation of the Scientific Knowledge Base?"), once a "critical mass" of faux knowledge is put into circulation via the scientific literature, even the ostensibly impartial experts' views can become tainted, dependent as they are on that very same scientific literature. Even worse, we don't know what that critical mass is - or whether we've reached it already.

-- SS