The info mail below might interest folks on the list who have taken an
active interest in some of the ethical/regulatory/ and research issues
surrounding Pozac and concerns about it being linked to suicide . This info
mail is from a well established U.S. human rights advocacy
group consisting of medical doctors, lay people and academics.
MHW
ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
Promoting Openness, Full Disclosure, and Accountability
<http://www.ahrp.org>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 1984years before the FDA approved
the drugLilly 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 attemptstwo 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 tricyclicseven 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 ProzacR-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 guidanceand Prozac is no different.” [3] No
different? A drug that increases the risk of suicidewhose label the FDA
requires to carry a Black Box warningis 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 suicideeven 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>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 acknowledgedand 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
<[log in to unmask]" target="_blank">http:[log in to unmask]>[log in to unmask]
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>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>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>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-INje4Nglah4nZ2sa4KIa6yHm4,00.html>http://online.wsj.com/article_email/0,,SB110684070739638014-INje4Nglah4nZ2sa4KIa6yHm4,00.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>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>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>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>http://www.sciencedaily.com/releases/2005/01/050123210312.htm
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