FDA Oversight Lacking with Questionable Data in Journals: Professor
Why does FDA turn its head when pharmaceutical companies publish glowing reports in medical journals about their drugs and clinical trial data, particularly when it goes against the agency’s own statistical analyses it performed when reviewing data in a marketing application? That is the question Duke University Medical Center professor and former FDA Psychopharmacologic Drugs Advisory Committee chairman Bernard J. Carroll asks as he advances a proposal seeking Congress’ help to mandate that the agency exercise oversight over clinical trial data published in journals.
“There is a disconnection between the FDA’s drug approval process and the reports we see in medical journals,” Carroll says. “Pharmaceutical corporations exploit this gap through adulterated, self-serving analyses, and the FDA sits on its hands... 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.”
Because of his background, Carrol takes particular interest in antidepressant data. He points to a recent exposé by researchers examining a Forest Labs clinical trial of an antidepressant drug in children and adolescents. The statistical analyses performed by Forest allegedly deviated from the IND analysis plan and negative results were edited out, Carroll notes. Published data “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,” he contends. “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... 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.”
The solution, according to Carroll, is an Underwriters Laboratory-type outfit to verify the statistical analyses of clinical trials. “Who should assume that responsibility?” he asks. “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.”
Certainly, Carroll expects some push back from the pharmaceutical industry, and quite possibly a First Amendment challenge to the proposal. “It will fail,” he says, “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. ”
Carroll points to other examples of data bias published in journals. “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 online here.” And 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 is time for Congress to grasp this nettle,” urges Carroll. “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.”
So, what is FDA’s response to why it turns a blind eye to questionable data finding its way to a medical journal article? FDA Webview is still waiting for a response to that question. Could it be a lack of resources or no clear mandate to oversee the large universe of medical journal publications? And then there is the agency’s recent defeats in First Amendment-related cases that seem to have paralyzed its decision making on what companies can say about their products.