Zoloft Study in JAMA Questioned by Peers

[Guest guest]

FYI

At the time that two manufacturers publicly acknowledged that their

antidepressant drugs (Paxil / Seroxat and Effexor) were unsafe, and

ineffective for children, the Journal of the American Medical Association

(JAMA) published a clinical trial report by the " Sertraline Pediatric Study

Group " (i.e., Pfizer sponsored investigators) claiming: " Sertraline [Zoloft]

-treated patients experienced statistically

Significantly greater improvement than placebo. "

See: http://www.ahrp.org/infomail/03/10/01a.html

The press uncritically swallowed those unsubstantiated claims, and proceeded

to mislead the public and treating physicians.

The disputed 'favorable findings' claimed for Zoloft are challenged in

letters published in the current issue of JAMA (Jan 1, 2004). Five

psychiatrists from the US and UK question the validity of those claims and

indeed, question the integrity of the method by which those claims were

obtained. In essence, the claimed 'positive' findings were made by EXCLUDING

noncompleters and nonresponders.

The British authority, once alerted to how the methods by which drug

manufacturers have manipulated clinical trials to show 'positive findings,'

took action to protect children from the hazards of SSRIS. FDA, in sharp

contrast, is fiddling while children are needlessly being made to suffer.

FDA is tinkering with the clinical trial data, attempting to airbrush the

evidence so as to neutralize the negative.

Furthermore, FDA has refused to allow expert scientific testimony that

updates the findings of the information received by the British Medicines

and Healthcare Regulatory Agency. As a result, American children prescribed

SSRIS are at risk of developing drug-induced mania, violence and suicidal

behavior.

The JAMA letters:

Drs. Maju, Manu, and Joanne Mathews from Dexel University, East Surrey

Hospital and West Suffolk Eng (respectively) noted:

" [T]he authors excluded some randomized patients from their analyses.

According to the principle of mention to treat (ITT),

the authors could have assigned the 'worst-case outcome' to the excluded

patients. "

Dr. Price from Colorado Permanente Medical Group questions the

rationale for conducting 2 separate trials--that introduce additional

variability rather than 1 large trial. He questions the rationale for

lowering the bar on the 'improvement' standard--from commonly used 50%

response rate to 40% which, as Dr. Price points out,

" This seems to create a bias for a favorable result for sertraline. And Dr.

Price faults the authors for using a questionable " last

observation-carried-over method rather than the more conservative analyssis

considering noncopleters and nonresponders. "

Dr. Antal E. Solyom from the University of Virginia questions the scientific

and ethical justification of using children in rigid double-blind controlled

clinical trials inasmuch as the pitfalls of placebo-controlled trials in

antidepressants have been acknowledged even by Dr. Kupfer, former

president of the American College of Neuropsychopharmacologists. Dr. Solyom

points out that

" individual case study designs that enroll patients with severe depression

from which suicidal patients are not excluded may be more appropriate.

Finally, Dr. Soyom notes:

" Most troubling is the uncritical duplication of all of these trials in the

even more heterogeneous and vulnerable child and adolescent psychiatric

populations. It would be more constructive to focus on the 40% of depressed

adolescents who do not respond to the initial trial and antidepressant

treatment. "

Glen Spilmans a statistician from the department of psychiatry, Indiana

University, notes that the absence of evidence about the validity of the two

scales used to measure an improvement in outcome. " Because of the small

magnitude of difference between groups [on Zoloft compared to those on

placebo] and the failure to truly assess the degree to which the double

blind may have been penetrated, this trial suggests that sertraline shows

little to no perceptible benefit compared with placebo in the treatment of

depressed youth. "

An unpublished letter by Dr. Jan Garland, Clinical Professor, Psychiatry

University of British Columbia and Clinical Head, Mood and Anxiety Disorders

Clinic BC's Children's Hospital appears below.

Letter to Editor, JAMA:

As one of the many investigators in various sites who was involved in the

Pfizer sertraline pediatric depression trials published in JAMA in August,

2003 (1), I was very concerned for a number of reasons about the data

analysis reported in this paper. The most striking feature was the pooling

of two trials which is not the orthodox way of handling trial data. The

pooled data, a sample size of 376 patients, showed a marginal superiority of

medication which is not likely to be clinically meaningful in terms of

risk/benefit balance. On selected improvement measures, only 10% more

patients improved on sertraline than on placebo, remission rates were not

different, and there were more discontinuations in the sertraline group due

to adverse effects including suicidality and aggression. Based on this

report, it appeared very likely that the individual trials were in fact

negative, but this possibility was not discussed by the authors. By pooling

the data, what might have been reported as two negative trials was instead

converted into one marginally positive trial with the conclusion that

“sertraline is an effective and well-tolerated short-term treatment for

children and adolescents with MDD”.

New information about these trials is now available. The recent review of

pediatric antidepressant trials by the British regulatory agency includes

the appropriate separate analysis of these two trials, and the summary

results are now in the public domain (2). >From this analysis, it is clear

that the two individual trials each of a good size (almost 190 patients) did

not demonstrate the effectiveness of sertraline in treating major depressive

disorder in children and adolescents. Hence, the correct conclusion from the

data reported by Wagner et al should be that " sertraline is ineffective when

compared to placebo and is associated with increased adverse effects " .

E. Jane Garland, M.D.

1. Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, et al. Efficacy of

Sertraline in the Treatment of Children and Adolescents With Major

Depressive Disorder: Two Randomized Controlled Trials JAMA.

2003;290:1033-1041.

2. Committee on Safety of Medicines. Medicines and Health Care Products

Regulatory Agency. Selective Serotonin Reuptake Inhibitors (SSRIs): overview

of regulatory status and CSM advice relating to major depressive disorder

(MDD) in children and adolescents: Summary of clinical trials

http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ssrio

verviewclintrialdata_101203.htm

_________________________________________________________________

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[Guest guest]

FYI

At the time that two manufacturers publicly acknowledged that their

antidepressant drugs (Paxil / Seroxat and Effexor) were unsafe, and

ineffective for children, the Journal of the American Medical Association

(JAMA) published a clinical trial report by the " Sertraline Pediatric Study

Group " (i.e., Pfizer sponsored investigators) claiming: " Sertraline [Zoloft]

-treated patients experienced statistically

Significantly greater improvement than placebo. "

See: http://www.ahrp.org/infomail/03/10/01a.html

The press uncritically swallowed those unsubstantiated claims, and proceeded

to mislead the public and treating physicians.

The disputed 'favorable findings' claimed for Zoloft are challenged in

letters published in the current issue of JAMA (Jan 1, 2004). Five

psychiatrists from the US and UK question the validity of those claims and

indeed, question the integrity of the method by which those claims were

obtained. In essence, the claimed 'positive' findings were made by EXCLUDING

noncompleters and nonresponders.

The British authority, once alerted to how the methods by which drug

manufacturers have manipulated clinical trials to show 'positive findings,'

took action to protect children from the hazards of SSRIS. FDA, in sharp

contrast, is fiddling while children are needlessly being made to suffer.

FDA is tinkering with the clinical trial data, attempting to airbrush the

evidence so as to neutralize the negative.

Furthermore, FDA has refused to allow expert scientific testimony that

updates the findings of the information received by the British Medicines

and Healthcare Regulatory Agency. As a result, American children prescribed

SSRIS are at risk of developing drug-induced mania, violence and suicidal

behavior.

The JAMA letters:

Drs. Maju, Manu, and Joanne Mathews from Dexel University, East Surrey

Hospital and West Suffolk Eng (respectively) noted:

" [T]he authors excluded some randomized patients from their analyses.

According to the principle of mention to treat (ITT),

the authors could have assigned the 'worst-case outcome' to the excluded

patients. "

Dr. Price from Colorado Permanente Medical Group questions the

rationale for conducting 2 separate trials--that introduce additional

variability rather than 1 large trial. He questions the rationale for

lowering the bar on the 'improvement' standard--from commonly used 50%

response rate to 40% which, as Dr. Price points out,

" This seems to create a bias for a favorable result for sertraline. And Dr.

Price faults the authors for using a questionable " last

observation-carried-over method rather than the more conservative analyssis

considering noncopleters and nonresponders. "

Dr. Antal E. Solyom from the University of Virginia questions the scientific

and ethical justification of using children in rigid double-blind controlled

clinical trials inasmuch as the pitfalls of placebo-controlled trials in

antidepressants have been acknowledged even by Dr. Kupfer, former

president of the American College of Neuropsychopharmacologists. Dr. Solyom

points out that

" individual case study designs that enroll patients with severe depression

from which suicidal patients are not excluded may be more appropriate.

Finally, Dr. Soyom notes:

" Most troubling is the uncritical duplication of all of these trials in the

even more heterogeneous and vulnerable child and adolescent psychiatric

populations. It would be more constructive to focus on the 40% of depressed

adolescents who do not respond to the initial trial and antidepressant

treatment. "

Glen Spilmans a statistician from the department of psychiatry, Indiana

University, notes that the absence of evidence about the validity of the two

scales used to measure an improvement in outcome. " Because of the small

magnitude of difference between groups [on Zoloft compared to those on

placebo] and the failure to truly assess the degree to which the double

blind may have been penetrated, this trial suggests that sertraline shows

little to no perceptible benefit compared with placebo in the treatment of

depressed youth. "

An unpublished letter by Dr. Jan Garland, Clinical Professor, Psychiatry

University of British Columbia and Clinical Head, Mood and Anxiety Disorders

Clinic BC's Children's Hospital appears below.

Letter to Editor, JAMA:

As one of the many investigators in various sites who was involved in the

Pfizer sertraline pediatric depression trials published in JAMA in August,

2003 (1), I was very concerned for a number of reasons about the data

analysis reported in this paper. The most striking feature was the pooling

of two trials which is not the orthodox way of handling trial data. The

pooled data, a sample size of 376 patients, showed a marginal superiority of

medication which is not likely to be clinically meaningful in terms of

risk/benefit balance. On selected improvement measures, only 10% more

patients improved on sertraline than on placebo, remission rates were not

different, and there were more discontinuations in the sertraline group due

to adverse effects including suicidality and aggression. Based on this

report, it appeared very likely that the individual trials were in fact

negative, but this possibility was not discussed by the authors. By pooling

the data, what might have been reported as two negative trials was instead

converted into one marginally positive trial with the conclusion that

“sertraline is an effective and well-tolerated short-term treatment for

children and adolescents with MDD”.

New information about these trials is now available. The recent review of

pediatric antidepressant trials by the British regulatory agency includes

the appropriate separate analysis of these two trials, and the summary

results are now in the public domain (2). >From this analysis, it is clear

that the two individual trials each of a good size (almost 190 patients) did

not demonstrate the effectiveness of sertraline in treating major depressive

disorder in children and adolescents. Hence, the correct conclusion from the

data reported by Wagner et al should be that " sertraline is ineffective when

compared to placebo and is associated with increased adverse effects " .

E. Jane Garland, M.D.

1. Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, et al. Efficacy of

Sertraline in the Treatment of Children and Adolescents With Major

Depressive Disorder: Two Randomized Controlled Trials JAMA.

2003;290:1033-1041.

2. Committee on Safety of Medicines. Medicines and Health Care Products

Regulatory Agency. Selective Serotonin Reuptake Inhibitors (SSRIs): overview

of regulatory status and CSM advice relating to major depressive disorder

(MDD) in children and adolescents: Summary of clinical trials

http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ssrio

verviewclintrialdata_101203.htm

_________________________________________________________________

There are now three new levels of MSN Hotmail Extra Storage! Learn more.

http://join.msn.com/?pgmarket=en-us & page=hotmail/es2 & ST=1