By Bernard J. Carroll, Professor and Chairman Emeritus, Department of Psychiatry, Duke University Medical Center, and a former chairman of the Psychopharmacologic Drugs Advisory Committee, Food and Drug Administration, U.S Public Health Service. E-mail: firstname.lastname@example.org. Cross posted from Health Care Renewal
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 publishedin 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 reportin 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 challengedin the journal about this concealment. Their responsewas 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.
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.
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.
Foxes everywhere. The FDA is one of them. Congress is a pack of them. The president is at the head of the pack. These are the people that will make clinical trials honest?
Our entire country has been turned into a racket. The numbers of people involved are now so large that it would be incredibly difficult to cut out all of the rot. I’d love to see the corporate execs, the writers of ads-disguised-as-science, and the corrupt academics who put their names on said ads, all placed in stocks and publicly shamed on national TV…but I don’t think there’s enough airtime or cable channels to get everyone who deserves that.
A noble profession of ethics, but the nuts and bolts here will determine the future. How can the, let us be charitable, FDA enforce it’s mandate? May I suggest an expansion of corporate liability under law? Let the heads of the divisions in a corporation convicted of data manipulation be held criminally responsible for any deaths or damages arising from drugs or devices approved by said persons. Then make the executions public spectacles. On another front, since the Supreme Court has ruled that corporations are legal ‘persons,’ why not put those ‘persons’ ‘to death?’ How would one ‘kill’ a corporation? Simply re-arranging the parts under a new name is not good enough. Banning the executives from working in the field for life? Stripping all of the assets and placing them in a third party trust? This will be a thorny question for the future.
Perhaps they could volunteer to be the recipients of free testing of their own corporation’s drugs. And perhaps, for a time, they should be the only ones allowed into these tests. Then, the public can see how it goes. We’ll use our “enforcement discretion.”
You’re wrong in your interpretation of the First Amendment. Over the last generation, “free speech” has increasingly been used to gut economic regulation by equating money with speech – culminating in the Orwellian-entitled, _Citizens United_ decision. The next time there’s a feasible conservative majority on the court, it won’t be long before all economic regulation gets gutted. They’ll claim the First Amendment supersedes the commerce clause or something – and if not by the court then it will be gutted by secret tribunals in TPP, TISA or some other agreement. The Chamber of Commerce won’t rest until we have government by lobbyist.
And in a strange way, it is about printing presses. The falsification of information to enhance the value of an item in white collar fraud is pretty much essentially counterfeiting. They might as well be running off their own dollar bills at the expense of the rest of us. Instead of inflation, though, the cost in medicine is the euphemistic “adverse events.” It is a grim irony that antidepressants marketed to children increases the risk of one very deadly symptom of depression, suicide.
Until you cut off the flow of money – the basic auctioning off of high office – all of these incentives will remain. You have to pay employees at the FDA based not on the health of the average executive bonus but instead on the health of the average American. Until you severe that connection, there will always be an incentive to corrupt data. Next go around, they’ll just fabricate patients or outright invent data. The boys from McKinsey know all the tricks.
Increasing the external tools of auditing will help. You need non-profits gathering data on efficacy once a drug is on the market. You need medical tricorders that will allow patients to test their blood (not to mention food and water) to see what’s in it and how their symptoms change on a medication.
It sounds common-sensical but wait until the tech actually threatens to hit the market. Then you’ll see the FDA explode with all sorts of bizarre excuses that make no sense until you realize the only organized, competent parts of it are actively involved in the coverup.
This isn’t the fault of the FDA or the concept of government in general. If you shrink government down to nothing, then who’s going to secure the blessings of liberty for you and provide justice? This is what you get when corporations own and operate the government – a state of affairs technically known as fascism (to use Mussolini’s term).
Your logic is somewhat backwards. The commerce clause is, in fact, the entire pinnacle of what capitalism has become. Essentially, commerce is what they used to justify equality among races as well as a host of other things. You write “They’ll claim the First Amendment supersedes the commerce clause”, buts its the exact opposite that has happened: commerce has taken precedence to EVERYTHING. Wherever profits are to be made, regulation disappears into the gray smoke of politics.
Why do you refer to arbitration panels as ‘secret’? They’re not at all.
Don’t make stuff up. It’s against house rules. The ISDS panels, which is what Wade referred to, most assuredly are secret.
“Complaints are decided in secret by panels of lawyers specialized in commercial law.”
Excellent article and just the tip of the iceberg. The Cochrane reviews out of England study the evidence of efficacy of treatment and in the US it is rarely followed. It is estimated that over half of the surgeries in the US are unnecessary. The only solution is to put all doctors on salary with no production bonus and eliminate patient satisfaction metrics. Doctors will then do what they should do which is treat patients based on what has been proven to work and if it is not likely to work they won`t have any incentive to do it. If we consider medical care to be a public service like fire protection and 911 for medical emergencies and we do since the government pays for most of it one way or another this makes sense. We don`t complain if firemen are not working all the time and we don`t burn down buildings to make them more efficient and medical care is no different. Patients used to getting whatever they think they want will be upset at first but they will end up healthier. Fee for service funded by the government or incentives to do more funded by the government in today`s environment of excess doctors is insane as we are seeing.
Isn’t that what agencies and commissions are for? To pass and support questionable products and policies.
Richard Olney, Atty Gen and Sec of State under Cleveland said of them:
“The Commission… is, or can be made, of great use to the railroads. It satisfies the popular clamor for a government supervision of the railroads, at the same time that that supervision is almost entirely nominal. Further, the older such a commission gets to be, the more inclined it will be found to take the business and railroad view of things.… The part of wisdom is not to destroy the Commission, but to utilize it.”
OK this is only a parenthetical, throwaway remark…. but it is not hard to understand why antidepressants and why antidepressants for children, especially. We live in a culture where traditional communal cultures are very hard to maintain and have largely been replaced with a sacred devotion to the individual. There are some positive aspects to our cult of individuality, but there are also some very important negatives, including an enhanced insecurity and sense of isolation which exacerbates ordinary feelings of sadness. We celebrate aloneness, but have no healthy cultural methods for dealing with loneliness.
The model held out for adults to transform their sadness into happiness is, “have a drink”. From the Distilled Spirits Council of the United States: “The U.S. beverage alcohol industry is a major contributor to the economy, responsible for over $400 billion in total U.S. economic activity in 2010.” Yet our traditional culture maintains that giving alcohol to children is unacceptable. But having unhappy children is also unacceptable, and lacking normal and healthy means for dealing with sadness and loneliness in children leaves a huge market for childhood antidepressants. Of course, there is also a large market for adult antidepressants because adult drinking is culturally appropriate only “after hours” (can’t have happy drunks interfering with production), while adult sadness and ennui do not restrict themselves to after work schedules and can strike at any time. And we, both adults and children, have a lot to be sad about, given the state of the economy, the direction our leaders tend to march and our prospects for the future.
When you mistreat masses of people and remove their traditional means for comforting one another through stable social communities and replace that with “every one for themself” social ethics… how could you not get a huge profit opportunity in chemical happiness?
Drinking to feel happy is so 1970s. Coke followed by Qualudes is much more suited to the modern life style.
Ye Gods! Might as well boot up an 8Ball.
All of this, as I think you know all too well, is basic avoidance of lifes’ problems. It’s when there seems to be no hope that the Vikes start calling you from out of the medicine cabinet. That is one reason to embrace the “olde tyme virtues;” facing and working through pain is so much more productive. That’s where the Bene Gesserit Litany Against Fear, from the book Dune, makes sense.
The conflict of interest inherent in the relationships described have been well
documented in other venues. What are the conditions of the environment that
create the blindness? Is it the old expediency of making a few dollars or getting along with those who have more authority, or convenience. For example, how can anyone blame an unsupported school teacher who is relieved when a pill, prescribed by science can alter a child’s disruptive behavior resulting in a more manageable classroom. How
does the blindness take over at different levels?
I remember when the idea of “chemical imbalance” was being promoted as the cause of “emotional problems” by the religion of science as opposed to the methodology of science. It was as if the chemical imbalance, being the cause, was both the answer and
the cure and the ‘pragmatic’ solution was to take the pill and get on with the ‘business’ of life. Is there time being found or energy being allocated to ask about the value of the human natural process of confronting our existential dilemma of occupying and navigating the territories of our interior selves while confronting the challenges and joys of our physical environments. I believe that personal power or individuality is achieved
by knowing that we can use our innate individual creativity and our individual intelligence and our patience along with what we deem helpful that presents itself
to resolve deeply felt incongruities and discover unexplored gifts and levels of
personal realities. The solutions foisted upon people by the not human corporate
imperative squanders another level of our natural resources which is inflicting our
society but not with individual perspective.
“· Unplanned, new secondary measures of response were inserted ex post facto because they were positive (that is a real no-no).”
As the new head of the FDA, maybe Robert Califf will improve matters. Oh, wait: “During his tenure at Duke University, Califf racked up a long history of extensive financial ties to multiple drug and medical device companies, including Amgen, AstraZeneca, Eli Lilly, Johnson & Johnson, Merck Sharp & Dohme and Sanofi-Aventis, to name a few,” Carome said. http://time.com/4036811/fda-new-head-robert-califf/
But there’s no actual exchange of cash in a white envelope (or a brown bag). So there’s no corruption. Money is speech, remember — now accepted by both party Establishments.
This totally sounds like how GMO’s are being approved by the FDA and will be forced on the world through the TPP. Corruption isn’t a strong enough word for it
Corruption isn’t a strong enough word for it
Why no mention of the AllTrials campaign to force all clinical trials to be registered and all results timely reported?
AllTrials unfortunately is not AllData, but it should be. Its founder, Dr. Ben Goldacre, capitulated to GSK when they refused to disclose patient-level raw data, preferring to disclose summaries instead. I don’t know if that’s why Dr. Carroll omitted mention. He also failed to mention other advocates of reform like RxIsk.org.
Private for profit development of critical new drugs should be entirely disallowed. All research and development should be done by public institutions (as they significantly already are) and the drugs developed–for their curative rather than as currently their financial potential–made available as generic and having no IP rights, national or international, associated with them. Any other approach is a hornet’s nest of perverse and immoral incentives.
The corruption will continue while the penalties remain meaningless. Even the $3B fine GSK “paid” was nothing when it all boiled down. It’s not unlike the fake redress for harmed borrowers than Bank of America et al. “paid” for some of their malfeasance in the ongoing foreclosure horror. David Dayen gets into that in his writings.