Wednesday, June 22, 2016



There is a disconnection between the FDA’s drug approval process and the reports we see in medical journals. Pharmaceutical corporations exploit this gap through adulterated, self-serving analyses, and the FDA sits on its hands. I suggest we need a new mechanism to fix the problem – by independent analyses of clinical trials data.

When they analyze and publish their clinical trials in medical journals, pharmaceutical corporations have free rein to shape the analyses. The FDA conducts independent analyses of the data submitted by the corporations, and it may deny or delay approval. But the FDA does not challenge the reports that flood our medical journals, both before and after FDA approval. It is no secret that these publications are routinely biased for marketing effect, but the FDA averts its gaze. That failure of the FDA – a posture known as enforcement discretion – has been well documented. The question is why? At the same time, exposing the biases has been difficult for outsiders because the data are considered proprietary secrets.

A Case Study
Now, a detailed example of deliberate corporate bias has finally been documented, through materials released in litigation. This exposé was reported by Drs. Jon Jureidini, Jay Amsterdam, and Leemon McHenry. Their findings were recently published, and their article is freely available on-line. This example concerned a clinical trial of an antidepressant drug in children and adolescents. The drug, citalopram, was already approved for use in adults, and its off-label use in children would spread if there was published supportive evidence. An Investigational New Drug (IND) protocol and plan of analysis were filed by Forest Laboratories with the FDA in 1999. The trial was completed in 2002, and the results were published in American Journal of Psychiatry in 2004 – but the FDA did not accept the results as sufficient to approve this drug for use in children or adolescent patients. By that time the patent on citalopram had expired and Forest Laboratories introduced a virtual twin drug, escitalopram (single active enantiomer). That more expensive version of citalopram was heavily promoted, and it was approved in 2009 for use in children, but even then the FDA specifically noted that safety and efficacy were not established in children under age 12. Since then, new analyses suggest that most antidepressant drugs have little evidence of efficacy even in older children.

Tricks of the Trade
In service of a positive report, the statistical analyses performed by Forest Laboratories deviated from the IND plan of analysis, and negative results were edited out. The biases now documented by Dr. Jureidini and his colleagues for that 2004 sponsored report in American Journal of Psychiatry included:
·       Inflating the main measure of the drug's effect by reporting an incorrect and clearly exaggerated effect size. On being challenged, the authors later explained their misinformed computation without actually acknowledging the error.

·    Failure to report secondary measures of response because they were negative. Those measures had been stipulated in the IND protocol to serve as cross-checks on the main result. These negative findings were airbrushed out of the publication by corporate marketing.

·    Unplanned, new secondary measures of response were inserted ex post facto because they were positive (that is a real no-no).

·    Violations of the IND protocol were not reported and were then fudged (patients who had properly been excluded per protocol were put back in for analysis, which made a nonsignificant primary outcome analysis turn positive).

·    Adverse events were analyzed and summarized in a misleading way.

·    The finding that the drug had no effect on depression in children under age 12 was not reported, even though an age-effect interaction analysis had been specifically projected in the IND protocol. This strategic omission left the impression that off label use of citalopram in younger children could be clinically reasonable.

·    The corporation knew that another, unpublished, trial in children, conducted by their European partner Lundbeck was negative, and that it raised concerns about suicide risk, but that information was withheld. The authors later were challenged in the journal about this concealment. Their response was utterly disingenuous.

·    The published article failed to acknowledge that it was authored by a non-medical ghostwriter, who took direction from marketing executives – the 2004 publication was a marketing product purporting to be an objective scientific report.

·    Academic authors were recruited only after the manuscript was written, reviewed, and approved in-house – these nominal academic authors were signed on to front for the corporate narrative.

·    The perfunctory role of the academic (ahem) authors is clear from the fact that they failed to recognize the wildly inflated effect size claimed for the drug – something that was instantly obvious to several groups of competent readers.

The Payoff
These changes created the appearance of a positive result, and the publication drew wide attention. According to Thomson Reuters Web of Science, it has been cited over 160 times, placing it in the top 5% of cited articles in clinical medicine from 2004. This early publication gave plausible justification for off-label use of citalopram/escitalopram in children, even with FDA approval having been denied, and even though the trial was actually negative. The FDA has reported that between 2005 and 2010 well over 750,000 patients up to age 17 received escitalopram, including almost 160,000 under age 12. Thus, the sleight of hand about failure to show even fudged efficacy in younger children is especially deplorable. Internal memoranda reproduced in the exposé by Dr. Jureidini and his colleagues give a clear picture of the corporate manipulation of the scientific publication process. Now we know – in black and white – just how bad the bias can be. This kind of data manipulation, with ad hoc cherry picking and moving of goalposts, is unacceptable, but it is entrenched. Indeed, it is business as usual – and the FDA looks away.

A Specific Proposal
Our primary defense against such perversions of scientific reporting is fidelity to the registered IND protocol and plan of statistical analysis. The solution is not hard to see: We need independent analyses of clinical trials because we cannot trust the corporate analyses. In effect, we need something like the Underwriters Laboratory to verify the statistical analyses of clinical trials. Nobody takes the manufacturing corporation’s word for it concerning the safety and performance of X-ray machines or cardiac defibrillators. Why treat the statistical analysis of drug trials any differently? It’s highly technical work.
Who should assume that responsibility? Why not the FDA? After all, they alone see all the data. My specific proposal is for Congress to mandate that the FDA analyze all clinical trials data strictly according to the registered protocols and analysis plans. That requirement should apply to new drugs or to approved drugs being tested for new indications. It should apply also to publications reporting new trials of approved drugs. Corporations and investigators should be prohibited from publishing their own in-house statistical analyses unless verified by FDA oversight.

Why Bother?
There are three good reasons for prohibiting in-house corporate analyses of clinical trials data. First, as the present example illustrates, the inherent conflict of interest is simply too great to be ignored. Second, when corporate statisticians who answer to marketing executives get “creative” in the ways exposed here, then the conditions for valid statistical analyses no longer apply – the statisticians are then on a fishing expedition and they are no longer testing the defined study question with fidelity to the methods specified in the IND protocol. In that case, any nominally significant statistical findings are just exploratory, not actionable – not good enough to justify off-label use of the drug, especially when properly evaluated alternatives are available.
Third, there can be no justification for treating the production of influential publications in medical journals any differently than we treat the production of potent drugs. Our FDA continuously inspects production facilities for evidence of physical adulteration, even as far away as China. They now need to monitor the adulteration of clinical trials reports in medical journals. The harms of adulterated analyses can be just as serious as the harms of adulterated products.

Push Back from Pharma?
We can expect the pharmaceutical industry to mount a First Amendment challenge to this proposal. It will fail, because the public health is too important. Just as there is no First Amendment right to shout fire in a crowded theater, so also corporations have no First Amendment right to say a drug is safe and effective when they know it isn’t. That is a betrayal of patients.
The corporations will also claim piously that their publications undergo peer review. Sadly, that is no barrier to this pervasive corporate bias because the peer reviewers for medical journals don’t see all the real data – they see only the data the corporation wants them to see. Only the FDA sees all the data. We can no longer cling to the myth of informed and unbiased peer review of clinical trials reports. The corporations rely on that myth as a fig leaf to support their First Amendment claims and to defend their practice of in-house statistical analyses. Moreover, medical journals also are subject to bias and conflict of interest. We could note that the Associate Editor of American Journal of Psychiatry in 2004 was also a major U.S. key opinion leader for Forest Laboratories. According to one of the released depositions, he was instrumental in securing acceptance of the report by the journal.

Business as Usual?
The present example is not an isolated case. Dr. Jureidini and his co-authors described several similar, recent examples. One of those was the reanalysis by Jureidini and others of an infamous trial of paroxetine for pediatric depression. And still, fresh exposés keep appearing. The latest is from Lisa Cosgrove at the University of Massachusetts in Boston and her colleagues, involving “ghost management of the information delivery process” for another new antidepressant drug, vortioxetine – available on-line here. (What is it with the antidepressants, anyway?) On this Health Care Renewal blog, Roy Poses has called attention to these issues. As recently as June 8, 2016 he discussed the Transparency International report on corruption in the pharmaceutical sector.
Eric Topol, who helped to expose the Vioxx scandal, made similar points recently in a BMJ commentary: “The bad science in clinical trials has been well documented and includes selective publication of positive results, data dredging, P hacking, HARKing, and changing the outcomes that were prespecified at the beginning of the study…. Furthermore, the disparity between what appears in peer reviewed journals and what has been filed with regulatory agencies is long standing and unacceptable.

It’s No Time for Old Solutions 
As the eye-popping numbers of children treated with escitalopram show, even off-label use of an undistinguished drug in a niche population can be highly profitable. That is why I am proposing that the statistical analysis of clinical trials data can no longer be entrusted to pharmaceutical corporations, on account of their massive inherent conflict of interest. Open access to patient level data, as well as pre-registration of protocols and of data analysis plans, have been actively promoted for some years now to clean up the corporate bias in clinical trials. These are positive developments, but they will not close the disconnection highlighted just above by Dr. Topol. The once idealistic world of clinical trials has changed irreversibly in the past 30 years. As one observer has noted, “… in the course of time the coordinated actions of industry, government, and the biomedical research community have degraded the basic rules of empirical science…” We would do well to acknowledge this fact, and to recognize with Abramson and Starfield thatThe first step is to give up the illusion that the primary purpose of modern medical research is to improve Americans’ health most effectively and efficiently. In our opinion, the primary purpose of commercially funded clinical research is to maximize financial return on investment, not health.”

When corporations are involved, there is no point in prolonging the myth of noble and dispassionate clinical scientists searching for truth in clinical trials. It’s over. We would do better to stop pretending that corporate articles in medical journals are anything but marketing messages disguised with the fig leafs of coöpted academic authors and of so-called peer review. The case study reported out by Drs. John Jureidini, Jay Amsterdam, and Leemon McHenry shows us the real face of business as usual in commercial clinical trials. That being the case, it makes no sense to expect corporations and academic key opinion leaders suddenly to reform their biased and conflicted behavior. Only a structural change from the outside like I propose here has any chance of succeeding. The statistical analysis of clinical trials is too important to be entrusted to the sponsoring corporations.

It is time for Congress to grasp this nettle. The time for enforcement discretion is past, and we need Congress either to direct the FDA to act or to create a new mechanism of oversight. To do nothing would be unthinkable.

Bernard J. Carroll
Professor and Chairman Emeritus,
Department of Psychiatry, 
Duke University Medical Center.


The writer is a former chairman of the Psychopharmacologic Drugs Advisory Committee, Food and Drug Administration, U.S Public Health Service.

Acknowledgment: Several colleagues commented and made suggestions on drafts of this post – in particular John M. Nardo, MD, Donald F. Klein, M.D., and Patrick Skerrett from STAT News.

Update 06-23-2016:  This post was cross-posted on Naked Capitalism, where some interesting comments can be found.


david egilman said...

A non-starter. Criminal prosecution is required with jail time.

InformaticsMD said...

Nobody takes the manufacturing corporation’s word for it concerning the safety and performance of X-ray machines or cardiac defibrillators.

This is horrendous but not surprising. Agree with the need for external, impartial oversight. On s personal note, several young relatives were adversely affected by such drugs in the late 1990s-early 2000s, with violent behavior and suicidal thoughts, that contributed to their needing acute psychiatric emergency care and having problems that persist to this day. At the time I was astonished by the suicidal ideation in my relative on a new antidepressant, xceptionally out of character, that I observed personally.

(As an aside, sadly, too many people take the manufacturing corporation’s "word for it" concerning the safety and performance of healthcare information technology.)

I increasingly believe my reputation for ruthless pursuit of the truth, already online about EHRs since the late 1990s, led to my being declared persona not grata in pharma. For instance, when I sought rehire in drug safety surveillance. After being sought by a department executive ca. 2005 who knew me, I was flat turned out of the office of his boss, a former FDA official, after a short visit - with the refrain that "we don't need medical informatics here." Post at

I experienced similar, perplexing shunning by the Senior VP of a CRO I spoke with a decade ago (in that case, he said he "found nothing in my CV of value to a CRO").

Perhaps what they meant was "we don't need an honest medical informaticist here who can actually detect and who may blow the whistle on our activities."

-- SS

Ken Gillman said...

The power is with the consumer:I suggested 10 years ago in this letter


that patient advocacy groups should organise it so that patients only sign up to be the subjects in trials that are independently organised and analysed. Do that and it would be a 'lay down misere'.

afraid said...

I'm sorry to hear you felt it too Scot. It seems to have gotten worse over the years. To advance in today's corporate culture, honesty is not the best and living by the golden rule will get you laid off. It's one reason why older more life experienced workers have a hard time finding jobs.

There are some things I just won't do. Maybe that's a choice, and we have to live with our choices. I know my income has suffered because of it.

But doctors, you got yourselves into this corporate healthcare mess. Lead the way out. We consumers do not have the education, background, experience to fix this problem. You doctors do, and I think it's your responsibility to do so.

The outright mistruth fed to us every day on the TV, Internet, and elsewhere has stretched past the point of credulity.

Now is the time real change can occur.

david egilman said...

Patient advocacy groups are wholly owned and funded subsidiaries of big Pharma.

Ken Gillman said...

Quite so. Perhaps I should have made it clear that I was thinking of the formation of groups representing patients in this context, independent of partisan interests. I fully appreciate that many existing groups David is referring to may have hidden financing and hidden agendas. I am sure there must be at least some existing groups that are not tied to pharmaceutical companies. With appropriate help and direction from the profession it would not be difficult to initiate a system whereby a small nucleus of such groups could be encouraged and expanded. I can see a mobile app here…

Just think outside the square.

Anonymous said...

Absolutely true David. It's no solution unless it's a patient union.

Portland17 said...

I agree about the Patient Union and independent data analysis. The other issue not mentioned is that we need to ban big pharma reps from becoming FDA regulators or vice versa for an extended period of time. Personally, I'd like to see a requirement of a percentage of laypeople or experts from related fields (like biochemistry professors or chemical engineers or others with sufficient science background to understand the issues) being part of any FDA panel, to assure there is some outside scrutiny of people who aren't already indoctrinated into "the way we do things" in the field.

Big Pharma corruption is rampant and very dangerous. It's definitely past time to do something major to stop this travesty masquerading as "science."

Unknown said...

I taught an evidence-based pharmacotherapy course in pharmacy schools. i showed the students how to access FDA and VA monographs reviewing new drugs. Routinely, the students would find publications of results from the same trials in the review and other studies not included in the reviews. What was worse was when they found information on the drugs from their classroom presentations from clinical faculty that contradicted FDA reviews, and sometimes the origin of the slides presented to them by instructors came from "slide-decks" given to the professors by the companies. I could not get the students to believe the results of the FDA for themselves.