An inappropriate analysis of clinical trial data by Glaxo researchers obscured suicide risks associated with Paxil for 15 years, writes
The New Scientist, citing court documents that were recently unsealed in by a federal court in California. ( Take a look).Two years ago, Glaxo alerted the public to an increased risk of suicide associated with its pill. However, an analysis of internal Glaxo memos and reports suggests the drugmaker had data demonstrating an eightfold increase in suicide risk as early as 1989.
Harvard University psychiatrist Joseph Glenmullen, who studied the papers, tells the mag it was “virtually impossible” Glaxo misunderstood the data. The drugmaker calls that "absolutely false." He reached his conclusion after reviewing documents obtained by lawyers who have filed about 30 cases against Glaxo over Paxil and suicides or suicide attempts.
The analysis focuses on the so-called washout phase preceding a trial, when subjects stop taking most or all meds to avoid confusion with results from the trial itself. Because the washout occurs before patients randomly receive either the drug or a placebo, side effects can't be attributed to the trial and so are seldom, if ever included in final results, New Scientist notes.
UPDATE: Chuck Grassley of the Senate Finance Committee has just written Glaxo seeking nine pages that weren't made available with the unsealed documents. Here is the letter.
However, Glaxo researchers submitted data to the FDA in the late 1980s and early 1990s that included suicides and suicide attempts from the washout period in the results for the placebo arms, or portions of the trials, but not from the Paxil arms. Glenmullen alleges these extra “placebo” suicides negated suicides attributed to Paxil, making the pill appear safer. He argues that if the washout results had been excluded, the data would have shown Paxil posted an eightfold increase in the risk of suicidal behavior in adults.
Glaxo spokeswoman Mary Anne Rhyne tells the mag that including washout data "was intended to present the full picture of events that occurred in all phases of the clinical trials, starting from the time patients were enrolled, before they were randomized." She adds that even without the washout data, paxil still came out as safe as the placebo in the trial. And she accused Glenmullen of incorrectly analyzing the data to reach the opposite conclusion, but she ddidn’t respond the the mag's request for numerical proof that his conclusion was incorrect.
For his part, Glenmullen suggests the FDA would have acted differently had the washout data been used more explicitly. Rhyne says that documents still under court seal show the FDA to be fully aware of how the washout data was being used. But Glenmullen quotes Martin Becher, the FDA staffer who reviewed Paxil safety data, as agreeing during a pre-trial hearing that the use of washout data was "scientifically illegitimate."
12 Comments
All I can say is wow. As far as I know, none of the standard AE coding dictionaries had (or have) suicide/suicidal ideation hard-coded to emotional lability; while people who are emotionally labile are prone to suicidal ideation, they are most definitely not the same thing. This means that someone at SKF (now GSK) intentionally directed Safety/Pharmaovigilance & Data Management to code as such (this direction should, theoretically, be delineated in the Data Management Plan and/or Edit/Coding specifications).
Also, I knew Bruce Wallin had worked at SKF but am confused as to why a Rheumatologist headed up CNS and handled development of psych compounds. Did SKF have it's pain & inflammation group bundled under CNS?
Skimming through the judge's ruling in the latest law suit (13 year old boy committed suicide while taking Paxil), I noticed something that I don't understand. Maybe you can shed some light. GSK contended that there was no data to indicate that risk of suicide was an issue in adolescents. There was some indication for adults. This is confusing to me, not being of a Pharmaceutical background. Seems to me if it's a problem for adults it might be a problem for adolescents. What would the divisions of age be for drug studies, if there are any?
Children aren't just miniature adults so the pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body) can be different in various age groups. They also have a different set of co-morbidities/concomitant meds that can impact the safety and efficacy profile of a drug. That being said, people with mental illness (especially depression) are prone to suicidal ideation so one would think that, in seeing a statistically significant difference in reports of suicidality (or even just ideation) with paxil treatment in adults, that SKF/GSK would have put additional safety precautions and an independent Data & Safety Monitoring Committee in place for pediatric trials in this indication.
Adults are 18 and 65 Geriatrics > 65
Pediatrics <18 - Adolescents (a sub-set of pediatrics) are 12-17 - they tend to block younger pediatric age groups for subset analysis in studies of those ages
Jaynesday
Paxil has never been FDA approved for the use in children and Adolescents, and it carries a Black Box Warning for increased violence and suicide.
You can read some of GSK's internal Documents here: http://www.paxilharmschildren.com
GSK shouldn't have bragged about winning Preemption in a case involving a dead child
Ed,
Did you notice the similarities between GSK's words, and the words that are written in the Antidepressant Medication Guide!!!!!!!
The obfuscation of the risks via creative coding undermines the FDA approval. Unless the FDA was explicitly aware that the data being presented as emotional liability was, in fact, a mix of suicidality/suicidal ideation and emotional lability, the data presented in the tables, figures and listings is an example of intentionally misleading reviewers and undermining the federal regulatory process. In such a situation, wouldn't there be a possibility of an extremely strong case in the federal courts?
If the FDA was aware and did not ensure accurate representation of the data, correct labeling and prescribing information, would it be possible to appeal the federal pre-emption ruling with an argument that the FDA failed to fulfill its obligations?
Regardless, I think this is a situation in which individual personnel directly involved in this fraud (including, but not limited to executives) could and should being held criminally responsible.
[...] IN AN UPDATE FROM PHARMALOT: Chuck Grassley of the Senate Finance Committee has just written Glaxo seeking nine pages that weren’t made available with the unsealed documents. Here is the letter. Posted in Uncategorized. [...]
"Glaxo spokeswoman Mary Anne Rhyne tells the mag that including washout data “was intended to present the full picture of events that occurred in all phases of the clinical trials, starting from the time patients were enrolled, before they were randomized.” She adds that even without the washout data, paxil still came out as safe as the placebo in the trial. And she accused Glenmullen of incorrectly analyzing the data to reach the opposite conclusion, but she ddidn’t respond the the mag’s request for numerical proof that his conclusion was incorrect" ..
I wonder why Mary Anne Rhyne failed to respond to the mags request for numerical proof that Glenmullens conclusion was incorrect? ... Could it be because his interpretation of the Paxil data was NOT incorrect ?
Mary Anne Rhyne has been sprouting corporate bull about Paxil for Years.. Never once has she publically apologised about Study 329, Paxil's damage to children, or the hundreds of thousands of people who were lied to about Paxil side effects and withdrawals.. Is she a spokesperson or just a paid propagandaist? Either way...I'm sure Joeseph Goebells would be proud..
Paxil was named as the Primary Suspect Drug responsible for 495 Suicide Attempts (not completed), 841 Completed Suicides, 82 other Deaths not from Suicide and 54 Homicides (the act, not the body count) in reports sent to the FDA's Adverse Event Reporting System (MedWatch) between 2004 and 2006 (http://www.psychdrugdangers.com/?drugtable=paroxetine)
There were also 1,308 reports of Suicidal Depression / Suicidal Ideation attributed to Paxil, 119 instances of Homicidal Ideation and 158 reports of Mania.
Taking another view, 1,277 Individual Safety Reports were submitted to the FDA between 2004 and 2007 where the Adverse Reactions were experienced by a pregnant or new mother taking Paxil or her unborn or newborn child being exposed to the drug via the placenta or breast milk. These reports include 65 miscarriages among 112 Deaths: http://www.psychdrugdangers.com/MothersAct.html
The majority of MedWatch (AERS) reports are submitted to the FDA by the Manufactuer after learning of an Adverse Reaction to its product.
These miscarriages and other severe congenital defects (such a Transposition of the Great Vessels wherein the position of the aorta and pulmonary artery are reversed, or Anencephaly where most of the brain and spinal chord are missing at birth) were not caused by a sugar pill.
Sam
Of the 29,945 Individual Safety Reports submitted to the FDA between 2004 and 2007 naming Paxil as the Primary Suspect Drug for the Adverse Reactions, 28,635 (over 95%) of them were EXPedited or PERiodic reports from the Manufacturer to the FDA and 1,310 of them were DIRect from the Consumer, Doctor, Lawyer, Other Healtcare Professional or Pharmacist to the FDA.
Sam
Ol Cranky (who actually doesn't seem that way) wrote:
"The obfuscation of the risks via creative coding undermines the FDA approval. Unless the FDA was explicitly aware that the data being presented as emotional liability was, in fact, a mix of suicidality/suicidal ideation and emotional lability, the data presented in the tables, figures and listings is an example of intentionally misleading reviewers and undermining the federal regulatory process. In such a situation, wouldn’t there be a possibility of an extremely strong case in the federal courts?
If the FDA was aware and did not ensure accurate representation of the data, correct labeling and prescribing information, would it be possible to appeal the federal pre-emption ruling with an argument that the FDA failed to fulfill its obligations?"
One would assume, based on reasonable notions of justice, there would be grounds for such a case, there would almost certainly not be under preemption.
The reason is that, in the first scenario, FDA would have itself to conclude that it was defrauded (if it so believed) and successfully prosecute for felony fraud. Given the history of such cases, the odds of that happening are virtually zero. It's Office of Criminal Investigation simply do not pursue these kinds of cases. This would apply to either civil or criminal penalties under the first scenario that OC presents.
Re: the second - that the FDA, in effect, collaborated in what some would view as fraud - again, the odds of action are slim to none. Based on relevant precedents, if the FDA does not agree that it was defrauded, I do not believe there is an arena in which that judgment (or that of any similar federal agency) could be challenged.
Probably, the only grounds for action would be if an FDA-insider/whistleblower was able to bring forth evidence that agency officials knowingly colluded with what they knew was non-compliant action by GSK. But, even then, you'd virtually have to have evidence of behavior on the level of bribe-taking or unambiguously damning memos for this to go anywhere. Again, a whistleblower would be needed to produce such stuff.
I'm going to slightly amend my comment above. I have only skimmed some of the unsealed court documents. But there is direct reference to FDA memos that concern GSK's "coding maneuvers" and similar language that clearly suggests some in FDA knew they were being misled, and deliberately so.
Given relevant history, it still seems extremely unlikely to me that FDA/DOJ would itself take legal action for any of this.
However, FDA preemption has not yet been upheld, and it seems conceivable that a state-level damages case could include some of this material. Again, the defense would be that only FDA can rule about its own defrauding, based on the Buckman case. But in Kent v. Warner-Lambert the SC was tied 4-4 (Roberts recused himself because of stock-holdings), a case that turned, in part, on Buckman and its relevance.
Thus, while a very long long-shot, it now does seem to me that there _may_ be material here that, at some level, could be used in relevant legal action.
Either way, the airing of the story via Grassley's committee will - one hopes - provide one more cautionary tale about how things sometimes happen.
I'll also ask what I often do: Assuming there were such "coding maneuvers," how do industry folks view this? Is this the kind of thing that hardly ever happens? The kind of thing relatively easy to make happen? The kind of thing that happens more than it used to?
Thank you.