Re:[drugawareness] Psychiatric News-System Flawed Insuring Safety of All Drugs

July 17, 2004

Believe it or not reading the July 16 issue of

Psychiatric News is like reading my book on the

SSRI antidepressants!!!

The opening statement is explosive! Ready?

Here it is:

_______________________________

The ongoing controversy surrounding SSRIs in children

is now threatening the very foundations of clinical

drug research on the efficacy and safety of all of

the drugs physicians prescribe.

Physicians in the trenches are beginning to wonder

what exactly they really know— or perhaps don't

know— about the drugs they are prescribing and how

that knowledge base affects what is written on the

prescriptions that bear their signatures.

Many of the concerns raised recently have been

heard before. In this last year, however, they

have risen to a level that seriously challenges

physicians' comfort level with prescription drugs.

Particularly disconcerting are new allegations that

question the integrity of not only the scientific

evidence base, but also the system that produces

the data and the researchers who analyze it.

___________________________

FINALLY they are beginning to see the light!

Too bad we are not yet seeing that in reality.

Doctors are still blindly prescribing these drugs

at an alarming rate even to children. So get

this article out to as many professionals and

news media as possible in an effort to educate

more of them.

Then to see in print one of the strongest negative

statements yet on the dangers of SSRIs given to

children is very encouraging.

______________________________

" In discussing their own data, the authors of all

of the four larger studies have exaggerated the

benefits, downplayed the harms, or both, " Jureidini

and his coauthors wrote.

" Improvement in control groups is strong; additional

benefit from drugs is of doubtful clinical significance, "

they said, adding, " adverse effects have been down-

played. " They concluded that " antidepressant drugs

cannot confidently be recommended as a treatment

option for childhood depression. "

Jureidini and his coauthors pointed out that

" accurate trial reports are a foundation of good

medical care. It is vital that authors, reviewers,

and editors ensure that published interpretations

of data are more reasonable and balanced than is

the case in the industry-dominated literature on

childhood antidepressants. "

_________________________________________

Please allow me to repeat that conclusion for you:

" antidepressant drugs cannot confidently be

recommended as a treatment option for childhood

depression. "

This is what we have been saying all along. Why did

so many have to die before we saw this statement in

mainstream literature? And how long must we wait

to see the same statement for the adult population

as well?

Alos most interesting to note is the following

statement on what our doctors, in whom we place

so much trust, actually have access to in making

decisions about medications.

______________________________

In response to Laughren's comments, the government

official who asked not to be named said, " It is

not only possible that the FDA does not have all

the data, it is highly probable. "

Yet, Psychiatric News discovered that even if the

FDA possesses all of the relevant data on a particular

product, that data may not be easily accessible to

the medical community, researchers, the media, or

the public.

" Data become available only after an approval action, "

Laughren said, " and then only data that clinical and

statistical reviewers [at the FDA] decide to include

in their reviews [become part of the drug approval

package]. The original data sets are proprietary and

never available unless a sponsor decides to release

them. "

<A

HREF= " http://pn.psychiatryonline.org/cgi/content/full/39/14/1?maxtoshow=h

ttp://pn.psychiatryonline.org/cgi/content/full/39/14/1?maxtoshow= & HITS=20

&

hits=20 & RESULTFORMAT= & stored_search= & FIRSTINDEX=0 & tocsectionid=Profession

al* &

displaysectionid=Professional+News & journalcode=psychnews

Ann Blake , Ph.D.,

Executive Director, International Coalition For Drug Awareness

Author: Prozac: Panacea or Pandora? - Our Serotonin Nightmare

& audio tape on safe withdrawal: " Help! I Can't Get

Off My Antidepressant! "

Order Number: 800-280-0730

Website: www.drugawareness.org

_____________________________________________

Similar articles found in:

Psychiatric News

Download to Citation Manager

Psychiatric News July 16, 2004

Volume 39 Number 14

p. 1

Professional News

Clinical Trials Controversy Spotlights Flawed System

Jim ck

The ongoing controversy surrounding SSRIs in

children is now threatening the very foundations

of clinical drug research on the efficacy and

safety of all of the drugs physicians prescribe.

Under the frequent—and often hyperbolic—headlines

in major newspapers throughout the United States,

the debate on whether SSRIs really cause children

and adolescents to become suicidal has boiled down

to a critical realization: Physicians now face a

crisis of confidence in the American-bred system

that conducts clinical research and, it would seem,

publishes only the most marketable results.,

Physicians in the trenches are beginning to wonder

what exactly they really know— or perhaps don't know—

about the drugs they are prescribing and how that

knowledge base affects what is written on the

prescriptions that bear their signatures.

Many of the concerns raised recently have been heard

before. In this last year, however, they have risen

to a level that seriously challenges physicians'

comfort level with prescription drugs. Particularly

disconcerting are new allegations that question the

integrity of not only the scientific evidence base,

but also the system that produces the data and the

researchers who analyze it.

In April the British Medical Journal published a

paper by Jon Jureidini, M.D., head of the department

of psychological medicine at Women's and Children's

Hospital in North Adelaide, Australia, and colleagues.

The article reviewed the evidence base for efficacy

and safety of antidepressants in children and

adolescents. The authors included in their review

published clinical trials, as well as some unpublished

data made public by the U.K. Committee on Safety of

Medicines. At best, Jureidini's conclusions were

direct and to the point, but by some people's

estimation the conclusions seemed inflammatory, with

abundant references to the individuals who led the

research or wrote the articles, rather than to the

research methods, data analysis, or conclusions.

" In discussing their own data, the authors of all

of the four larger studies have exaggerated the

benefits, downplayed the harms, or both, " Jureidini

and his coauthors wrote.

" Improvement in control groups is strong; additional

benefit from drugs is of doubtful clinical significance, "

they said, adding, " adverse effects have been down-

played. " They concluded that " antidepressant drugs

cannot confidently be recommended as a treatment

option for childhood depression. "

Jureidini and his coauthors pointed out that " accurate

trial reports are a foundation of good medical care.

It is vital that authors, reviewers, and editors ensure

that published interpretations of data are more

reasonable and balanced than is the case in the industry-

dominated literature on childhood antidepressants. "

Jureidini listed a " competing interest " with the BMJ

study, noting he is the chair of Healthy Skepticism,

an international lobbying organization based in

Australia whose goal is " improving health by reducing

harm from inappropriate, misleading, or unethical

marketing of health products or services, especially

misleading pharmaceutical promotion. "

So, it was a bit unusual that an article in a major

peer-reviewed publication appeared to be directly

questioning the very integrity of the researchers who

had overseen clinical antidepressant trials. Many

researchers interviewed for this article saw it as

an unusually personal attack.

The researchers who took the brunt of the apparent

attack were the principal investigators and lead

authors of the trials in question: Graham Emslie, M.D.,

the E. and M. Seay Chair in Child

Psychiatry and professor of psychiatry in the Graduate

School of Biomedical Sciences at the University of

Texas Southwestern Medical Center at Dallas;

Keller, M.D., a professor of psychiatry and

human behavior at Brown University; and Dineen

Wagner, M.D., Ph.D., the Clarence Ross Professor

of Psychiatry and Behavioral Sciences and director of

child and adolescent psychiatry at the University of

Texas Medical Branch at Galveston

Emslie was the principal investigator on the fluoxetine

(Prozac) pediatric trials; Keller oversaw pediatric

clinical trials of paroxetine (Paxil); and Wagner was

the principal investigator on two sertraline (Zoloft)

pediatric clinical trials.

Two weeks after the BMJ article, Lancet published a

systematic review of SSRIs for childhood depression

that also compared published and unpublished data

from the same clinical trials that Jureidini analyzed.

Picking Through the Data

Tim Kendall, M.D., deputy director of the Royal College

of Psychiatry's Research Unit in London and co-author

on the Lancet article, talked with Psychiatric News

about the group's findings. Kendall explained that for

each antidepressant medication, the group analyzed

published clinical trial data separately from unpublished

data from U.K. regulatory authorities and found discrepancies.

" From the published data, we thought we might have

recommended some of these drugs, " Kendall said. " In

other words, the risk-benefit profile, in the main,

was favorable—not massively so, but at least modestly

so. " Then, he said, " we looked at the unpublished

data, and they clearly were not favorable. "

For example, Kendall said, the response data for

paroxetine looked better than for placebo, though

the difference was only modest (see chart). With

regard to adverse events, even in the published

data, there " was clearly a problem with the drug. "

When the group analyzed the unpublished data, the

findings shifted. For example, response rates were

significantly lower for paroxetine, and the placebo

effect was even more pronounced than it was in the

published data. This effectively narrowed the

difference between the two groups, voiding the

statistical significance. In addition, the adverse-

event picture, including the data on suicidal behavior,

looked more troubling.

When the researchers analyzed the published and

unpublished data together, the SSRI no longer held

a reasonable benefit for pediatric depression to

justify the apparent risks.

There was not a " massive difference " between " the

published stuff versus the unpublished, " Kendall

said, " but [the profile] certainly switches from a

favorable risk benefit profile to an unfavorable one. "

And with each of the SSRIs the researchers examined,

they found the same trend: the published data were

significantly more favorable than the data that had

not been peer reviewed.

Defining Context

Neither Keller nor Wagner responded to multiple

requests for interviews for this article; however,

Emslie agreed to an extended phone interview.

" Apart from the first Prozac trial and one of the

Paxil trials, all the rest of the data [in question]

arise from an act of Congress, not from the industry

wanting to do these studies, " Emslie told Psychiatric

News.

Indeed, the data on SSRI use in children largely

resulted from Food and Drug Administration (FDA)

requests to drug manufacturers issued through the

old " Pediatric Rule " —a regulation born from the

Food and Drug Administration Modernization Act of

1997 (FDAMA). However, FDAMA did not require that

studies be carried out and provided little if any

penalty for a company not agreeing to the FDA's

request. In essence, the Pediatric Rule gave companies'

an additional six months of patent protection for

conducting minimal research to collect data on safety

of a medication in pediatric populations. Under the

Rule, the FDA requested pediatric data from

manufacturers of the 100 top-selling medications

in the U.S.

Drug companies were slow to undertake pediatric

research, and the FDA's legal authority to mandate

pediatric clinical trials was challenged. Finally,

the Pediatric Rule was given the weight of law under

The Pediatric Research Equity Act of 2003 (PREA)

which left in place patent extension but further

defined the FDA's legal authority to mandate studies.

In addition, PREA required pediatric studies as part

of every application for approval of every drug—with

few exceptions—retroactive to include all applications

submitted since January 1, 1999.

However, between the Pediatric Rule and PREA, the

FDA began receiving pediatric data that did not

live up to the expectations of either Congress or

the FDA.

" Many of the companies simply threw together the

quickest, cheapest, easiest, clinical trial of their

drug in kids they possibly could, " said one government

official, a senior researcher who is familiar with the

situation and agreed to comment if not named.

" The companies pretty much knew from the outset that

they wouldn't get a full pediatric indication, and

the Pediatric Rule [initially] didn't really have

any stipulations that the data had to be good or

the methods solid. The rule simply said if they

submitted some data, they'd get their patent extended.

And that, simply, translated into dollars, " the official

explained.

Indeed, in many cases, the Pediatric Rule was directly

responsible for hundreds of millions of dollars in

additional sales of a branded product over the

six-month extension.

The official continued, " Data collection in these

studies was sloppy, recruitment was sloppy, the

statistics and methods were manipulated, and, of

course, only the positive studies were submitted.

Why would a drug company put out data that are

negative? That would amount to commercial suicide.

But what can you expect, really? Garbage in,

garbage out. "

Emslie agreed in part. " Getting all the positive

as well as the negative data " is an issue, he said.

But this is true for many different classes of

medications, " not just antidepressants, he said

(see box).

Wanted: All Relevant Data

The PREA was intended to ensure that the FDA was

given all the appropriate pediatric data, both

positive and negative, on a product so that an initial

approval decision could be made on the whole data set,

not just the most marketable data set.

The law includes language mandating that for any

application to the FDA for a " new active ingredient,

new indication, new dosage form, new dosing regimen,

or new route of administration, " the application

must include " data, gathered using appropriate

formulations for each age group... to assess the

safety and effectiveness of the drug or the biological

product for the claimed indications in all relevant

pediatric subpopulations [and data to] support dosing

and administration for each pediatric subpopulation

for which the drug or biological product is safe and

effective. "

If a drug maker fails to submit all of the data,

the drug could be declared " misbranded solely because

of that failure and subject to relevant enforcement

action. "

Yet the FDA acknowledges that even today—a year and

a half after the PREA went into effect—the agency

isn't sure whether it has all the data it's supposed

to have on the medications submitted under PREA's

requirements.

" I'm not aware of any standard mechanism in place

for assuring that all pertinent data have been

submitted, " Laughren, M.D., medical team

leader of the FDA's Neuropharmacological Drug Products

division, told Psychiatric News. " It depends mostly

on the review team being aware of what has been done. "

Nonetheless, Laughren was not aware of any instance

in which a company was found to have purposefully

withheld data from the agency.

In response to Laughren's comments, the government

official who asked not to be named said, " It is not

only possible that the FDA does not have all the

data, it is highly probable. "

Yet, Psychiatric News discovered that even if the FDA

possesses all of the relevant data on a particular

product, that data may not be easily accessible to the

medical community, researchers, the media, or the public.

" Data become available only after an approval action, "

Laughren said, " and then only data that clinical and

statistical reviewers [at the FDA] decide to include

in their reviews [become part of the drug approval

package]. The original data sets are proprietary and

never available unless a sponsor decides to release them. "

The FDA has attempted with some success to increase

access to the information by posting a large amount

of summary data on its Web site under an " Approvals "

section.

If someone is looking for data not posted on the FDA's

Web site, the person must file a Freedom of Information

Act (FOIA) request. Over the last year, in the course

of this ongoing investigative report, Psychiatric News

filed FOIA requests for " all approval package documents

[and] their attachments and appendices " for each of the

antidepressant medications being questioned. To date, a

large amount of data has been received in response to

those requests.

Over the last several months, several SSRI manufacturers

have been accused in the media of attempting to " bury or

hide " negative study data. The increasingly heated issue

led the AMA, at the request of APA and the American

Academy of Child and Adolescent Psychiatry, to advocate

for a mandatory, federally administrated, clinical trials

registry (see page 1). Separately, a large group of

medical journal editors called for the same thing.

In the meantime, GlaxoKline announced it would

create its own registry and publicly post it on its

Web site. At the same time the company posted summary

data from all of its pediatric paroxetine studies,

the majority of which had never been made public.

Shortly thereafter, Merck announced it would support

such a clinical trials register, and Forest Labs

released pediatric data on both citalopram and

escitalopram. In Washington, D.C., several senators

and representatives called for legislation establishing

a mandatory registry for all clinical research, even

though FDAMA already contains an obscure requirement

that all trials be registered.

Comparing Apples and Oranges

The most significant issue facing regulators and

researchers in attempting to analyze the safety

and effectiveness of SSRIs in pediatric populations

is the extreme variability between and within the

studies (see chart on page 1).

" First of all, some of these [pediatric antidepressant]

studies were conducted in Europe, some in America, "

Arif Khan, M.D., pointed out. Khan is medical director

at the Northwest Clinical Research Center in Bellevue,

Wash., and was involved in conducting or reviewing many

of the studies now in question. " The conduct of American

trials by American psychiatrists is a situation that is

entirely different from European trials conducted by

psychiatrists there. "

Some differences in these studies, Khan told

Psychiatric News, include differences in the studies'

methodology, populations, and data assessment, and may

not be directly comparable.

" Some of the European studies had an overabundance

of adolescent girls in the drug groups versus the

placebo groups, " Khan said as an example. " The

randomization wasn't even. "

Emslie echoed this same point, adding that he suspects

that most subjects in the European trials had mild to

moderate depression, rather than severe depression.

Significant evidence in adult populations indicates

that SSRIs are not very effective for mild to moderate

adult depression. Thus, Emslie asked, " why would they

work for mild or moderate depression in kids? "

In addition, many methodological differences exist

among the studies in the number of sites used and the

number of researchers involved, the protocols for

assessment and randomization into the study, and the

statistical analyses of the resulting data.

" You have an extremely heterogeneous group of trials

using differing definitions and assessments on

differing study populations and different analyses, "

Khan said. " So obviously any comparisons are going

to be questionable. "

Experts consulted by Psychiatric News agreed that

meta-analyses and overall reviews of the two dozen

or so pediatric antidepressant clinical trials may

never reach any reliable conclusions about efficacy

and safety of SSRIs in pediatric populations.

" The FDA and the Columbia University group may not

come up with any solid answers, " Khan suggested,

referring to the group of suicidality experts

contracted by the FDA to reanalyze the SSRIs'

adverse-effect profiles. " What you see is that

this suicidal behavior in the placebo group runs

anywhere from 0.6 percent to just under 5 percent.

In the drug groups it runs from a low of just under

3 percent to a high of 8 percent. There's a lot of

variability, but in general the pattern holds true.

There is a fairly clear trend in increased risk in

the drug groups versus the placebo groups, regardless

of which drug you are looking at. "

Common Ground Sought

That trend does have one exception: fluoxetine.

It is the only antidepressant whose data were

strong enough to have won FDA approval for the

treatment of pediatric depression. Most of the

experts interviewed for this article, including

Khan and Kendall, agreed that the published and

unpublished data on fluoxetine's effectiveness

and safety in children and adolescents show that

the drug provides significant clinical improvement

and has not been as closely associated with the

harmful and suicidal behaviors of other SSRIs

in children.

Emslie— " the father of pediatric Prozac " —can't be

sure why fluoxetine is different from the other SSRIs.

" First of all, with respect to efficacy, you have

to ask whether or not it really is any better than

the other SSRIs, " Emslie said. " But no controlled

head-to-head studies have been done in children and

adolescents. So it could be methodological differences.

We did those studies early on [in the evolution of

SSRI pediatric clinical trials], and maybe we did

something better with respect to study population or

had better quality sites with better investigators.

As far as safety is concerned, it may be that the

drug is better tolerated on some level, and I

certainly think that dosing is probably easier with

fluoxetine. "

The FDA expects to schedule a second advisory committee

meeting on the issue as soon as it receives the

reanalysis from the Columbia University group. The

report had been expected in early July, but as this

article went to press, neither the agency nor the

university indicated that the release of the report

was imminent.

So for those clinicians who continue to question their

confidence in SSRI prescriptions for children and

adolescents, there is no immediate resolution in sight.

" We really don't know anything different today than

we did five years ago, " Khan said. " What we have is

a mixture of trial results that generally favor the

active drug. The trials certainly do not favor placebo,

and it is important that that is understood. Failed

trials don't necessarily mean that a drug does not

work. "

Emslie echoed Khan's statement, adding that " it's

really a question of how do these clinical trials

inform us about clinical guidelines for care. I

think they inform us that generally the SSRIs are

probably effective— the data are largely ambiguous,

but certainly not negative. But every medication

[requires] a risk-benefit analysis. "

Khan added, " As long as the patient and the clinician

understand what the risk profile is, I think it is

very appropriate to prescribe [sSRIs]. "

The individuals interviewed by Psychiatric News

agreed on at least one point: " We've really got

to get this right, " Kendall said. " The whole

clinical and scientific community, as well as

regulators and the public, need to be involved

in assuring that we do get it right. Our patients

deserve nothing less. "

An abstract of the Lancet article, " Selective

Serotonin Reuptake Inhibitors in Childhood Depression:

Systematic Review of Published Versus Unpublished

Data, " is posted online at:

<

www.thelancet.com/journal/vol363/iss9418/abs/llan.363.9418.original_resea

rch.29377.1 >.

The BMJ article, " Efficacy and Safety of Antidepressants

for Children and Adolescents, " is posted at:

< http://bmj.bmjjournals.com/cgi/content/full/328/7444/879 >.

BMJ 2004 328 879

[Free Full Text]

========

..

July 17, 2004

Believe it or not reading the July 16 issue of

Psychiatric News is like reading my book on the

SSRI antidepressants!!!

The opening statement is explosive! Ready?

Here it is:

_______________________________

The ongoing controversy surrounding SSRIs in children

is now threatening the very foundations of clinical

drug research on the efficacy and safety of all of

the drugs physicians prescribe.

Physicians in the trenches are beginning to wonder

what exactly they really know— or perhaps don't

know— about the drugs they are prescribing and how

that knowledge base affects what is written on the

prescriptions that bear their signatures.

Many of the concerns raised recently have been

heard before. In this last year, however, they

have risen to a level that seriously challenges

physicians' comfort level with prescription drugs.

Particularly disconcerting are new allegations that

question the integrity of not only the scientific

evidence base, but also the system that produces

the data and the researchers who analyze it.

___________________________

FINALLY they are beginning to see the light!

Too bad we are not yet seeing that in reality.

Doctors are still blindly prescribing these drugs

at an alarming rate even to children. So get

this article out to as many professionals and

news media as possible in an effort to educate

more of them.

Then to see in print one of the strongest negative

statements yet on the dangers of SSRIs given to

children is very encouraging.

______________________________

" In discussing their own data, the authors of all

of the four larger studies have exaggerated the

benefits, downplayed the harms, or both, " Jureidini

and his coauthors wrote.

" Improvement in control groups is strong; additional

benefit from drugs is of doubtful clinical significance, "

they said, adding, " adverse effects have been down-

played. " They concluded that " antidepressant drugs

cannot confidently be recommended as a treatment

option for childhood depression. "

Jureidini and his coauthors pointed out that

" accurate trial reports are a foundation of good

medical care. It is vital that authors, reviewers,

and editors ensure that published interpretations

of data are more reasonable and balanced than is

the case in the industry-dominated literature on

childhood antidepressants. "

_________________________________________

Please allow me to repeat that conclusion for you:

" antidepressant drugs cannot confidently be

recommended as a treatment option for childhood

depression. "

This is what we have been saying all along. Why did

so many have to die before we saw this statement in

mainstream literature? And how long must we wait

to see the same statement for the adult population

as well?

Alos most interesting to note is the following

statement on what our doctors, in whom we place

so much trust, actually have access to in making

decisions about medications.

______________________________

In response to Laughren's comments, the government

official who asked not to be named said, " It is

not only possible that the FDA does not have all

the data, it is highly probable. "

Yet, Psychiatric News discovered that even if the

FDA possesses all of the relevant data on a particular

product, that data may not be easily accessible to

the medical community, researchers, the media, or

the public.

" Data become available only after an approval action, "

Laughren said, " and then only data that clinical and

statistical reviewers [at the FDA] decide to include

in their reviews [become part of the drug approval

package]. The original data sets are proprietary and

never available unless a sponsor decides to release

them. "

<A

HREF= " http://pn.psychiatryonline.org/cgi/content/full/39/14/1?maxtoshow=h

ttp://pn.psychiatryonline.org/cgi/content/full/39/14/1?maxtoshow= & HITS=20

&

hits=20 & RESULTFORMAT= & stored_search= & FIRSTINDEX=0 & tocsectionid=Profession

al* &

displaysectionid=Professional+News & journalcode=psychnews

Ann Blake , Ph.D.,

Executive Director, International Coalition For Drug Awareness

Author: Prozac: Panacea or Pandora? - Our Serotonin Nightmare

& audio tape on safe withdrawal: " Help! I Can't Get

Off My Antidepressant! "

Order Number: 800-280-0730

Website: www.drugawareness.org

_____________________________________________

Similar articles found in:

Psychiatric News

Download to Citation Manager

Psychiatric News July 16, 2004

Volume 39 Number 14

p. 1

Professional News

Clinical Trials Controversy Spotlights Flawed System

Jim ck

The ongoing controversy surrounding SSRIs in

children is now threatening the very foundations

of clinical drug research on the efficacy and

safety of all of the drugs physicians prescribe.

Under the frequent—and often hyperbolic—headlines

in major newspapers throughout the United States,

the debate on whether SSRIs really cause children

and adolescents to become suicidal has boiled down

to a critical realization: Physicians now face a

crisis of confidence in the American-bred system

that conducts clinical research and, it would seem,

publishes only the most marketable results.,

Physicians in the trenches are beginning to wonder

what exactly they really know— or perhaps don't know—

about the drugs they are prescribing and how that

knowledge base affects what is written on the

prescriptions that bear their signatures.

Many of the concerns raised recently have been heard

before. In this last year, however, they have risen

to a level that seriously challenges physicians'

comfort level with prescription drugs. Particularly

disconcerting are new allegations that question the

integrity of not only the scientific evidence base,

but also the system that produces the data and the

researchers who analyze it.

In April the British Medical Journal published a

paper by Jon Jureidini, M.D., head of the department

of psychological medicine at Women's and Children's

Hospital in North Adelaide, Australia, and colleagues.

The article reviewed the evidence base for efficacy

and safety of antidepressants in children and

adolescents. The authors included in their review

published clinical trials, as well as some unpublished

data made public by the U.K. Committee on Safety of

Medicines. At best, Jureidini's conclusions were

direct and to the point, but by some people's

estimation the conclusions seemed inflammatory, with

abundant references to the individuals who led the

research or wrote the articles, rather than to the

research methods, data analysis, or conclusions.

" In discussing their own data, the authors of all

of the four larger studies have exaggerated the

benefits, downplayed the harms, or both, " Jureidini

and his coauthors wrote.

" Improvement in control groups is strong; additional

benefit from drugs is of doubtful clinical significance, "

they said, adding, " adverse effects have been down-

played. " They concluded that " antidepressant drugs

cannot confidently be recommended as a treatment

option for childhood depression. "

Jureidini and his coauthors pointed out that " accurate

trial reports are a foundation of good medical care.

It is vital that authors, reviewers, and editors ensure

that published interpretations of data are more

reasonable and balanced than is the case in the industry-

dominated literature on childhood antidepressants. "

Jureidini listed a " competing interest " with the BMJ

study, noting he is the chair of Healthy Skepticism,

an international lobbying organization based in

Australia whose goal is " improving health by reducing

harm from inappropriate, misleading, or unethical

marketing of health products or services, especially

misleading pharmaceutical promotion. "

So, it was a bit unusual that an article in a major

peer-reviewed publication appeared to be directly

questioning the very integrity of the researchers who

had overseen clinical antidepressant trials. Many

researchers interviewed for this article saw it as

an unusually personal attack.

The researchers who took the brunt of the apparent

attack were the principal investigators and lead

authors of the trials in question: Graham Emslie, M.D.,

the E. and M. Seay Chair in Child

Psychiatry and professor of psychiatry in the Graduate

School of Biomedical Sciences at the University of

Texas Southwestern Medical Center at Dallas;

Keller, M.D., a professor of psychiatry and

human behavior at Brown University; and Dineen

Wagner, M.D., Ph.D., the Clarence Ross Professor

of Psychiatry and Behavioral Sciences and director of

child and adolescent psychiatry at the University of

Texas Medical Branch at Galveston

Emslie was the principal investigator on the fluoxetine

(Prozac) pediatric trials; Keller oversaw pediatric

clinical trials of paroxetine (Paxil); and Wagner was

the principal investigator on two sertraline (Zoloft)

pediatric clinical trials.

Two weeks after the BMJ article, Lancet published a

systematic review of SSRIs for childhood depression

that also compared published and unpublished data

from the same clinical trials that Jureidini analyzed.

Picking Through the Data

Tim Kendall, M.D., deputy director of the Royal College

of Psychiatry's Research Unit in London and co-author

on the Lancet article, talked with Psychiatric News

about the group's findings. Kendall explained that for

each antidepressant medication, the group analyzed

published clinical trial data separately from unpublished

data from U.K. regulatory authorities and found discrepancies.

" From the published data, we thought we might have

recommended some of these drugs, " Kendall said. " In

other words, the risk-benefit profile, in the main,

was favorable—not massively so, but at least modestly

so. " Then, he said, " we looked at the unpublished

data, and they clearly were not favorable. "

For example, Kendall said, the response data for

paroxetine looked better than for placebo, though

the difference was only modest (see chart). With

regard to adverse events, even in the published

data, there " was clearly a problem with the drug. "

When the group analyzed the unpublished data, the

findings shifted. For example, response rates were

significantly lower for paroxetine, and the placebo

effect was even more pronounced than it was in the

published data. This effectively narrowed the

difference between the two groups, voiding the

statistical significance. In addition, the adverse-

event picture, including the data on suicidal behavior,

looked more troubling.

When the researchers analyzed the published and

unpublished data together, the SSRI no longer held

a reasonable benefit for pediatric depression to

justify the apparent risks.

There was not a " massive difference " between " the

published stuff versus the unpublished, " Kendall

said, " but [the profile] certainly switches from a

favorable risk benefit profile to an unfavorable one. "

And with each of the SSRIs the researchers examined,

they found the same trend: the published data were

significantly more favorable than the data that had

not been peer reviewed.

Defining Context

Neither Keller nor Wagner responded to multiple

requests for interviews for this article; however,

Emslie agreed to an extended phone interview.

" Apart from the first Prozac trial and one of the

Paxil trials, all the rest of the data [in question]

arise from an act of Congress, not from the industry

wanting to do these studies, " Emslie told Psychiatric

News.

Indeed, the data on SSRI use in children largely

resulted from Food and Drug Administration (FDA)

requests to drug manufacturers issued through the

old " Pediatric Rule " —a regulation born from the

Food and Drug Administration Modernization Act of

1997 (FDAMA). However, FDAMA did not require that

studies be carried out and provided little if any

penalty for a company not agreeing to the FDA's

request. In essence, the Pediatric Rule gave companies'

an additional six months of patent protection for

conducting minimal research to collect data on safety

of a medication in pediatric populations. Under the

Rule, the FDA requested pediatric data from

manufacturers of the 100 top-selling medications

in the U.S.

Drug companies were slow to undertake pediatric

research, and the FDA's legal authority to mandate

pediatric clinical trials was challenged. Finally,

the Pediatric Rule was given the weight of law under

The Pediatric Research Equity Act of 2003 (PREA)

which left in place patent extension but further

defined the FDA's legal authority to mandate studies.

In addition, PREA required pediatric studies as part

of every application for approval of every drug—with

few exceptions—retroactive to include all applications

submitted since January 1, 1999.

However, between the Pediatric Rule and PREA, the

FDA began receiving pediatric data that did not

live up to the expectations of either Congress or

the FDA.

" Many of the companies simply threw together the

quickest, cheapest, easiest, clinical trial of their

drug in kids they possibly could, " said one government

official, a senior researcher who is familiar with the

situation and agreed to comment if not named.

" The companies pretty much knew from the outset that

they wouldn't get a full pediatric indication, and

the Pediatric Rule [initially] didn't really have

any stipulations that the data had to be good or

the methods solid. The rule simply said if they

submitted some data, they'd get their patent extended.

And that, simply, translated into dollars, " the official

explained.

Indeed, in many cases, the Pediatric Rule was directly

responsible for hundreds of millions of dollars in

additional sales of a branded product over the

six-month extension.

The official continued, " Data collection in these

studies was sloppy, recruitment was sloppy, the

statistics and methods were manipulated, and, of

course, only the positive studies were submitted.

Why would a drug company put out data that are

negative? That would amount to commercial suicide.

But what can you expect, really? Garbage in,

garbage out. "

Emslie agreed in part. " Getting all the positive

as well as the negative data " is an issue, he said.

But this is true for many different classes of

medications, " not just antidepressants, he said

(see box).

Wanted: All Relevant Data

The PREA was intended to ensure that the FDA was

given all the appropriate pediatric data, both

positive and negative, on a product so that an initial

approval decision could be made on the whole data set,

not just the most marketable data set.

The law includes language mandating that for any

application to the FDA for a " new active ingredient,

new indication, new dosage form, new dosing regimen,

or new route of administration, " the application

must include " data, gathered using appropriate

formulations for each age group... to assess the

safety and effectiveness of the drug or the biological

product for the claimed indications in all relevant

pediatric subpopulations [and data to] support dosing

and administration for each pediatric subpopulation

for which the drug or biological product is safe and

effective. "

If a drug maker fails to submit all of the data,

the drug could be declared " misbranded solely because

of that failure and subject to relevant enforcement

action. "

Yet the FDA acknowledges that even today—a year and

a half after the PREA went into effect—the agency

isn't sure whether it has all the data it's supposed

to have on the medications submitted under PREA's

requirements.

" I'm not aware of any standard mechanism in place

for assuring that all pertinent data have been

submitted, " Laughren, M.D., medical team

leader of the FDA's Neuropharmacological Drug Products

division, told Psychiatric News. " It depends mostly

on the review team being aware of what has been done. "

Nonetheless, Laughren was not aware of any instance

in which a company was found to have purposefully

withheld data from the agency.

In response to Laughren's comments, the government

official who asked not to be named said, " It is not

only possible that the FDA does not have all the

data, it is highly probable. "

Yet, Psychiatric News discovered that even if the FDA

possesses all of the relevant data on a particular

product, that data may not be easily accessible to the

medical community, researchers, the media, or the public.

" Data become available only after an approval action, "

Laughren said, " and then only data that clinical and

statistical reviewers [at the FDA] decide to include

in their reviews [become part of the drug approval

package]. The original data sets are proprietary and

never available unless a sponsor decides to release them. "

The FDA has attempted with some success to increase

access to the information by posting a large amount

of summary data on its Web site under an " Approvals "

section.

If someone is looking for data not posted on the FDA's

Web site, the person must file a Freedom of Information

Act (FOIA) request. Over the last year, in the course

of this ongoing investigative report, Psychiatric News

filed FOIA requests for " all approval package documents

[and] their attachments and appendices " for each of the

antidepressant medications being questioned. To date, a

large amount of data has been received in response to

those requests.

Over the last several months, several SSRI manufacturers

have been accused in the media of attempting to " bury or

hide " negative study data. The increasingly heated issue

led the AMA, at the request of APA and the American

Academy of Child and Adolescent Psychiatry, to advocate

for a mandatory, federally administrated, clinical trials

registry (see page 1). Separately, a large group of

medical journal editors called for the same thing.

In the meantime, GlaxoKline announced it would

create its own registry and publicly post it on its

Web site. At the same time the company posted summary

data from all of its pediatric paroxetine studies,

the majority of which had never been made public.

Shortly thereafter, Merck announced it would support

such a clinical trials register, and Forest Labs

released pediatric data on both citalopram and

escitalopram. In Washington, D.C., several senators

and representatives called for legislation establishing

a mandatory registry for all clinical research, even

though FDAMA already contains an obscure requirement

that all trials be registered.

Comparing Apples and Oranges

The most significant issue facing regulators and

researchers in attempting to analyze the safety

and effectiveness of SSRIs in pediatric populations

is the extreme variability between and within the

studies (see chart on page 1).

" First of all, some of these [pediatric antidepressant]

studies were conducted in Europe, some in America, "

Arif Khan, M.D., pointed out. Khan is medical director

at the Northwest Clinical Research Center in Bellevue,

Wash., and was involved in conducting or reviewing many

of the studies now in question. " The conduct of American

trials by American psychiatrists is a situation that is

entirely different from European trials conducted by

psychiatrists there. "

Some differences in these studies, Khan told

Psychiatric News, include differences in the studies'

methodology, populations, and data assessment, and may

not be directly comparable.

" Some of the European studies had an overabundance

of adolescent girls in the drug groups versus the

placebo groups, " Khan said as an example. " The

randomization wasn't even. "

Emslie echoed this same point, adding that he suspects

that most subjects in the European trials had mild to

moderate depression, rather than severe depression.

Significant evidence in adult populations indicates

that SSRIs are not very effective for mild to moderate

adult depression. Thus, Emslie asked, " why would they

work for mild or moderate depression in kids? "

In addition, many methodological differences exist

among the studies in the number of sites used and the

number of researchers involved, the protocols for

assessment and randomization into the study, and the

statistical analyses of the resulting data.

" You have an extremely heterogeneous group of trials

using differing definitions and assessments on

differing study populations and different analyses, "

Khan said. " So obviously any comparisons are going

to be questionable. "

Experts consulted by Psychiatric News agreed that

meta-analyses and overall reviews of the two dozen

or so pediatric antidepressant clinical trials may

never reach any reliable conclusions about efficacy

and safety of SSRIs in pediatric populations.

" The FDA and the Columbia University group may not

come up with any solid answers, " Khan suggested,

referring to the group of suicidality experts

contracted by the FDA to reanalyze the SSRIs'

adverse-effect profiles. " What you see is that

this suicidal behavior in the placebo group runs

anywhere from 0.6 percent to just under 5 percent.

In the drug groups it runs from a low of just under

3 percent to a high of 8 percent. There's a lot of

variability, but in general the pattern holds true.

There is a fairly clear trend in increased risk in

the drug groups versus the placebo groups, regardless

of which drug you are looking at. "

Common Ground Sought

That trend does have one exception: fluoxetine.

It is the only antidepressant whose data were

strong enough to have won FDA approval for the

treatment of pediatric depression. Most of the

experts interviewed for this article, including

Khan and Kendall, agreed that the published and

unpublished data on fluoxetine's effectiveness

and safety in children and adolescents show that

the drug provides significant clinical improvement

and has not been as closely associated with the

harmful and suicidal behaviors of other SSRIs

in children.

Emslie— " the father of pediatric Prozac " —can't be

sure why fluoxetine is different from the other SSRIs.

" First of all, with respect to efficacy, you have

to ask whether or not it really is any better than

the other SSRIs, " Emslie said. " But no controlled

head-to-head studies have been done in children and

adolescents. So it could be methodological differences.

We did those studies early on [in the evolution of

SSRI pediatric clinical trials], and maybe we did

something better with respect to study population or

had better quality sites with better investigators.

As far as safety is concerned, it may be that the

drug is better tolerated on some level, and I

certainly think that dosing is probably easier with

fluoxetine. "

The FDA expects to schedule a second advisory committee

meeting on the issue as soon as it receives the

reanalysis from the Columbia University group. The

report had been expected in early July, but as this

article went to press, neither the agency nor the

university indicated that the release of the report

was imminent.

So for those clinicians who continue to question their

confidence in SSRI prescriptions for children and

adolescents, there is no immediate resolution in sight.

" We really don't know anything different today than

we did five years ago, " Khan said. " What we have is

a mixture of trial results that generally favor the

active drug. The trials certainly do not favor placebo,

and it is important that that is understood. Failed

trials don't necessarily mean that a drug does not

work. "

Emslie echoed Khan's statement, adding that " it's

really a question of how do these clinical trials

inform us about clinical guidelines for care. I

think they inform us that generally the SSRIs are

probably effective— the data are largely ambiguous,

but certainly not negative. But every medication

[requires] a risk-benefit analysis. "

Khan added, " As long as the patient and the clinician

understand what the risk profile is, I think it is

very appropriate to prescribe [sSRIs]. "

The individuals interviewed by Psychiatric News

agreed on at least one point: " We've really got

to get this right, " Kendall said. " The whole

clinical and scientific community, as well as

regulators and the public, need to be involved

in assuring that we do get it right. Our patients

deserve nothing less. "

An abstract of the Lancet article, " Selective

Serotonin Reuptake Inhibitors in Childhood Depression:

Systematic Review of Published Versus Unpublished

Data, " is posted online at:

<

www.thelancet.com/journal/vol363/iss9418/abs/llan.363.9418.original_resea

rch.29377.1 >.

The BMJ article, " Efficacy and Safety of Antidepressants

for Children and Adolescents, " is posted at:

< http://bmj.bmjjournals.com/cgi/content/full/328/7444/879 >.

BMJ 2004 328 879

[Free Full Text]

========

..

July 17, 2004

Believe it or not reading the July 16 issue of

Psychiatric News is like reading my book on the

SSRI antidepressants!!!

The opening statement is explosive! Ready?

Here it is:

_______________________________

The ongoing controversy surrounding SSRIs in children

is now threatening the very foundations of clinical

drug research on the efficacy and safety of all of

the drugs physicians prescribe.

Physicians in the trenches are beginning to wonder

what exactly they really know— or perhaps don't

know— about the drugs they are prescribing and how

that knowledge base affects what is written on the

prescriptions that bear their signatures.

Many of the concerns raised recently have been

heard before. In this last year, however, they

have risen to a level that seriously challenges

physicians' comfort level with prescription drugs.

Particularly disconcerting are new allegations that

question the integrity of not only the scientific

evidence base, but also the system that produces

the data and the researchers who analyze it.

___________________________

FINALLY they are beginning to see the light!

Too bad we are not yet seeing that in reality.

Doctors are still blindly prescribing these drugs

at an alarming rate even to children. So get

this article out to as many professionals and

news media as possible in an effort to educate

more of them.

Then to see in print one of the strongest negative

statements yet on the dangers of SSRIs given to

children is very encouraging.

______________________________

" In discussing their own data, the authors of all

of the four larger studies have exaggerated the

benefits, downplayed the harms, or both, " Jureidini

and his coauthors wrote.

" Improvement in control groups is strong; additional

benefit from drugs is of doubtful clinical significance, "

they said, adding, " adverse effects have been down-

played. " They concluded that " antidepressant drugs

cannot confidently be recommended as a treatment

option for childhood depression. "

Jureidini and his coauthors pointed out that

" accurate trial reports are a foundation of good

medical care. It is vital that authors, reviewers,

and editors ensure that published interpretations

of data are more reasonable and balanced than is

the case in the industry-dominated literature on

childhood antidepressants. "

_________________________________________

Please allow me to repeat that conclusion for you:

" antidepressant drugs cannot confidently be

recommended as a treatment option for childhood

depression. "

This is what we have been saying all along. Why did

so many have to die before we saw this statement in

mainstream literature? And how long must we wait

to see the same statement for the adult population

as well?

Alos most interesting to note is the following

statement on what our doctors, in whom we place

so much trust, actually have access to in making

decisions about medications.

______________________________

In response to Laughren's comments, the government

official who asked not to be named said, " It is

not only possible that the FDA does not have all

the data, it is highly probable. "

Yet, Psychiatric News discovered that even if the

FDA possesses all of the relevant data on a particular

product, that data may not be easily accessible to

the medical community, researchers, the media, or

the public.

" Data become available only after an approval action, "

Laughren said, " and then only data that clinical and

statistical reviewers [at the FDA] decide to include

in their reviews [become part of the drug approval

package]. The original data sets are proprietary and

never available unless a sponsor decides to release

them. "

<A

HREF= " http://pn.psychiatryonline.org/cgi/content/full/39/14/1?maxtoshow=h

ttp://pn.psychiatryonline.org/cgi/content/full/39/14/1?maxtoshow= & HITS=20

&

hits=20 & RESULTFORMAT= & stored_search= & FIRSTINDEX=0 & tocsectionid=Profession

al* &

displaysectionid=Professional+News & journalcode=psychnews

Ann Blake , Ph.D.,

Executive Director, International Coalition For Drug Awareness

Author: Prozac: Panacea or Pandora? - Our Serotonin Nightmare

& audio tape on safe withdrawal: " Help! I Can't Get

Off My Antidepressant! "

Order Number: 800-280-0730

Website: www.drugawareness.org

_____________________________________________

Similar articles found in:

Psychiatric News

Download to Citation Manager

Psychiatric News July 16, 2004

Volume 39 Number 14

p. 1

Professional News

Clinical Trials Controversy Spotlights Flawed System

Jim ck

The ongoing controversy surrounding SSRIs in

children is now threatening the very foundations

of clinical drug research on the efficacy and

safety of all of the drugs physicians prescribe.

Under the frequent—and often hyperbolic—headlines

in major newspapers throughout the United States,

the debate on whether SSRIs really cause children

and adolescents to become suicidal has boiled down

to a critical realization: Physicians now face a

crisis of confidence in the American-bred system

that conducts clinical research and, it would seem,

publishes only the most marketable results.,

Physicians in the trenches are beginning to wonder

what exactly they really know— or perhaps don't know—

about the drugs they are prescribing and how that

knowledge base affects what is written on the

prescriptions that bear their signatures.

Many of the concerns raised recently have been heard

before. In this last year, however, they have risen

to a level that seriously challenges physicians'

comfort level with prescription drugs. Particularly

disconcerting are new allegations that question the

integrity of not only the scientific evidence base,

but also the system that produces the data and the

researchers who analyze it.

In April the British Medical Journal published a

paper by Jon Jureidini, M.D., head of the department

of psychological medicine at Women's and Children's

Hospital in North Adelaide, Australia, and colleagues.

The article reviewed the evidence base for efficacy

and safety of antidepressants in children and

adolescents. The authors included in their review

published clinical trials, as well as some unpublished

data made public by the U.K. Committee on Safety of

Medicines. At best, Jureidini's conclusions were

direct and to the point, but by some people's

estimation the conclusions seemed inflammatory, with

abundant references to the individuals who led the

research or wrote the articles, rather than to the

research methods, data analysis, or conclusions.

" In discussing their own data, the authors of all

of the four larger studies have exaggerated the

benefits, downplayed the harms, or both, " Jureidini

and his coauthors wrote.

" Improvement in control groups is strong; additional

benefit from drugs is of doubtful clinical significance, "

they said, adding, " adverse effects have been down-

played. " They concluded that " antidepressant drugs

cannot confidently be recommended as a treatment

option for childhood depression. "

Jureidini and his coauthors pointed out that " accurate

trial reports are a foundation of good medical care.

It is vital that authors, reviewers, and editors ensure

that published interpretations of data are more

reasonable and balanced than is the case in the industry-

dominated literature on childhood antidepressants. "

Jureidini listed a " competing interest " with the BMJ

study, noting he is the chair of Healthy Skepticism,

an international lobbying organization based in

Australia whose goal is " improving health by reducing

harm from inappropriate, misleading, or unethical

marketing of health products or services, especially

misleading pharmaceutical promotion. "

So, it was a bit unusual that an article in a major

peer-reviewed publication appeared to be directly

questioning the very integrity of the researchers who

had overseen clinical antidepressant trials. Many

researchers interviewed for this article saw it as

an unusually personal attack.

The researchers who took the brunt of the apparent

attack were the principal investigators and lead

authors of the trials in question: Graham Emslie, M.D.,

the E. and M. Seay Chair in Child

Psychiatry and professor of psychiatry in the Graduate

School of Biomedical Sciences at the University of

Texas Southwestern Medical Center at Dallas;

Keller, M.D., a professor of psychiatry and

human behavior at Brown University; and Dineen

Wagner, M.D., Ph.D., the Clarence Ross Professor

of Psychiatry and Behavioral Sciences and director of

child and adolescent psychiatry at the University of

Texas Medical Branch at Galveston

Emslie was the principal investigator on the fluoxetine

(Prozac) pediatric trials; Keller oversaw pediatric

clinical trials of paroxetine (Paxil); and Wagner was

the principal investigator on two sertraline (Zoloft)

pediatric clinical trials.

Two weeks after the BMJ article, Lancet published a

systematic review of SSRIs for childhood depression

that also compared published and unpublished data

from the same clinical trials that Jureidini analyzed.

Picking Through the Data

Tim Kendall, M.D., deputy director of the Royal College

of Psychiatry's Research Unit in London and co-author

on the Lancet article, talked with Psychiatric News

about the group's findings. Kendall explained that for

each antidepressant medication, the group analyzed

published clinical trial data separately from unpublished

data from U.K. regulatory authorities and found discrepancies.

" From the published data, we thought we might have

recommended some of these drugs, " Kendall said. " In

other words, the risk-benefit profile, in the main,

was favorable—not massively so, but at least modestly

so. " Then, he said, " we looked at the unpublished

data, and they clearly were not favorable. "

For example, Kendall said, the response data for

paroxetine looked better than for placebo, though

the difference was only modest (see chart). With

regard to adverse events, even in the published

data, there " was clearly a problem with the drug. "

When the group analyzed the unpublished data, the

findings shifted. For example, response rates were

significantly lower for paroxetine, and the placebo

effect was even more pronounced than it was in the

published data. This effectively narrowed the

difference between the two groups, voiding the

statistical significance. In addition, the adverse-

event picture, including the data on suicidal behavior,

looked more troubling.

When the researchers analyzed the published and

unpublished data together, the SSRI no longer held

a reasonable benefit for pediatric depression to

justify the apparent risks.

There was not a " massive difference " between " the

published stuff versus the unpublished, " Kendall

said, " but [the profile] certainly switches from a

favorable risk benefit profile to an unfavorable one. "

And with each of the SSRIs the researchers examined,

they found the same trend: the published data were

significantly more favorable than the data that had

not been peer reviewed.

Defining Context

Neither Keller nor Wagner responded to multiple

requests for interviews for this article; however,

Emslie agreed to an extended phone interview.

" Apart from the first Prozac trial and one of the

Paxil trials, all the rest of the data [in question]

arise from an act of Congress, not from the industry

wanting to do these studies, " Emslie told Psychiatric

News.

Indeed, the data on SSRI use in children largely

resulted from Food and Drug Administration (FDA)

requests to drug manufacturers issued through the

old " Pediatric Rule " —a regulation born from the

Food and Drug Administration Modernization Act of

1997 (FDAMA). However, FDAMA did not require that

studies be carried out and provided little if any

penalty for a company not agreeing to the FDA's

request. In essence, the Pediatric Rule gave companies'

an additional six months of patent protection for

conducting minimal research to collect data on safety

of a medication in pediatric populations. Under the

Rule, the FDA requested pediatric data from

manufacturers of the 100 top-selling medications

in the U.S.

Drug companies were slow to undertake pediatric

research, and the FDA's legal authority to mandate

pediatric clinical trials was challenged. Finally,

the Pediatric Rule was given the weight of law under

The Pediatric Research Equity Act of 2003 (PREA)

which left in place patent extension but further

defined the FDA's legal authority to mandate studies.

In addition, PREA required pediatric studies as part

of every application for approval of every drug—with

few exceptions—retroactive to include all applications

submitted since January 1, 1999.

However, between the Pediatric Rule and PREA, the

FDA began receiving pediatric data that did not

live up to the expectations of either Congress or

the FDA.

" Many of the companies simply threw together the

quickest, cheapest, easiest, clinical trial of their

drug in kids they possibly could, " said one government

official, a senior researcher who is familiar with the

situation and agreed to comment if not named.

" The companies pretty much knew from the outset that

they wouldn't get a full pediatric indication, and

the Pediatric Rule [initially] didn't really have

any stipulations that the data had to be good or

the methods solid. The rule simply said if they

submitted some data, they'd get their patent extended.

And that, simply, translated into dollars, " the official

explained.

Indeed, in many cases, the Pediatric Rule was directly

responsible for hundreds of millions of dollars in

additional sales of a branded product over the

six-month extension.

The official continued, " Data collection in these

studies was sloppy, recruitment was sloppy, the

statistics and methods were manipulated, and, of

course, only the positive studies were submitted.

Why would a drug company put out data that are

negative? That would amount to commercial suicide.

But what can you expect, really? Garbage in,

garbage out. "

Emslie agreed in part. " Getting all the positive

as well as the negative data " is an issue, he said.

But this is true for many different classes of

medications, " not just antidepressants, he said

(see box).

Wanted: All Relevant Data

The PREA was intended to ensure that the FDA was

given all the appropriate pediatric data, both

positive and negative, on a product so that an initial

approval decision could be made on the whole data set,

not just the most marketable data set.

The law includes language mandating that for any

application to the FDA for a " new active ingredient,

new indication, new dosage form, new dosing regimen,

or new route of administration, " the application

must include " data, gathered using appropriate

formulations for each age group... to assess the

safety and effectiveness of the drug or the biological

product for the claimed indications in all relevant

pediatric subpopulations [and data to] support dosing

and administration for each pediatric subpopulation

for which the drug or biological product is safe and

effective. "

If a drug maker fails to submit all of the data,

the drug could be declared " misbranded solely because

of that failure and subject to relevant enforcement

action. "

Yet the FDA acknowledges that even today—a year and

a half after the PREA went into effect—the agency

isn't sure whether it has all the data it's supposed

to have on the medications submitted under PREA's

requirements.

" I'm not aware of any standard mechanism in place

for assuring that all pertinent data have been

submitted, " Laughren, M.D., medical team

leader of the FDA's Neuropharmacological Drug Products

division, told Psychiatric News. " It depends mostly

on the review team being aware of what has been done. "

Nonetheless, Laughren was not aware of any instance

in which a company was found to have purposefully

withheld data from the agency.

In response to Laughren's comments, the government

official who asked not to be named said, " It is not

only possible that the FDA does not have all the

data, it is highly probable. "

Yet, Psychiatric News discovered that even if the FDA

possesses all of the relevant data on a particular

product, that data may not be easily accessible to the

medical community, researchers, the media, or the public.

" Data become available only after an approval action, "

Laughren said, " and then only data that clinical and

statistical reviewers [at the FDA] decide to include

in their reviews [become part of the drug approval

package]. The original data sets are proprietary and

never available unless a sponsor decides to release them. "

The FDA has attempted with some success to increase

access to the information by posting a large amount

of summary data on its Web site under an " Approvals "

section.

If someone is looking for data not posted on the FDA's

Web site, the person must file a Freedom of Information

Act (FOIA) request. Over the last year, in the course

of this ongoing investigative report, Psychiatric News

filed FOIA requests for " all approval package documents

[and] their attachments and appendices " for each of the

antidepressant medications being questioned. To date, a

large amount of data has been received in response to

those requests.

Over the last several months, several SSRI manufacturers

have been accused in the media of attempting to " bury or

hide " negative study data. The increasingly heated issue

led the AMA, at the request of APA and the American

Academy of Child and Adolescent Psychiatry, to advocate

for a mandatory, federally administrated, clinical trials

registry (see page 1). Separately, a large group of

medical journal editors called for the same thing.

In the meantime, GlaxoKline announced it would

create its own registry and publicly post it on its

Web site. At the same time the company posted summary

data from all of its pediatric paroxetine studies,

the majority of which had never been made public.

Shortly thereafter, Merck announced it would support

such a clinical trials register, and Forest Labs

released pediatric data on both citalopram and

escitalopram. In Washington, D.C., several senators

and representatives called for legislation establishing

a mandatory registry for all clinical research, even

though FDAMA already contains an obscure requirement

that all trials be registered.

Comparing Apples and Oranges

The most significant issue facing regulators and

researchers in attempting to analyze the safety

and effectiveness of SSRIs in pediatric populations

is the extreme variability between and within the

studies (see chart on page 1).

" First of all, some of these [pediatric antidepressant]

studies were conducted in Europe, some in America, "

Arif Khan, M.D., pointed out. Khan is medical director

at the Northwest Clinical Research Center in Bellevue,

Wash., and was involved in conducting or reviewing many

of the studies now in question. " The conduct of American

trials by American psychiatrists is a situation that is

entirely different from European trials conducted by

psychiatrists there. "

Some differences in these studies, Khan told

Psychiatric News, include differences in the studies'

methodology, populations, and data assessment, and may

not be directly comparable.

" Some of the European studies had an overabundance

of adolescent girls in the drug groups versus the

placebo groups, " Khan said as an example. " The

randomization wasn't even. "

Emslie echoed this same point, adding that he suspects

that most subjects in the European trials had mild to

moderate depression, rather than severe depression.

Significant evidence in adult populations indicates

that SSRIs are not very effective for mild to moderate

adult depression. Thus, Emslie asked, " why would they

work for mild or moderate depression in kids? "

In addition, many methodological differences exist

among the studies in the number of sites used and the

number of researchers involved, the protocols for

assessment and randomization into the study, and the

statistical analyses of the resulting data.

" You have an extremely heterogeneous group of trials

using differing definitions and assessments on

differing study populations and different analyses, "

Khan said. " So obviously any comparisons are going

to be questionable. "

Experts consulted by Psychiatric News agreed that

meta-analyses and overall reviews of the two dozen

or so pediatric antidepressant clinical trials may

never reach any reliable conclusions about efficacy

and safety of SSRIs in pediatric populations.

" The FDA and the Columbia University group may not

come up with any solid answers, " Khan suggested,

referring to the group of suicidality experts

contracted by the FDA to reanalyze the SSRIs'

adverse-effect profiles. " What you see is that

this suicidal behavior in the placebo group runs

anywhere from 0.6 percent to just under 5 percent.

In the drug groups it runs from a low of just under

3 percent to a high of 8 percent. There's a lot of

variability, but in general the pattern holds true.

There is a fairly clear trend in increased risk in

the drug groups versus the placebo groups, regardless

of which drug you are looking at. "

Common Ground Sought

That trend does have one exception: fluoxetine.

It is the only antidepressant whose data were

strong enough to have won FDA approval for the

treatment of pediatric depression. Most of the

experts interviewed for this article, including

Khan and Kendall, agreed that the published and

unpublished data on fluoxetine's effectiveness

and safety in children and adolescents show that

the drug provides significant clinical improvement

and has not been as closely associated with the

harmful and suicidal behaviors of other SSRIs

in children.

Emslie— " the father of pediatric Prozac " —can't be

sure why fluoxetine is different from the other SSRIs.

" First of all, with respect to efficacy, you have

to ask whether or not it really is any better than

the other SSRIs, " Emslie said. " But no controlled

head-to-head studies have been done in children and

adolescents. So it could be methodological differences.

We did those studies early on [in the evolution of

SSRI pediatric clinical trials], and maybe we did

something better with respect to study population or

had better quality sites with better investigators.

As far as safety is concerned, it may be that the

drug is better tolerated on some level, and I

certainly think that dosing is probably easier with

fluoxetine. "

The FDA expects to schedule a second advisory committee

meeting on the issue as soon as it receives the

reanalysis from the Columbia University group. The

report had been expected in early July, but as this

article went to press, neither the agency nor the

university indicated that the release of the report

was imminent.

So for those clinicians who continue to question their

confidence in SSRI prescriptions for children and

adolescents, there is no immediate resolution in sight.

" We really don't know anything different today than

we did five years ago, " Khan said. " What we have is

a mixture of trial results that generally favor the

active drug. The trials certainly do not favor placebo,

and it is important that that is understood. Failed

trials don't necessarily mean that a drug does not

work. "

Emslie echoed Khan's statement, adding that " it's

really a question of how do these clinical trials

inform us about clinical guidelines for care. I

think they inform us that generally the SSRIs are

probably effective— the data are largely ambiguous,

but certainly not negative. But every medication

[requires] a risk-benefit analysis. "

Khan added, " As long as the patient and the clinician

understand what the risk profile is, I think it is

very appropriate to prescribe [sSRIs]. "

The individuals interviewed by Psychiatric News

agreed on at least one point: " We've really got

to get this right, " Kendall said. " The whole

clinical and scientific community, as well as

regulators and the public, need to be involved

in assuring that we do get it right. Our patients

deserve nothing less. "

An abstract of the Lancet article, " Selective

Serotonin Reuptake Inhibitors in Childhood Depression:

Systematic Review of Published Versus Unpublished

Data, " is posted online at:

<

www.thelancet.com/journal/vol363/iss9418/abs/llan.363.9418.original_resea

rch.29377.1 >.

The BMJ article, " Efficacy and Safety of Antidepressants

for Children and Adolescents, " is posted at:

< http://bmj.bmjjournals.com/cgi/content/full/328/7444/879 >.

BMJ 2004 328 879

[Free Full Text]

========

..

July 17, 2004

Believe it or not reading the July 16 issue of

Psychiatric News is like reading my book on the

SSRI antidepressants!!!

The opening statement is explosive! Ready?

Here it is:

_______________________________

The ongoing controversy surrounding SSRIs in children

is now threatening the very foundations of clinical

drug research on the efficacy and safety of all of

the drugs physicians prescribe.

Physicians in the trenches are beginning to wonder

what exactly they really know— or perhaps don't

know— about the drugs they are prescribing and how

that knowledge base affects what is written on the

prescriptions that bear their signatures.

Many of the concerns raised recently have been

heard before. In this last year, however, they

have risen to a level that seriously challenges

physicians' comfort level with prescription drugs.

Particularly disconcerting are new allegations that

question the integrity of not only the scientific

evidence base, but also the system that produces

the data and the researchers who analyze it.

___________________________

FINALLY they are beginning to see the light!

Too bad we are not yet seeing that in reality.

Doctors are still blindly prescribing these drugs

at an alarming rate even to children. So get

this article out to as many professionals and

news media as possible in an effort to educate

more of them.

Then to see in print one of the strongest negative

statements yet on the dangers of SSRIs given to

children is very encouraging.

______________________________

" In discussing their own data, the authors of all

of the four larger studies have exaggerated the

benefits, downplayed the harms, or both, " Jureidini

and his coauthors wrote.

" Improvement in control groups is strong; additional

benefit from drugs is of doubtful clinical significance, "

they said, adding, " adverse effects have been down-

played. " They concluded that " antidepressant drugs

cannot confidently be recommended as a treatment

option for childhood depression. "

Jureidini and his coauthors pointed out that

" accurate trial reports are a foundation of good

medical care. It is vital that authors, reviewers,

and editors ensure that published interpretations

of data are more reasonable and balanced than is

the case in the industry-dominated literature on

childhood antidepressants. "

_________________________________________

Please allow me to repeat that conclusion for you:

" antidepressant drugs cannot confidently be

recommended as a treatment option for childhood

depression. "

This is what we have been saying all along. Why did

so many have to die before we saw this statement in

mainstream literature? And how long must we wait

to see the same statement for the adult population

as well?

Alos most interesting to note is the following

statement on what our doctors, in whom we place

so much trust, actually have access to in making

decisions about medications.

______________________________

In response to Laughren's comments, the government

official who asked not to be named said, " It is

not only possible that the FDA does not have all

the data, it is highly probable. "

Yet, Psychiatric News discovered that even if the

FDA possesses all of the relevant data on a particular

product, that data may not be easily accessible to

the medical community, researchers, the media, or

the public.

" Data become available only after an approval action, "

Laughren said, " and then only data that clinical and

statistical reviewers [at the FDA] decide to include

in their reviews [become part of the drug approval

package]. The original data sets are proprietary and

never available unless a sponsor decides to release

them. "

<A

HREF= " http://pn.psychiatryonline.org/cgi/content/full/39/14/1?maxtoshow=h

ttp://pn.psychiatryonline.org/cgi/content/full/39/14/1?maxtoshow= & HITS=20

&

hits=20 & RESULTFORMAT= & stored_search= & FIRSTINDEX=0 & tocsectionid=Profession

al* &

displaysectionid=Professional+News & journalcode=psychnews

Ann Blake , Ph.D.,

Executive Director, International Coalition For Drug Awareness

Author: Prozac: Panacea or Pandora? - Our Serotonin Nightmare

& audio tape on safe withdrawal: " Help! I Can't Get

Off My Antidepressant! "

Order Number: 800-280-0730

Website: www.drugawareness.org

_____________________________________________

Similar articles found in:

Psychiatric News

Download to Citation Manager

Psychiatric News July 16, 2004

Volume 39 Number 14

p. 1

Professional News

Clinical Trials Controversy Spotlights Flawed System

Jim ck

The ongoing controversy surrounding SSRIs in

children is now threatening the very foundations

of clinical drug research on the efficacy and

safety of all of the drugs physicians prescribe.

Under the frequent—and often hyperbolic—headlines

in major newspapers throughout the United States,

the debate on whether SSRIs really cause children

and adolescents to become suicidal has boiled down

to a critical realization: Physicians now face a

crisis of confidence in the American-bred system

that conducts clinical research and, it would seem,

publishes only the most marketable results.,

Physicians in the trenches are beginning to wonder

what exactly they really know— or perhaps don't know—

about the drugs they are prescribing and how that

knowledge base affects what is written on the

prescriptions that bear their signatures.

Many of the concerns raised recently have been heard

before. In this last year, however, they have risen

to a level that seriously challenges physicians'

comfort level with prescription drugs. Particularly

disconcerting are new allegations that question the

integrity of not only the scientific evidence base,

but also the system that produces the data and the

researchers who analyze it.

In April the British Medical Journal published a

paper by Jon Jureidini, M.D., head of the department

of psychological medicine at Women's and Children's

Hospital in North Adelaide, Australia, and colleagues.

The article reviewed the evidence base for efficacy

and safety of antidepressants in children and

adolescents. The authors included in their review

published clinical trials, as well as some unpublished

data made public by the U.K. Committee on Safety of

Medicines. At best, Jureidini's conclusions were

direct and to the point, but by some people's

estimation the conclusions seemed inflammatory, with

abundant references to the individuals who led the

research or wrote the articles, rather than to the

research methods, data analysis, or conclusions.

" In discussing their own data, the authors of all

of the four larger studies have exaggerated the

benefits, downplayed the harms, or both, " Jureidini

and his coauthors wrote.

" Improvement in control groups is strong; additional

benefit from drugs is of doubtful clinical significance, "

they said, adding, " adverse effects have been down-

played. " They concluded that " antidepressant drugs

cannot confidently be recommended as a treatment

option for childhood depression. "

Jureidini and his coauthors pointed out that " accurate

trial reports are a foundation of good medical care.

It is vital that authors, reviewers, and editors ensure

that published interpretations of data are more

reasonable and balanced than is the case in the industry-

dominated literature on childhood antidepressants. "

Jureidini listed a " competing interest " with the BMJ

study, noting he is the chair of Healthy Skepticism,

an international lobbying organization based in

Australia whose goal is " improving health by reducing

harm from inappropriate, misleading, or unethical

marketing of health products or services, especially

misleading pharmaceutical promotion. "

So, it was a bit unusual that an article in a major

peer-reviewed publication appeared to be directly

questioning the very integrity of the researchers who

had overseen clinical antidepressant trials. Many

researchers interviewed for this article saw it as

an unusually personal attack.

The researchers who took the brunt of the apparent

attack were the principal investigators and lead

authors of the trials in question: Graham Emslie, M.D.,

the E. and M. Seay Chair in Child

Psychiatry and professor of psychiatry in the Graduate

School of Biomedical Sciences at the University of

Texas Southwestern Medical Center at Dallas;

Keller, M.D., a professor of psychiatry and

human behavior at Brown University; and Dineen

Wagner, M.D., Ph.D., the Clarence Ross Professor

of Psychiatry and Behavioral Sciences and director of

child and adolescent psychiatry at the University of

Texas Medical Branch at Galveston

Emslie was the principal investigator on the fluoxetine

(Prozac) pediatric trials; Keller oversaw pediatric

clinical trials of paroxetine (Paxil); and Wagner was

the principal investigator on two sertraline (Zoloft)

pediatric clinical trials.

Two weeks after the BMJ article, Lancet published a

systematic review of SSRIs for childhood depression

that also compared published and unpublished data

from the same clinical trials that Jureidini analyzed.

Picking Through the Data

Tim Kendall, M.D., deputy director of the Royal College

of Psychiatry's Research Unit in London and co-author

on the Lancet article, talked with Psychiatric News

about the group's findings. Kendall explained that for

each antidepressant medication, the group analyzed

published clinical trial data separately from unpublished

data from U.K. regulatory authorities and found discrepancies.

" From the published data, we thought we might have

recommended some of these drugs, " Kendall said. " In

other words, the risk-benefit profile, in the main,

was favorable—not massively so, but at least modestly

so. " Then, he said, " we looked at the unpublished

data, and they clearly were not favorable. "

For example, Kendall said, the response data for

paroxetine looked better than for placebo, though

the difference was only modest (see chart). With

regard to adverse events, even in the published

data, there " was clearly a problem with the drug. "

When the group analyzed the unpublished data, the

findings shifted. For example, response rates were

significantly lower for paroxetine, and the placebo

effect was even more pronounced than it was in the

published data. This effectively narrowed the

difference between the two groups, voiding the

statistical significance. In addition, the adverse-

event picture, including the data on suicidal behavior,

looked more troubling.

When the researchers analyzed the published and

unpublished data together, the SSRI no longer held

a reasonable benefit for pediatric depression to

justify the apparent risks.

There was not a " massive difference " between " the

published stuff versus the unpublished, " Kendall

said, " but [the profile] certainly switches from a

favorable risk benefit profile to an unfavorable one. "

And with each of the SSRIs the researchers examined,

they found the same trend: the published data were

significantly more favorable than the data that had

not been peer reviewed.

Defining Context

Neither Keller nor Wagner responded to multiple

requests for interviews for this article; however,

Emslie agreed to an extended phone interview.

" Apart from the first Prozac trial and one of the

Paxil trials, all the rest of the data [in question]

arise from an act of Congress, not from the industry

wanting to do these studies, " Emslie told Psychiatric

News.

Indeed, the data on SSRI use in children largely

resulted from Food and Drug Administration (FDA)

requests to drug manufacturers issued through the

old " Pediatric Rule " —a regulation born from the

Food and Drug Administration Modernization Act of

1997 (FDAMA). However, FDAMA did not require that

studies be carried out and provided little if any

penalty for a company not agreeing to the FDA's

request. In essence, the Pediatric Rule gave companies'

an additional six months of patent protection for

conducting minimal research to collect data on safety

of a medication in pediatric populations. Under the

Rule, the FDA requested pediatric data from

manufacturers of the 100 top-selling medications

in the U.S.

Drug companies were slow to undertake pediatric

research, and the FDA's legal authority to mandate

pediatric clinical trials was challenged. Finally,

the Pediatric Rule was given the weight of law under

The Pediatric Research Equity Act of 2003 (PREA)

which left in place patent extension but further

defined the FDA's legal authority to mandate studies.

In addition, PREA required pediatric studies as part

of every application for approval of every drug—with

few exceptions—retroactive to include all applications

submitted since January 1, 1999.

However, between the Pediatric Rule and PREA, the

FDA began receiving pediatric data that did not

live up to the expectations of either Congress or

the FDA.

" Many of the companies simply threw together the

quickest, cheapest, easiest, clinical trial of their

drug in kids they possibly could, " said one government

official, a senior researcher who is familiar with the

situation and agreed to comment if not named.

" The companies pretty much knew from the outset that

they wouldn't get a full pediatric indication, and

the Pediatric Rule [initially] didn't really have

any stipulations that the data had to be good or

the methods solid. The rule simply said if they

submitted some data, they'd get their patent extended.

And that, simply, translated into dollars, " the official

explained.

Indeed, in many cases, the Pediatric Rule was directly

responsible for hundreds of millions of dollars in

additional sales of a branded product over the

six-month extension.

The official continued, " Data collection in these

studies was sloppy, recruitment was sloppy, the

statistics and methods were manipulated, and, of

course, only the positive studies were submitted.

Why would a drug company put out data that are

negative? That would amount to commercial suicide.

But what can you expect, really? Garbage in,

garbage out. "

Emslie agreed in part. " Getting all the positive

as well as the negative data " is an issue, he said.

But this is true for many different classes of

medications, " not just antidepressants, he said

(see box).

Wanted: All Relevant Data

The PREA was intended to ensure that the FDA was

given all the appropriate pediatric data, both

positive and negative, on a product so that an initial

approval decision could be made on the whole data set,

not just the most marketable data set.

The law includes language mandating that for any

application to the FDA for a " new active ingredient,

new indication, new dosage form, new dosing regimen,

or new route of administration, " the application

must include " data, gathered using appropriate

formulations for each age group... to assess the

safety and effectiveness of the drug or the biological

product for the claimed indications in all relevant

pediatric subpopulations [and data to] support dosing

and administration for each pediatric subpopulation

for which the drug or biological product is safe and

effective. "

If a drug maker fails to submit all of the data,

the drug could be declared " misbranded solely because

of that failure and subject to relevant enforcement

action. "

Yet the FDA acknowledges that even today—a year and

a half after the PREA went into effect—the agency

isn't sure whether it has all the data it's supposed

to have on the medications submitted under PREA's

requirements.

" I'm not aware of any standard mechanism in place

for assuring that all pertinent data have been

submitted, " Laughren, M.D., medical team

leader of the FDA's Neuropharmacological Drug Products

division, told Psychiatric News. " It depends mostly

on the review team being aware of what has been done. "

Nonetheless, Laughren was not aware of any instance

in which a company was found to have purposefully

withheld data from the agency.

In response to Laughren's comments, the government

official who asked not to be named said, " It is not

only possible that the FDA does not have all the

data, it is highly probable. "

Yet, Psychiatric News discovered that even if the FDA

possesses all of the relevant data on a particular

product, that data may not be easily accessible to the

medical community, researchers, the media, or the public.

" Data become available only after an approval action, "

Laughren said, " and then only data that clinical and

statistical reviewers [at the FDA] decide to include

in their reviews [become part of the drug approval

package]. The original data sets are proprietary and

never available unless a sponsor decides to release them. "

The FDA has attempted with some success to increase

access to the information by posting a large amount

of summary data on its Web site under an " Approvals "

section.

If someone is looking for data not posted on the FDA's

Web site, the person must file a Freedom of Information

Act (FOIA) request. Over the last year, in the course

of this ongoing investigative report, Psychiatric News

filed FOIA requests for " all approval package documents

[and] their attachments and appendices " for each of the

antidepressant medications being questioned. To date, a

large amount of data has been received in response to

those requests.

Over the last several months, several SSRI manufacturers

have been accused in the media of attempting to " bury or

hide " negative study data. The increasingly heated issue

led the AMA, at the request of APA and the American

Academy of Child and Adolescent Psychiatry, to advocate

for a mandatory, federally administrated, clinical trials

registry (see page 1). Separately, a large group of

medical journal editors called for the same thing.

In the meantime, GlaxoKline announced it would

create its own registry and publicly post it on its

Web site. At the same time the company posted summary

data from all of its pediatric paroxetine studies,

the majority of which had never been made public.

Shortly thereafter, Merck announced it would support

such a clinical trials register, and Forest Labs

released pediatric data on both citalopram and

escitalopram. In Washington, D.C., several senators

and representatives called for legislation establishing

a mandatory registry for all clinical research, even

though FDAMA already contains an obscure requirement

that all trials be registered.

Comparing Apples and Oranges

The most significant issue facing regulators and

researchers in attempting to analyze the safety

and effectiveness of SSRIs in pediatric populations

is the extreme variability between and within the

studies (see chart on page 1).

" First of all, some of these [pediatric antidepressant]

studies were conducted in Europe, some in America, "

Arif Khan, M.D., pointed out. Khan is medical director

at the Northwest Clinical Research Center in Bellevue,

Wash., and was involved in conducting or reviewing many

of the studies now in question. " The conduct of American

trials by American psychiatrists is a situation that is

entirely different from European trials conducted by

psychiatrists there. "

Some differences in these studies, Khan told

Psychiatric News, include differences in the studies'

methodology, populations, and data assessment, and may

not be directly comparable.

" Some of the European studies had an overabundance

of adolescent girls in the drug groups versus the

placebo groups, " Khan said as an example. " The

randomization wasn't even. "

Emslie echoed this same point, adding that he suspects

that most subjects in the European trials had mild to

moderate depression, rather than severe depression.

Significant evidence in adult populations indicates

that SSRIs are not very effective for mild to moderate

adult depression. Thus, Emslie asked, " why would they

work for mild or moderate depression in kids? "

In addition, many methodological differences exist

among the studies in the number of sites used and the

number of researchers involved, the protocols for

assessment and randomization into the study, and the

statistical analyses of the resulting data.

" You have an extremely heterogeneous group of trials

using differing definitions and assessments on

differing study populations and different analyses, "

Khan said. " So obviously any comparisons are going

to be questionable. "

Experts consulted by Psychiatric News agreed that

meta-analyses and overall reviews of the two dozen

or so pediatric antidepressant clinical trials may

never reach any reliable conclusions about efficacy

and safety of SSRIs in pediatric populations.

" The FDA and the Columbia University group may not

come up with any solid answers, " Khan suggested,

referring to the group of suicidality experts

contracted by the FDA to reanalyze the SSRIs'

adverse-effect profiles. " What you see is that

this suicidal behavior in the placebo group runs

anywhere from 0.6 percent to just under 5 percent.

In the drug groups it runs from a low of just under

3 percent to a high of 8 percent. There's a lot of

variability, but in general the pattern holds true.

There is a fairly clear trend in increased risk in

the drug groups versus the placebo groups, regardless

of which drug you are looking at. "

Common Ground Sought

That trend does have one exception: fluoxetine.

It is the only antidepressant whose data were

strong enough to have won FDA approval for the

treatment of pediatric depression. Most of the

experts interviewed for this article, including

Khan and Kendall, agreed that the published and

unpublished data on fluoxetine's effectiveness

and safety in children and adolescents show that

the drug provides significant clinical improvement

and has not been as closely associated with the

harmful and suicidal behaviors of other SSRIs

in children.

Emslie— " the father of pediatric Prozac " —can't be

sure why fluoxetine is different from the other SSRIs.

" First of all, with respect to efficacy, you have

to ask whether or not it really is any better than

the other SSRIs, " Emslie said. " But no controlled

head-to-head studies have been done in children and

adolescents. So it could be methodological differences.

We did those studies early on [in the evolution of

SSRI pediatric clinical trials], and maybe we did

something better with respect to study population or

had better quality sites with better investigators.

As far as safety is concerned, it may be that the

drug is better tolerated on some level, and I

certainly think that dosing is probably easier with

fluoxetine. "

The FDA expects to schedule a second advisory committee

meeting on the issue as soon as it receives the

reanalysis from the Columbia University group. The

report had been expected in early July, but as this

article went to press, neither the agency nor the

university indicated that the release of the report

was imminent.

So for those clinicians who continue to question their

confidence in SSRI prescriptions for children and

adolescents, there is no immediate resolution in sight.

" We really don't know anything different today than

we did five years ago, " Khan said. " What we have is

a mixture of trial results that generally favor the

active drug. The trials certainly do not favor placebo,

and it is important that that is understood. Failed

trials don't necessarily mean that a drug does not

work. "

Emslie echoed Khan's statement, adding that " it's

really a question of how do these clinical trials

inform us about clinical guidelines for care. I

think they inform us that generally the SSRIs are

probably effective— the data are largely ambiguous,

but certainly not negative. But every medication

[requires] a risk-benefit analysis. "

Khan added, " As long as the patient and the clinician

understand what the risk profile is, I think it is

very appropriate to prescribe [sSRIs]. "

The individuals interviewed by Psychiatric News

agreed on at least one point: " We've really got

to get this right, " Kendall said. " The whole

clinical and scientific community, as well as

regulators and the public, need to be involved

in assuring that we do get it right. Our patients

deserve nothing less. "

An abstract of the Lancet article, " Selective

Serotonin Reuptake Inhibitors in Childhood Depression:

Systematic Review of Published Versus Unpublished

Data, " is posted online at:

<

www.thelancet.com/journal/vol363/iss9418/abs/llan.363.9418.original_resea

rch.29377.1 >.

The BMJ article, " Efficacy and Safety of Antidepressants

for Children and Adolescents, " is posted at:

< http://bmj.bmjjournals.com/cgi/content/full/328/7444/879 >.

BMJ 2004 328 879

[Free Full Text]

========

..

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