July 7

Did regulators fail over SSRIs? BMJ

Noting that controversy over the safety of antidepressants (and COX 2 inhibitor drugs) has shaken public confidence, he asks:  "Were mistakes made and could they have been avoided?"

Citing GlaxoSmithKline’s recent (May 2006) acknowledgement of an increased suicide risk for adults prescribed the antidepressant, Paxil (paroxetine) [1]  Dr. Healy asks what had prevented US and UK regulators (FDA and MHRA) from disclosing the lethal risk of suicide posed by SSRI antidepressants inasmuch as the evidence had been in the regulators' possession?

He notes: “Many people expect drug companies to be slow to concede that a drug causes hazards, but we do not expect our regulators to be even slower, so any hint that this might have been the case needs to be examined.”

Dr. Healy then challenges these regulators for accepting industry's favored, but flawed statistical methodology for analyzing clinical trial data:
"Although data submitted to the FDA show an excess of suicides with every antidepressant licensed since 1987 compared with placebo, this simple but crucial finding continues to be obscured."

“Regulators and companies have stated repeatedly that because the confidence interval for individual drugs and for a pooled analysis of the SSRI trials…overlaps 1.0, there is no credible evidence of a suicide risk…"

However, "The best estimate for the likely risk of suicide on SSRIs over placebo is 2.6, and although minimal or no risk is compatible with the scientific data, the data are also consistent with a 10-fold increase in risk, and 2.6 is the point on the confidence interval with the greatest probability. Statements such as these would mandate further trials powered to settle the issue.”

Dr. Healy also notes that government agency officials were inconsistent when they dismissed a 2.17 increased risk of suicidal acts for adult patients on an SSRI (compared to placebo) and a 4.61 increased risk for actual suicides, concluding “no credible evidence of a suicide risk” because the confidence intervals included 1.0.

By contrast, he notes, despite the fact that the data from SSRI trials in children also included 1.0 in the confidence interval, the 2.19 increased risk of suicidal acts for children on an SSRI (compared to placebo) was acknowledged by FDA and MHRA and forms the basis for SSRI black box label warnings.

Since GSK’s belated acknowledgement (May 2006) that its data analysis of controlled clinical trials show that Paxil poses a six-fold increased suicide risk for adults, serious questions arise about how GSK, officials of the FDA and MHRA failed to detect this six-fold increased suicide risk for a decade?

Had they all knowingly and deliberately deceived clinicians and the public? Or, does the fault lie in their statistical method for analyzing the data?

Dr. Healy lists the following summary points of his article:

1. The example of the selective serotonin reuptake inhibitors suggests that current regulatory practice overstates the benefits and underestimates the risks of drugs
2. Inappropriate inclusion of suicidal acts in the placebo group by manufacturers biased estimates of suicide risk on treatment.
3. Regulators’ rigid interpretation of confidence intervals may have delayed warnings of dangers of suicidal acts.
4. When individual drug trials are small regulators are in a unique position to analyze class effects but hitherto have rarely done so.

How many people must die from unacknowledged but real adverse drug effects to maintain profit margins?

Recent revelations suggest that pharmaceutical companies and regulators are losing out as public confidence in both plummets.

The public cannot be expected to suspend common sense and disregard empirically observable harm and  human casualties because the evidence, they are told, doesn't fit a statistical formula.

Full text (unfortunately for a fee): Healy, BMJ.2006; 333: 92-95
(or upon request).

GlaxoSmithKline documents acknowledging six-fold suicide risk for adults on Paxil and GSK label changes:
 http://www.gsk.com/media/paroxetine_adult.htm; http://www.gsk.com/media/paroxetine/adult_hcp_letter.pdf

See also:  https://ahrp.org/cms/content/view/166/28/ and https://ahrp.org/risks/SSRI0204/GSKpaxil/index.php

Contact: Vera Hassner Sharav

BMJ Press Release July 7, 2006

Drug approval processes may have delayed safety warnings for antidepressants

Did regulators fail over selective serotonin reuptake inhibitors? BMJ  Volume 333 pp [to be added]

Drug approval processes may have delayed warnings about the safety of  antidepressants, argues a senior doctor in this week's BMJ.

Following GlaxoSmithKline's recent letter to doctors pointing to a six fold increase in the risk of suicidal behaviour in adults taking paroxetine, Professor David Healy examines the regulation of selective serotonin reuptake inhibitors (SSRIs) and asks were mistakes made and could they have been avoided?

In February 1990 an article raised concerns that the recently licensed fluoxetine might trigger suicide acts in depressed patients. Subsequent  trials showed no differences between active treatment and placebo, but a recent study – a review of over 700 trials ? found that patients taking SSRIs were twice as likely to attempt suicide compared with those taking placebo.

This trend should have been seen by both companies and regulators as something that required investigation, writes the author.

Trials in children conducted from the mid-1990s also show a doubling of the risks of suicidal acts with SSRIs. These results have recently ormed the basis of warnings about the use of SSRIs in children. Trials in adults show a similar risk ratio yet, until May 2006, no warnings were ssued for adults.

"Although data submitted to the FDA show an excess of suicides with every antidepressant licensed since 1987 compared with placebo, this simple but crucial finding continues to be obscured," he says.

He also examines the way in which the data were presented to regulators by manufacturers, and suggests that inappropriate inclusion of suicidal acts in the placebo group biased estimates of suicide risk. Subsequent "rigid interpretation" of these data by the regulators "may have delayed warnings of dangers of suicidal acts," he adds.

Having re-analysed the evidence, he suggests that the best estimate for the likely risk of suicide on SSRIs over placebo is 2.6 (more than double the risk) and he calls for suitably powered studies to settle the issue.

He also believes that greater data transparency and statistical sophistication might lead to earlier research to discriminate between those who do well on new drugs and those who do not.

"The regulators seem stuck in a world where balancing evidence of potential benefit against actual risk causes real problems," he writes.
"The SSRI and rofecoxib disasters have harmed public confidence in drugs.
We urgently need to learn how to regulate both the risks and benefits of new treatments more effectively."

David Healy, Professor of Psychiatry, North Wales Department of Psychological Medicine, Cardiff University, Bangor, Wales

Tel: +44 (0)1248 384 452 Email: healy_hergest@compuserve.com


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