Antidepressant Ban for Kids Puts Pressure On U.S. / Canada

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ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

http://www.ahrp.org

Contact: Vera Hassner Sharav

Tel: 212-595-8974

e-mail: veracare@...

FYI

The British government ban for use of all but one SSRI antidepressant drug

in children and teens (Dec 10, 2003) is reverberating wherever these drugs

are widely prescribed. The action was taken after an independent committee

of experts examined the raw data from controlled clinical trials that had

been conducted by these drugs’ manufacturers. The evidence shows that

contrary to the claims made by their promoters, SSRIs are neither effective

against depression in children, nor safe. The hazards posed by SSRIs--of

which the most serious is self-harm and aggression toward others--had been

detected during company controlled clinical trials, but the hazards were

concealed--even in published reports in academic journals. Thus, doctors who

prescribed the drugs and patients and families for whom they have been

prescribed were kept in the dark.

The revelation about the hidden hazards posed by SSRIs raised serious

concerns about how drugs are tested, how the findings are reported, and how

the regulatory agencies meet their public responsibility.

* How is it that the prominent expert psychiatrists worldwide failed to

notice the significant finding of emergent suicidal behavior in adolescents

testing Paxil?

In a published paroxetine study, one in 10 (10.5 per cent) of the patients

taking Paxil had a " serious " adverse effect compared to just one in 100 of

the placebo patients and nearly eight of 100 (7.5 per cent) taking

paroxetine required hospitalization.

See: Keller, MD, ND, Strober M, Klein RG, Kutcher SP, Birmaher B, et

al. Efficacy of paroxetine in the treatment of adolescent major depression:

a randomized, controlled trial. Journal of the Academy of Child and

Adolescent Psychiatry (2001), 40:762-772.

Neither the leading experts in psychiatry nor officials of the FDA (or

equivalents in the UK) noticed these suicide findings. A British journalist

not trained in science readily detected the problem and brought it to public

attention.

* How do officials in the UK and US regulatory agencies explain their

failure to protect children from hazardous drugs that are no more effective

than placebo?

* How do regulators explain their role in helping drug companies conceal the

evidence by not even examining the efficacy and safety data from clinical

trials submitted to them 7 years ago?

* How do regulators explain their failure to read the published reports

and to inform the public about findings of potential hazards?

* How do regulators explain their failure to request long-term studies

to ensure that these problematic drugs don't pose irreversible damage?

The regulatory agencies failed to examine the data even as a body of

evidence accumulated from case reports of drug-induced adverse reactions.

Only after the manufacturers sought to obtain a marketing license for

depressed children did the British authority convene an expert panel to

examine the raw data from previous pediatric trials.

On Dec. 11, Health Canada announced it will review the data as well.

See: www.cbc.ca/cgi-bin/templates/print.cgi?/2003/12/12/Consumers/ssri031212

A two part article in the Canadian Sterling News Service reports that

warnings by the British authority in June, prompted Canadian doctors to ask

serious questions and to re-examine the wisdom of prescribing antidepressant

drugs for children, inasmuch as the evidence from clinical trials clearly

shows that children may be helped equally by the placebo effect without the

drug-related risks.

For example, Dr. Jane Garland, director of the mood disorders clinic at

British Columbia Children's Hospital, and one of the investigators who

tested SSRIs in clinical trials, put it this way: " As physicians, we want to

be helpful, but we often suffer individually and collectively from a

pharmacological imperative: If we have a drug, we feel compelled to

prescribe it. " Dr. Garland acknowledges, " We suffer from excessive

therapeutic optimism. "

But a re-examination of the data led her to conclude:

" If it were ethical, placebo treatment would be the recommended first step.

Alternatively, supplements such as omega-3 fatty acids could be plausible

and inexpensive 'active' placebos. "

US psychiatrists, by contrast, have consistently rallied in defense of

psychotropic drugs even as the evidence shows that the risks to outweigh any

benefits. Reporters rarely inform readers that the psychiatrists they quote

are paid consultants to the drug manufacturers.

See: THE NEW YORK TIMES December 11, 2003, British Warning on Antidepressant

Use for Youth

http://www.nytimes.com/2003/12/11/international/europe/11DRUG.html?pagewante

d=print & position=

See: WASHINGTON POST. December 11, 2003, Britain Warns Against Giving

Newer Antidepressants to Kids Only Prozac's Benefits Outweigh Risks, Health

Officials Say

http://www.washingtonpost.com/ac2/wp-dyn/A54446-2003Dec10?language=printer

Statements by FDA officials have sent confusing contradictory messages:

In June, after the British issued warnings about Paxil’s potential to induce

suicidal behavior in children, FDA followed suit. But on October 28, Dr.

Laughren, the FDA's team leader for psychiatric drug products, told

The New York Times: " I think probably that we have backed off a little bit

from the advisory issued in June, which recommended against using Paxil. I

believe our position now is that we just don't know. " When in doubt about

the risk of inducing suicide, shouldn't’t regulators err on the side of

children's safety?

Of equal concern is FDA’s announced method for examining the data: “FDA

plans to re-examine many of the clinical conclusions made during studies of

the drugs.” (See: NY Times, 10/28/2003.) Inasmuch as the physicians who

tested the drugs in children had first-hand contact with those children,

their professional judgment and written description about the nature of the

emerging severe adverse effects--such as suicidal behavior--cannot be set

aside by distant second-guessing.

Furthermore, inasmuch as these physicians were paid by the drugs’

manufacturers, they are not eager to find hazards. Thus, FDA’s attempt to

raise doubts about their professional judgment is an obvious effort to

explain away the higher suicide rate among children given the drugs compared

with those on placebo.

Why are FDA officials trying to avoid a scientifically legitimate

examination of the safety and efficacy data--such as was done by the

British?

There is growing concern that FDA’s planned advisory committee meeting on

Feb. 2, 2004 will be a re-play of the much criticized 1991 rigged meeting at

which experts who had documented evidence of drug-induced suicide attempts,

were not given an opportunity to present testimony. In 1991, Dr.

Teicher, the doctor who had first discovered a suicide effect in a minority

of patients prescribed Prozac, was denied an opportunity to testify at the

FDA committee hearing. In 2003, FDA officials have indicated once again,

their disinclination to provide Dr. Healy an opportunity to present

his analysis of the clinical

trial data. Dr. Healy is a uniquely qualified world expert

psychopharmacologist whose testimony led the British medicines authority to

examine the raw data, prompting the agency to take action accordingly.

http://www.canada.com/vancouver/vancouversun/story.asp?id=331DE462-7A38-4F00

-827A-CA672E122391

Sterling News Service

Depressed Kids: The Drug Debate

Are the young used as guinea pigs for untested antidepressants?

Daphne Bramham

Thursday, December 11, 2003

FIRST OF TWO PARTS

Every year more and more kids -- some still in preschool -- are popping

pills for anxiety, depression, even shyness.

What they're mostly taking are selective seratonin reuptake inhibitors, or

SSRIs.

Paxil, or paroxetine, is the most commonly prescribed SSRI and experts

estimate that five per cent of those prescriptions are written for patients

18 and younger, including some preschoolers. With 3.57 million prescriptions

written for Paxil in the 12 months from September 2002 to September 2003 in

Canada, that means about 178,500 of those were for kids. That's a 58 per

cent increase over just five years ago.

In B.C., an estimated 20,700 Paxil prescriptions were written for kids

between Oct. 1, 2002, and the end of October this year. That's a

68.8-per-cent increase over five years ago.

Yet with the exception of Prozac, or fluoxetine, Paxil and its SSRI cousins

have never been fully tested on kids. They've never been approved for

pediatric use and because drug companies have never sought pediatric

approval, they have never had to show regulators the results of clinical

trials.

And, by the way, nobody has ever done a study to determine what effect SSRIs

will have on their developing brains and bodies.

Doctors know how little real information there is about the effects of these

drugs on little kids and teens. Parents should.

Yet that hasn't slowed sales at all. Billions of dollars' worth are sold

globally each year. In Canada, nearly 14 million prescriptions for SSRIs

were filled in 2002 at a cost of $869 million. In B.C. alone, doctors wrote

1.69 million prescriptions for the drugs at a cost of $116.3 million.

There have always been questions about them -- their efficacy and their

effects. But again, it hasn't in any way dissuaded doctors from prescribing

them by the millions.

Until this spring. Evidence was presented to the British drug regulatory

agency in late May that wasn't new, it was only new to the regulators. It

was raw data from seven-year-old clinical trials that had never before been

available. There was no reason for the drug company GlaxoKline to

release it because until 2003, it was not applying for pediatric use of

paroxetine.

The data showed that kids on paroxetine (sold as Seroxat in Britain and

Paxil in North America) were 1.5 to 3.2 times more likely to be suicidal

than kids taking placebos. Ironically, the trials found that kids taking

placebos were almost as likely to get well as kids on the real pills.

In June, Britain advised doctors to quit prescribing the most popular of the

SSRIs -- paroxetine -- to anyone under 18.

The British regulatory agency said that paroxetine not only appears to be

harmful to kids, it may be no more effective in treating anxiety and

depression than sugar pills.

It was stunning news for families and physicians and it pushed other

regulatory agencies into action. Within a few weeks, the U.S. food and drug

administration warned physicians about the new evidence, but stopped short

of recommending against pediatric use of paroxetine. Instead it urged

physicians to watch their patients more carefully for suicide. A few weeks

later, it issued an advisory that another SSRI, venlafaxine (which is

marketed as Effexor) is " ineffective " in treating

childhood depression.

Canada followed the Americans' lead in both cases.

By October 2003, the clamour of parents, patients and physicians demanding

more information grew so loud that the FDA announced it will hold a special

meeting Feb. 2 to discuss all of the published data, the new data and, if

required, recommend further studies on eight different SSRIs. The list

includes paroxetine (Paxil), venlafaxine (Effexor), fluvoxamine (Luvox),

citalopram (Celexa), sertraline (Zoloft), nefazadone (Serzone) and

mirtazapine (Remeron).

The doctors -- mostly family physicians and pediatricians -- started calling

experts like Dr. Jane Garland, a psychiatrist and clinical head of the mood

disorders clinic at B.C.'s Children's Hospital, and Dr. Marshall Korenblum,

chief psychiatrist at Toronto's Hincks-Dellcrest Centre for Children and

training director in psychiatry at Toronto's Sick Children's Hospital. " We

were caught with our pants down, " says Garland.

But after spending the summer digging out everything she could find on

SSRIs, Garland says she and her colleagues shouldn't have been.

" The evidence was before us. We just weren't paying attention. "

In the fall, Garland circulated a couple of papers to her colleagues here

and internationally, summarizing the information that is available.

Here is a sampling of some of the information she has provided to B.C.

doctors.

- Prior to 1997, more than a dozen controlled studies demonstrated that

SSRIs were no more efficacious than placebos in treating childhood

depression.

- In a published paroxetine study, one in 10 (10.5 per cent) of the patients

taking Paxil had a " serious " adverse effect compared to just one in 100 of

the placebo patients and nearly eight of 100 (7.5 per cent) taking

paroxetine required hospitalization.

- Seven of 10 young patients treated with Zoloft (or sertraline) for a major

depressive episode would improve, but only one of those improvements could

be directly attributed to the medication.

Despite the evidence, Garland said Wednesday, " I don't think that it was

necessarily the right solution to go to a full ban [in Britain]. Their point

is that people are not looking at the data objectively, but it leaves people

with very few treatment options. ... It seems that they [the British

committee members] were reacting to the profession not dealing with this

issue rationally. "

The reassurance Garland offers physicians is this: Even though there has

been a consistently observed doubling of the rate of suicidal thinking in

patients treated with several different SSRIs, the incidence is only between

two and five per cent and " no completed suicides have been reported. "

xxx cut xxx

In a perfect world, there would be obvious heroes and villains in a story of

how kids as little as three came to be taking drugs that not only may not

work, but might actually hurt them. But at the confluence of drugs, big

money and politics, it is far from a perfect world.

To unravel this, let's start with some stark truths.

- There is not a single study that shows that an abnormality in a person's

ability to metabolize seratonin causes depression, according to Dr.

Healy, who has written three books and more than 1,200 articles about SSRIs.

In fact, he says there's not a single psychiatrist, pharmacologist,

pharmacist or pharmaceutical

executive who can explain exactly how a selective seratonin reuptake

inhibitor work or even how seratonin works.

- Most drugs given to children have never, ever been approved for pediatric

or adolescent use, whether they are drugs for liver disease, cancer or

depression, because drug companies ask for adult approval, not pediatric

approval.

Yet doctors routinely prescribe them as a so-called " off-label use " on the

assumption that the drugs are safe for adults, they'll be safe for kids too.

Off-label prescribing is such an accepted practice that even though SSRIs

have never been approved for pediatric use -- Prozac being the exception --

they are recommended as first-line treatment by the American Academy of

Children and Adolescent Psychiatry.

Dosages are determined by extrapolating from the recommended adult dose

based on considerations such as weight and height. One of the reasons drugs

aren't tested on kids is simple economics. Drug companies almost always

apply to have a drug licensed for adult use and because of that there is no

need for them to prove to the regulators that the drugs are safe for

children or teens. But once approved, doctors aren't limited to adult-only

uses. So why would pharmaceutical companies go to the substantial expense of

repeating drug trials on kids when doctors will be able to prescribe them

off-label anyway?

This is changing, albeit slowly. Two years ago, the United States passed

legislation extending patent protection to individual drugs for five years,

if pharmaceutical companies agreed to do pediatric trials on the drug. But

getting that legislation passed was difficult. Ethicists and parents raised

a troubling question: Should kids be guinea pigs? It was answered with

another even more troubling question: Is it ethical to put kids on drugs

that have never been tested on kids?

- There have never been any studies of the long-term effects of SSRIs on

adults or children.

Again it comes back to economics. Long-term studies cost tens of millions of

dollars. Pharmaceutical companies have no reasons to do them once their

drugs have regulatory approval and, so far, except in rare cases, countries

and research institutions have had little interest or money for doing them.

It's why nefazadone (Serozone) was sold for nearly a decade before it was

pulled off Canadian shelves in November. It took that long to establish the

link between its use and severe liver damage. But even with that link,

Canada waited nearly a year longer than European countries to ban its sale.

- No major studies involving adults or children have been done comparing the

long-term effectiveness of SSRIs versus extensive therapy that includes

exercise as well as talk and teaching patients skills to cope with anxiety-

and depression-inducing situations.

xxx cut xxx

Complete article at:

http://www.canada.com/vancouver/vancouversun/story.asp?id=331DE462-7A38-4F00

-827A-CA672E122391

Part Two: Drugs for kids need scrutiny: Canada slow to warn about pediatric

use of antidepressants at:

http://www.canada.com/vancouver/vancouversun/story.asp?id=331DE462-7A38-4F00

-827A-CA672E122391