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

[Guest guest]

> atracyphd2

> Sat, 17 Jul 2004 13:30:17 EDT

> [drugawareness] Psychiatric News-System

> Flawed Insuring Safety of All Drugs

>

>

> 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. "

>

>

> Ann Blake Tracy, 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

>

> ___________

>

> 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=http://p\

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

>

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>

displaysectionid=Professional+News & journalcode=psychnews

>

> Â Â Â

> Similar articles found in:

> Psychiatric News   Â

> Download to Citation Manager   Â

> Â Â Â

> Psychiatric News July 16, 2004

> Volume 39 Number 14

> © 2004 American Psychiatric Association

> p. 1

> Professional News

>

> Clinical Trials Controversy Spotlights Flawed System

>

>

> Jim Rosack

>

> 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.,

>

>

> Â Â Â

> Â Â Â

> Â Â Â

>

>

>

> Â Â Â

> Â Â Â

> Â Â Â

> 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 Charles E. and Sarah 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; Martin

> Keller, M.D., a professor

> of psychiatry and human behavior at Brown

> University; and Karen Dineen Wagner,

> M.D., Ph.D., the Clarence Ross Miller 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 riskbenefit 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, " Thomas

> 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, GlaxoSmithKline 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 n

> umber 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.36

> 3.9418.original_research.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]

>

>

>

> [Non-text portions of this message have been

> removed]

>

>