Eli Lilly Prozac Documents - What do They Reveal?
From: Dr. Jai Maharaj (usenet_at_mantra.com)
Date: 01/28/05
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Date: Fri, 28 Jan 2005 21:00:16 GMT
Forwarded message from "veracare" <veracare@ahrp.org>
[ Subject: Eli Lilly Prozac Documents: What do They Reveal?
[ From: "veracare" <veracare@ahrp.org>
[ Date: 27 Jan 2005
ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
Promoting Openness, Full Disclosure, and Accountability
www.ahrp.org
FYI
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
answer.. 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 ideation.it 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 documents. 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
veracare@ahrp.org
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 letter..: 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-INje4Nglah4nZ2sa
4KIa6yHm4,00.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
End of forwarded message from "veracare" <veracare@ahrp.org>
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"And a man's foes shall be they of his own household.
- Matthew 10:34-36.
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