Prozac Approval Flawed: Suicide Link Was Known Before FDA OK

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The British Medical Journal has apologized to Eli Lilly for implying in a recent article that scientific documents about Prozac's side effects had "gone missing" during a legal case some years ago, as reported by BBC today. But here is the important data that almost get drowned out by the noise over a largely irrelevant point: Eli Lilly, as the maker of Prozac, has been aware of serious side effects even before obtaining the FDA's approval for the drug.

"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", says Vera Hassner Sharav of the Alliance for Human Research Protection.

Among those who have been following developments in psychiatry and especially the side effects caused by psychiatric drugs, it is an open secret that Prozac and similar drugs do indeed induce suicides and violence. Christopher Pittman's case of double murder and arson, committed while on a heavy dose of Zoloft, is shortly to go to trial in the U.S.

So if Eli Lilly knew, and the FDA should have known, that Prozac is a potentially deadly drug, what exactly is it that went wrong with the drug approval process in the first place? Once approved, what THEN went wrong to prevent side effects, now obvious, from being critically evaluated? Those are the questions we should be asking. Vera Hassner Sharav in her recent report discusses what is known so far.

. . .

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
Promoting Openness, Full Disclosure, and Accountability
www.ahrp.org

(See original here)

A report in the BMJ (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 e