Eli Lilly Prozac Documents: What do They Reveal?

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[sSRI-Research] Eli Lilly Prozac Documents: What do They Reveal?

 

 

 

 

Eli Lilly Prozac Documents: What do They Reveal?

Thu, 27 Jan 2005

 

http://www.ahrp.org/infomail/05/01/27.php

 

A report in the BMJ (formerly the British Medical Journal) that relied

on internal Eli Lilly documents to challenge Lilly's claims about the

safety of Prozac has stirred a prickly hornet's nest. [1] The

documents show, among other things, that a 1988 review of clinical

trials found that 38% of patients taking Prozac compared to 19% of

patients on placebo experienced " activation, " which is linked by the

FDA in current labeling to violent and suicidal behavior. [2] [PZ-477] .

 

Lilly took out a full page advertisement ( " An open letter to patients

and doctors " signed by Lilly CEO, Sidney Taurel) in 15 newspapers

nationwide stating: " it was simply wrong to suggest that information

on Prozac was missing, or that important research data on the benefits

and possible side effects of the drug were not available to doctors

and regulators. " [3] The BMJ has just issued a correction and an

apology to Eli Lilly for suggesting that documents went " missing "

stating: " all the documents supplied to the BMJ were either Eli Lilly

documents or were in the hands of Eli Lilly [and] had in fact been

disclosed during the suit. " [4]

 

The Associated Press reports that BMJ editor, Kamran Abbasi, said the

apology was limited to the issue of whether the documents were missing

from the court case. " Whether or not Eli Lilly made all of the

information available to the FDA at the appropriate times is a

question for the FDA to answerS. we await their response. " Morry

Smulevitz, a spokesman for Lilly, said the company also awaited the

FDA's finding. [5]

 

Inasmuch as the documents' authenticity is not in dispute, and the

information about the hazardous drug effects contained in the

documents (stamped " confidential) is of vital importance to public

health - we will focus on their content rather than be diverted by who

said what to whom. The documents reveal that as early as 1984 - years

before the FDA approved the drug - Lilly knew or should have known

that Prozac frequently induced severe adverse side effects, including

" activation " and suicidality [6]:

 

" ...frequency of side effects was very high (partly more than 90%) and

side effects resulted nearly in each study in drop outs. The frequency

of side effects depended on the dose, the age, and the duration of

treatment... the clinical significance of side effects is not only the

frequency of their occurrence but also their severity. "

 

Lilly's submission of clinical trial data to the German regulatory

authority (BGA) from a pooled group of 1,427 patients who tested

Prozac, showed that there were 16 suicide attempts - two of which were

successful. Furthermore, " In 15-20% of cases side effects...involve

the central nervous system. As most of them resemble the clinical

picture of the underlying disease, even from theoretical reasons one

has to expect intensification and not an improvement in symptoms... "

[PZ 281, p. 1525] [6]

 

A June 1984 Lilly memo notes: " A critical issue for the BGA is safety

in long-term treatment. " Among BGA's concerns: Prozac was " a

stimulating/activating drug (side effect profile, suicides, suicide

attempts) " and " the increase in agitating effect occurs earlier than

the mood elevating effect and therefore an increased risk of suicide

exists. " [PZ 2469, p. 489] [6]

 

In light of the risks, the German regulatory agency rejected Prozac in

1984 stating: " Considering the benefit & risk we think this

preparation totally unsuitable for the treatment of depression. " [6]

In 1985, BGA once again rejected Prozac stating:

 

" The use of the preparations [fluoxetine] seems objectionable, as the

increase in agitating effect occurs earlier than the mood elevating

effect and therefore an increased risk of suicide exists. " [PZ 1124][7]

 

One of the BMJ documents was a review of spontaneous domestic reports

of adverse events (1982 to 1991) including charts and graphs comparing

adverse effect reports for Prozac (14,198) and four older comparator

antidepressants (Trazodone, Amitriptyline, Desipramine, Maprotiline

(total 6,119 reports). Spontaneous reports constitute the FDA's alert

system for identifying side-effects in marketed drugs. The number of

reports involving Prozac and suicide attempts and hostile or injurious

behavior is astronomical compared to the older tricyclics - even when

adjusting for the number of prescriptions for each. Among Prozac users

there were 519 Suicide attempts reported; 468 cases of overdose; 234

reports of hostility; 115 reports of intentional injury; and 321

reports of drug-linked psychotic depression. When compared to

Trazadone, (at the time the next most prescribed antidepressant) the

suicide attempt rate among the adverse event reports was 3.7% for

Prozac and 0.2% for Trazadone (4 reports). [8]

 

Although Lilly vehemently denied the risk of suicidal acts,

agressiveness, and self-mutilation, in 2000, Lilly purchased a patent

for an improved version of Prozac - R-fluoxetine--prompting the Boston

Globe to investigate. The Globe reports revealed that documents

submitted to the US patent office for R-fluoxetine contradict Lilly's

public position, stating that R-fluoxetine will not produce several

existing hazardous side effects including: " akathisia, suicidal

thoughts, and self-mutilation, " which the patent calls " one of its

more significant side effects. " Lilly paid the patent holder of

R-fluoxetine $20 million but never developed the improved Prozac. [9]

 

The Globe published excerpts from several Lilly documents stamped

" confidential " --including documents obtained by BMJ. [9]. For example,

an e-mail dated Nov. 13, 1990, from Claude Bouchy (a Lilly employee in

Germany) to three corporate executives at the company's US

headquarters, including Lilly's President, Sidney Taurel, complains

about questionable instructions he had been given for coding adverse

events: [10]

 

" the directions our safety people are getting from the corporate group

(Drug Epidemiology Unit) requesting that we change the identification

of events as they are reported by the physicians. . .Our safety staff

is requested to change the event term 'suicide attempt' [as reported

by the physician] to 'overdose.' .... it is requested that we change .

.. . 'suicidal ideation' to 'depression.' " [PZ 4003]

 

Bouchy tried to appeal to his US colleagues at Lilly headquarters:

 

" I do not think I could explain to the BGA, to a judge, to a reporter

or even to my family why we would do this especially on the sensitive

issue of suicide and suicide ideation. " [PZ 4003]

 

On November 14, 1990, Bouchy tried once more to appeal to his

colleagues at Lilly headquarters:

 

" I personally wonder whether we are really helping the credibility of

an excellent ADE system by calling overdose what a physician reports

as a suicide attempt and by calling depression what a physicians is

reporting as suicide ideationSit could be argued by people who have

little sympathy for the company or by regulatory authorities that it

is not a responsible way to deal with an issue which is getting so

much attention in the scientific and in the general press. " [bold

added PZ 1573]

 

The documents undermine the company's 16 years of denial: " there is

absolutely no medically sound evidence of an association between any

antidepressant medicine, including Prozac, and the induction of

suicidal ideation or violence.'' [11].

 

Those who have seen the documents, including Congressman Maurice

Hinchey, say the documents " clearly show a link between Prozac and

actions of violence perpetrated by people taking the drug against

themselves and against others. The documentsS show that the company

was instructing its employees to hide this information. We're seeing

evidence here that it was a conscious act on the part of the company. "

[12]

 

Lilly may have made the documents available to plaintiff lawyers,

expert witnesses, and the FDA, at some time, in some form.

Nevertheless, the fact remains that most patients psychiatrists,

pediatricians, family physicians that Prozac poses serious risks of

violence and suicidal behavior. And even the FDA reviewer says he did

not know about this information Indeed, it is hard to believe that

responsible doctors would widely prescribe a drug that they knew might

induce agitation, hostility, anxiety and violent / suicidal behavior

in as many as 1 out of every 5 patients! [2] Doctors don't generally

play Russian roulette with their patients' lives.

 

Dr Richard Kapit, who was the FDA clinical reviewer who approved

fluoxetine based on the data Lilly submitted to the FDA, said he was

not given the data in these documents. [1] And Dr. David Graham,

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

discovered that Lilly excluded 76 of 97 cases of reported suicidality

from its post-marketing surveillance data submitted to the FDA. Dr

Graham concluded in a memo dated September 11, 1990: " because of

apparent large-scale underreporting, [Lilly's] analysis cannot be

considered as proving that fluoxetine and violent behavior are

unrelated. " [1] Dr. Martin Teicher, a prominent Harvard researcher and

clinician who wrote the first crucial scientific paper in 1990 linking

violent /suicidal acts to Prozac, told USA Today that " lives were

threatened and Americans treated like " guinea pigs " because Eli Lilly

& Co. officials lied 15 years ago in denying there was any evidence

the anti-depressant Prozac could cause suicidal behavior. " [12]

 

Notwithstanding Lilly's recent claim about the company's

" transparency, " the " open letter to doctors and patients " once again

fails to disclose to the public vital safety information. Despite an

FDA requirement (since March 2004) for all antidepressants, including

Prozac, to warn physicians and the public, about the risks of

activation and increased suicidal behavior, nowhere in this public

document does Lilly make that disclosure. Instead, Lilly states that

depression can cause suicide, but Lilly avoids mentioning that Prozac

can cause activation, hostility, and suicide.

 

Furthermore, the " open " letter misrepresents the evidence in Lilly's

own documents by claiming: " It can be dangerous to stop taking any

prescription medicine without a doctor's guidance - and Prozac is no

different. " [3] No different? A drug that increases the risk of

suicide - whose label the FDA requires to carry a Black Box warning -

is not like most medicines. Lilly's " promise to publish the results of

all Lilly clinical trials....and to make this information available

online " is contradicted by its actions. Lilly fails to post any of the

disputed documents, disingenuously claiming: " Due to court orders

requiring confidentiality of some of the documents contained within

the 52 pages, Lilly is unable to release the 52 pages of documents. " [3]

 

Now, as in the past, Lilly has aggressively sought to discredit

researchers and journalists who published data linking Prozac to

suicide - even as its own documents confirmed the risk. One of Lilly's

early targets was Dr. Martin Teicher, whose published finding of a

3.5% suicide risk for patients put on Prozac. [14] Others include, Dr.

Peter Breggin (Talking Back to Prozac, 1995), Dr. Joseph Glenmullen

(Prozac Backlash, 2000), and Dr. David Healy (Let Them Eat Prozac,

2003). Each has been savagely pilloried for bringing to public

attention the concealed hazards of SSRI antidepressants. These

psychiatrists have examined the Lilly documents in their special

capacity as expert witnesses, and they dispute Lilly's claims, arguing

that the documents to the best of their knowledge were sealed and out

of public reach. Their separate written reviews of the documents will

be posted on the AHRP website. See:

http://www.ahrp.org/risks/SSRIbreggin0105.php

 

The marketing of Prozac is a microcosm of the pharmaceutical

industry's modus operandi for marketing drugs of dubious benefit but

hazardous side effects to millions of unsuspecting people. The

marketing of such drugs relies primarily on promotional campaigns and

the seal of legitimacy from paid medical opinion leaders. Neither the

drug's hazards nor the consulting fees of the experts are disclosed to

the public. Vioxx and the other COX-2 drugs were marketed like the

SSRIs to millions of people who didn't need them but who were harmed

from their concealed hazardous effects. [15] New York State Attorney

General, Eliot Spitzer, called the concealment of adverse drug effect

data from physicians--fraud. The matter of who did what, when, and how

it impacted on public safety is grist for Congressional oversight and

investigations by state and US attorneys general.

 

Lilly's documents cast doubt on the legitimacy of current psychiatric

practice guidelines that have been formulated on the basis of

incomplete, biased information about the safety and efficacy of widely

prescribed antidepressants, including Prozac. The focus of the debate

should be to determine whether doctors and patients were adequately

informed about the risks associated with Prozac, risks which Lilly

documents show the company knew for over 16 years. Congress needs to

consider the impact of not making the public aware of potentially

harmful effects of commonly prescribed drugs.

 

Questions for Lilly:

1. Has Eli Lilly ever acknowledged - and does the company acknowledge

today--that antidepressants, including Prozac (fluoxetine) and

Cymbalta (duloxetine), cause suicidal behavior?

 

2. Has the information about this clinically significant risk been

disclosed to physicians in prescribing guidelines? If so, show

documented evidence.

 

3. Is there any evidence that Lilly tried to make the suicide /

violence risks known to the public?

 

4. When can we expect the Black Box to appear on the labels of Lilly

products containing fluoxetine and duloxetine? (This is an FDA

requirement)

 

Questions for the FDA:

1. If, as Lilly insists, the company made available all " important

research data on the benefits and possible side effects of the drug "

to the FDA, why was information not disclosed about clinically

significant harmful side effects, including the risks of suicide and

violence, in the Prozac label all these years?

 

2. If, as Lilly insists, the FDA knew that Prozac induced activation

linked to suicide attempts in 38% of adult patients in clinical

trials, what was the justification for approving the drug for use in

depressed children?

 

Contact: Vera Hassner Sharav

212-595-8974

 

 

References:

1. Lenzer, J. FDA to Review " Missing " Drug Company Documents, BMJ

(formerly British Medical Journal), January 1, 2005.

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

 

2. See: Lilly Memo. Activation and Sedation in Fluoxetine Clinical

Trials, 1988 [PZ 477]

 

3. Lilly An open letterS.: http://www.lilly.com/news/prozac_bmj.html

 

4. BMJ. Eli Lilly: Correction and apology

http://bmj.bmjjournals.com/cgi/content/full/330/7481/7/DC1

 

5. Associated Press. U.K. Medical Journal Retracts Report on Missing

Prozac Data, WSJ, January 27, 2005 11:20,

http://online.wsj.com/article_email/0,,SB110684070739638014-INje4Nglah4nZ2sa4KIa\

6yHm4,00.html

 

6.. Lilly Memo, Keitz; Bad Homburg to Corporate Headquarters, May 25,

1984, with Comment on Clinical Documentation Fluoxetine from BGA

(Germany) rejecting Prozac for marketing. [bZ 281]

 

7. Lilly Memo, Hans Weber, February 27, 1985 with BGA rejection [PZ

1124 p. 336]

 

8. Spontaneous Domestic Reports January 1982-July 1991. [PZ-1548, See

pp. 5-14] online at:

http://www.house.gov/apps/list/press/ny22_hinchey/morenews/bmj_docs.pdf

 

9. Garnett, L. Prozac Revisited: As Drug Gets Remade, Concerns About

Suicides Surface, Boston Globe, May 7, 2000 p. A-1

 

10. Lilly Memo, Claude Bouchy to Lilly Executives at Headquarters,

including Sidney Taurel. November 13 and 14, 1990. [Pz -4003] [PZ-1573]

 

11. The statement was made under oath by Dr. Gary Tollefson, a Lilly

scientist. See: Zuckoff, M. Prozac data was kept from trial, Boston

Globe, June 8, 2000. p.A-1.

 

12. Belson K. " Lilly Shares Fall on Report About Prozac Documents NY

Times, January 1, 2005, C- p.; CNN at:

http://edition.cnn.com/2005/HEALTH/01/03/prozac.documents

 

13. Elias, M. Psychiatrist: Company hid link between Prozac, suicide

Documents raise questions; Eli Lilly denies accusations USA TODAY.

January 6, 2005 Page 2A

http://www.usatoday.com/printedition/news/20050106/a_prozac06.art.htm

 

14. Teicher MH, Glod C, Cole JO. Emergence of intense suicidal

preoccupation during fluoxetine treatment . American Journal of

Psychiatry,1990: 147: 207-210.

 

15. Vioxx Went Mostly To Patients Who Didn't Need It, Stanford

Researcher Says. Press Release, Stanford University Medical Center.

January 24, 2005.

http://www.sciencedaily.com/releases/2005/01/050123210312.htm