FDA to review missing drug company documents

[Guest guest]

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness and Full Disclosure

www.ahrp.org

FYI

In the final hours of 2004, an investigative reporter for the British

Medical Journal obtained long " missing " Eli Lilly company documents,

suggesting " a link between the drug fluoxetine (Prozac) and suicide attempts

and violence " in adults who tested the drug in the 1980s. Dr. ph

Glenmullen said the missing documents provide " the missing link " between the

recent advisory issued by the FDA [black Box warnings of increased suicide

risk for children and adolescents] and what Lilly scientists knew 16 years

ago about adult trials.

Jeanne Lenzer, whose article in the Jan 1 issue of the BMJ has generated a

great deal of interest, forwarded the documents to the FDA. The documents

reveal that Lilly knew that Prozac posed a twofold increased risk of

" activation " -i.e.,

<http://bmj.bmjjournals.com/cgi/content/full/330/7481/7?maxtoshow= & HITS=10 & h

its=10 & RESULTFORMAT= & fulltext=prozac & searchid=1104477088217_17118 & stored_sea

rch= & FIRSTINDEX=0 & volume=330 & issue=7481> symptoms such as agitation, panic

attacks, insomnia and aggressiveness:

" One of the internal company documents, a report of 8 November 1988,

entitled " Activation and Sedation in Fluoxetine Clinical Trials, " found that

in clinical trials " 38% of fluoxetine-treated patients reported new

activation but 19% of placebo-treated patients also reported new activation

yielding a difference of 19% attributable to fluoxetine. " Another document

dated 1990 shows that " Lilly failed to obtain systematic assessments of

violence and had excluded 76 of 97 cases of reported suicidality. "

Congressman Maurice Hinchey, whose staff is reviewing the documents to

determine whether Lilly withheld data from the public and the FDA, said:

" This is an alarming study that should have been shared with the public and

the FDA from the get-go, not 16 years later.

The sudden surfacing of the " missing " Lilly documents put the FDA, Lilly,

and the drug industry on the rope-much as the 1998 GlaxoKline memo

revealing a strategy of concealement, prompted NYS Attorney General, Eliot

Spitzer, to charge the company with fraudulent marketing. See:

http://www.ahrp.org/risks/SSRI0204/GSKpaxil/index.php

The unprecedented marketing success of Prozac and the other SSRIs and the

company's defense strategy in the Wesbecker case provide a microcosm of the

pharmaceutical industry's corrupt practices and immoral calculation of risk

/ benefit. The drugs' benefits are calculated in multi-billion dollar sales

without concern for the life-threatening risks borne by individual

consumers.

The " missing " documents validate critics who have for years warned that

Prozac, and subsequent " me too " antidepressants of the SSRI class pose

life-threatening risks of suicide and homicide. One such early critic,

psychiatrist, Breggin, MD cautions that the 38% activation rate

reported in the missing document is probably low because " it doesn't include

other symptoms of activation such as panic attacks, hypomania, and mania. "

Dr. Breggin and other who have raised concerns about the safety of these

drugs were tarred and feathered by the psychiatric establishment which

continues to promote the drugs, and who participated in the suppression of

facts from physicians and the public.

Neither the FDA nor Eli Lilly would comment about the revelations in the

documents.

Recently a similar scenario been uncovered in the marketing of another class

of hazardous drugs--COX 2 pain killers.

How many more preventable deaths due to drug hazards will occur before the

industry and the FDA are held accountable?

Below is the BMJ article and Forbes-

See also: The Wall Street Journal

http://online.wsj.com/article_email/0,,SB110447135481013956-IVjf4NplaN3m56mZ

XqJcKaEm4,00.html

The New York Times

http://www.nytimes.com/financialtimes/business/FT20041230_6538_386196.html?e

x=1105497800

<http://www.nytimes.com/financialtimes/business/FT20041230_6538_386196.html?

ex=1105497800 & ei=1 & en=5f511d9500fca256> & ei=1 & en=5f511d9500fca256

The Herald (UK) http://www.theherald.co.uk/news/30682.html

among others.

Contact: Vera Hassner Sharav

212-595-8974

veracare@...

http://bmj.bmjjournals.com/cgi/content/full/330/7481/7

FDA to review " missing " drug company documents

Jeanne Lenzer New York

The US Food and Drug Administration has agreed to review confidential drug

company documents that went missing during a controversial product liability

suit more than 10 years ago. The documents appear to suggest a link between

the drug fluoxetine (Prozac), made by Eli Lilly, and suicide attempts and

violence.

The missing documents, which were sent to the BMJ by an anonymous source

last month, include reviews and memos indicating that Eli Lilly officials

were aware in the 1980s that fluoxetine had troubling side effects and

sought to minimise their likely negative effect on prescribing.

The documents received by the BMJ reportedly went missing during the 1994

Wesbecker case that grew out of a lawsuit filed on behalf of victims of a

work-place shooting in 1989. ph Wesbecker, armed with an AK-47, shot

eight people dead and wounded another 12. He then shot and killed himself.

Mr Wesbecker, who had a long history of depression, had been placed on

fluoxetine one month before the shootings.

One of the internal company documents, a report of 8 November 1988, entitled

" Activation and Sedation in Fluoxetine Clinical Trials, " found that in

clinical trials " 38% of fluoxetine-treated patients reported new activation

but 19% of placebo-treated patients also reported new activation yielding a

difference of 19% attributable to fluoxetine. "

The FDA recently issued a warning that antidepressants can cause a cluster

of " activating " or stimulating symptoms such as agitation, panic attacks,

insomnia, and aggressiveness. Dr ph Glenmullen, a Harvard psychiatrist

and author of The Antidepressant Solution, published by Free Press, said it

should come as little surprise that fluoxetine might cause serious

behavioural disturbances, as it is similar to cocaine in its effects on

serotonin.

Dr Kapit, the FDA clinical reviewer who approved fluoxetine, said he

was not given the Lilly data. " These data are very important. If this report

was done by Lilly or for Lilly, it was their responsibility to report it to

us and to publish it. "

Congressman Maurice Hinchey's office is currently reviewing the documents to

determine whether Lilly withheld data from the public and the FDA. Mr

Hinchey (Democrat, New York) said: " This is an alarming study that should

have been shared with the public and the FDA from the get-go, not 16 years

later.

" This case demonstrates the need for Congress to mandate the complete

disclosure of all clinical studies for FDA-approved drugs so that patients

and their doctors, not the drug companies, decide whether the benefits of

taking a certain medicine outweigh the risks. "

The plaintiffs in the Wesbecker product liability sought to show that Eli

Lilly withheld negative study data from the FDA and that fluoxetine tipped

Wesbecker over into a homicidal rage. Lilly won a 9 to 3 jury verdict in

late 1994 and subsequently claimed that it was " proven in a court of law...

that Prozac is safe and effective. "

The trial judge, Justice Potter, suspecting that a secret deal had been

struck, pursued Lilly and the plaintiffs, eventually forcing Lilly in 1997

to admit that it had made a secret settlement with the plaintiffs during the

trial. Infuriated by Lilly's actions, Judge Potter ordered the finding

changed from a verdict in Lilly's favour to one of " dismissed as settled

with prejudice, " saying, " Lilly sought to buy not just the verdict but the

court's judgment as well. "

Graham, currently associate director in the FDA's Office of Drug

Safety, criticised the analysis of post-marketing surveillance data

submitted by Lilly to the FDA. After discovering that Lilly failed to obtain

systematic assessments of violence and had excluded 76 of 97 cases of

reported suicidality, Dr Graham concluded in a memo dated 11 September 1990

that " because of apparent large-scale underreporting, [Lilly's] analysis

cannot be considered as proving that fluoxetine and violent behavior are

unrelated. " <http://bmj.bmjjournals.com/cgi/content/full/330/7481/7#FIG1>

An FDA advisory panel was convened in 1991 to review the fluoxetine data. It

concluded that fluoxetine was safe despite the concerns raised by Dr Graham

and others, leading critics to point out that several of the panellists had

financial ties to Eli Lilly.

Dr Glenmullen said the missing documents obtained by the BMJ provide " the

missing link " between the recent advisory issued by the FDA and what Lilly

scientists knew 16 years ago.

Since the 1991 FDA hearings Dr Breggin, who served as the medical

expert in the Wesbecker case, has warned that the stimulant effects of

fluoxetine can cause suicide and violence. He cautions that the 38%

activation rate reported in the missing document is probably low because " it

doesn't include other symptoms of activation such as panic attacks,

hypomania, and mania. "

Dr Kapit, the original reviewer for fluoxetine, told the BMJ, " If we have

good evidence that we were misled and data were withheld then I would change

my mind [about the safety of fluoxetine]. I do agree now that these

stimulatory side effects, especially in regards to suicidal ideation and

homicidal ideation, are worse than I thought at the time that I reviewed the

drug. "

Lilly declined to be interviewed but issued a written statement saying,

" Prozac has helped to significantly improve millions of lives. It is one of

the most studied drugs in the history of medicine, and has been prescribed

for more than 50 million people worldwide. The safety and efficacy of Prozac

is well studied, well documented, and well established. "

http://www.forbes.com/lifestyle/health/feeds/hscout/2004/12/30/hscout523176.

html

FORBES

Health

Report: Prozac Maker Knew of Problems in 1988

By Gardner

HealthDay Reporter <b>By Gardner</b><br><i>HealthDay Reporter</i>,

THURSDAY, Dec. 30 (HealthDayNews) -- Confidential company documents obtained

by a leading medical journal suggest that drug giant Eli Lilly & Co. was

aware that its antidepressant Prozac was linked to troubling side effects as

far back as 1988, the same year the drug was introduced to the U.S. market.

The discovery is reported in the Jan. 1 issue of the British Medical

Journal, and adds to the growing body of bad news for pharmaceutical

companies. The papers have been turned over to the U.S. Food and Drug

Administration.

Amid the pile of internal reviews and memos, according to the journal, is a

document dated November 1988 that reports Prozac (fluoxetine) had caused

behavioral problems, including agitation and panic attacks, in clinical

trials.

The issue of disclosure is a loaded one. The FDA announced in October that

antidepressants such as Prozac would now have to carry a " black box " warning

that health-care providers should be on the lookout for, among other things,

increased agitation, panic attacks, and aggression among users of the drugs.

This latest report also fuels the ongoing debate over which clinical studies

should come to the attention of federal regulators and which should never

the see the light of day.

" The discovery of research, reportedly 'missing' for the past 10 years, that

connects Prozac to increased suicidal tendencies and violence is one more

tragic example of a greater problem: Unless we mandate that all research be

disclosed to the FDA during the drug approval process, regulators have no

choice but to make their decisions based on the best-case scenarios that

drug companies report to them, " U.S. Rep. Maurice Hinchey (D-N.Y.), whose

office is reviewing the documents, said in a statement. " These decisions

affect the health and lives of millions of Americans. If Eli Lilly's

research indicated dangerous side effects of their product and they withheld

that information, they knowingly jeopardized the public's health. Their

failure to disclose what they knew may have cost lives. "

Morry Smulevitz, manager of global product communications at Eli Lilly, said

he could not comment on the documents because he hasn't seen them.

" Certainly Lilly is committed to public disclosure of all clinical trial

data so health-care providers and patients can make informed treatment

decisions, " he said. " Prozac has been prescribed for over 50 million people

worldwide. It is one of the most studied drugs in the history of medicine,

and its safety and efficacy is well-studied and well-documented and

well-established. Beyond that, unfortunately, it's really difficult without

having the ability to review the supposed missing documents that we're not

aware of to know what we're trying to make comments upon. "

Smulevitz said he had requested the documents from Jeanne Lenzer, a New

York-based medical investigative journalist who received them and then sent

them on to the BMJ and the FDA. But, he said, the request was not met.

Dr. Kapit, the FDA reviewer who originally approved fluoxetine in

1987, told the BMJ that he had never been given the Lilly data.

" If we have good evidence that we were misled and that data was withheld,

then I would change my mind [about the safety of fluoxetine], " he said in a

statement. " I do agree now that these stimulatory side effects, especially

in regard to suicidal ideation and homicidal ideation, are worse than I

thought at the time that I reviewed the drug. "

The documents in question reportedly disappeared during a product liability

suit brought in 1994 by families of the victims of ph Wesbecker, who, in

1989, killed eight people and wounded another 12 with an AK-47 before

turning the gun on himself at his workplace in Louisville, Ky. Wesbecker,

who had suffered a long history of depression, had started using fluoxetine

just one month before the shootings.

The relatives' civil suit alleged that the company had known about possible

side effects of the drugs, including a tendency towards violence.

The jury ruled 9-3 in favor of Lilly, but, in a shocking turnaround, the

company later admitted it had made a secret deal with the plaintiffs. In

1997, the judge on the case, Potter, amended the verdict to " dismissed

as settled with prejudice, " meaning it could be reopened. Potter was

presiding over another case Thursday, and could not be reached for comment

on the latest developments.

" It's been a big puzzle for many years, " Lenzer said. " The documents went

missing during a critical period in the [wrongful death] trial. " Lenzer

would not reveal who had sent her the documents.

The internal company document that stood out to Lenzer, she said, was one

that discussed the finding that 38 percent of people have a stimulation

effect, such as panic attacks and agitation, and that 19 percent of those

could be attributed to the drug.

According to Lenzer, the document stated " one in five [patients] could be

expected to experience this activation. And, later in the document, they

talk about how to do damage control, how to get the doctors not to worry

about this. Maybe the information actually got out and got buried. It's like

a little flicker of a flame. Obviously they didn't get this out to a wide

circulation. They didn't get it out to the people who needed to know. They

didn't get it to the FDA safety officer who reviewed it. "

Dr. Breggin, the medical expert in the Wesbecker case, has said the

activation effects could be higher than 38 percent.

Lenzer, however, said she is concerned that what she called a pattern of

secrecy among drug companies continues.

She referred to the Treatment for Adolescents with Depression Study (TADS),

the results of which appeared in the Aug. 18 issue of the Journal of the

American Medical Association. Although the findings were hailed as a victory

for antidepressants, Lenzer stated in a September letter to the BMJ that the

research had a flawed methodology and failed to report certain negative

results.

" This is still going on. It's not just 16 years ago. It's going on today,

right now, " she said.

An FDA spokeswoman said the agency had no comment at this point.

More information

The U.S. Food <http://www.fda.gov/cder/drug/antidepressants/default.htm>

and Drug Administration has more on antidepressant use in children.

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