Fwd: [SSRI-Research] SSRI RISKS: NEW DATA OR RENEWED SCRUTINY?

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Thu, 04 Dec 2003 08:38:37 -0500

[sSRI-Research] SSRI RISKS: NEW DATA OR RENEWED SCRUTINY?

 

SSRI RISKS: NEW DATA OR RENEWED SCRUTINY?

http://www.prozactruth.com/ssri_research.htm

 

By David Healy, MD, Ph.D

 

Even before Prozac was licensed at the end of 1987 regulators in Germany had

raised the issue of suicidality. Prozac was held up for many years in

Germany and only finally licensed at the end of 1989 after some apparently

unorthodox lobbying of supposedly independent regulatory panel members.[1]

In the course of handling various problems including suicidality before and

after launch in the US, executives from Lilly had access to the head of the

CNS Division of the FDA out of hours, and to FDA Director David Kessler at

his home, as well as to other officials involved in vetting the applications

for other SSRIs such as Paxil.[2]

 

Did this access help the cause of patient safety? A lot depends on how one

interprets how Lilly and the FDA managed the assessments of Prozac in

Germany. In a letter to Lilly on September 9th, 1987, indicating Prozac was

approvable, Robert Temple of the FDA wrote:

 

We require a review of the status of all fluoxetine actions taken or pending

before foreign regulatory authorities. Approval actions can be noted, but we

ask that you describe in detail any and all actions taken that have been

negative, supplying a full explanation of the views of all parties and the

resolution of the matter.[3]

 

In response, on October 26th, 1987, Lilly submitted a series of reports

including one from the German regulatory body, the BGA.[4] The first point

(1.0) the Germans made was " the drug is not sufficiently tested .. and the

therapeutic efficacy claimed for [Prozac] is insufficiently substantiated. "

The second point (2.0) referred to Prozac's: " unacceptable damaging

effects " . Following this, under 2.1, the BGA noted " [an] increase in

agitating effect occurs earlier than the mood elevating effect and therefore

an increased risk of suicide exists. " Under 2.2, the BGA noted that during

treatment with the drugs " some symptoms of the underlying disease (anxiety,

insomnia, agitation) increase, which as adverse effects exceed those which

are considered acceptable by medical standards. " The letter containing all

this was sent to the FDA by Max Talbott, Lilly's regulatory advisor, a

former FDA employee himself.

 

It is not clear what the FDA understood unacceptable damaging effects to

mean or whose job it was÷Lilly's or the FDA's÷to make sure the FDA

understood.[5] The FDA routinely sends letters to companies prior to

approving drugs asking to be fully informed about any decisions made by

foreign regulators. But it is clear that the question was asked as to just

what unacceptable and damaging meant. There were phone calls between

Laughren and Kapit of the FDA and members of Lilly, which led to a letter

from Talbott on December 4th stating " In February 1985... the BGA had

alluded to 'unacceptable damaging effects'· This phrase was not defined. " [6]

He went on to say that " the data submitted to the BGA have also been

submitted to the FDA, which has reviewed data on more patients using more

sophisticated analyses than those submitted to the BGA up to this time. "

 

A memo from Richard Kapit on December 8th 1987 records receipt of this

letter, the teleconference that had given rise to it, and the assertion that

the

 

....German authorities never defined or documented the phrases 'severe organ

damage' or 'unacceptable damaging effect.' The company asserts that all

information made available to the BGA has been made available to the FDA...

Conclusion: the BGA comments do not appear to reflect clinical events, since

no such events have been reported to the FDA and according to the company we

have received all information submitted to the BGA. Recommendation: The

comments by the BGA should not affect FDA's conclusion that NDA 18-936 is

approvable.[7]

 

By the end of December that year Prozac had been approved.

 

Nearly seven years later, having claimed that if he even overheard someone

report a side effect of Prozac in a corridor at a party he would report it

to the FDA, Nancy Zettler, the attorney for the plaintiffs in the Wesbecker

case, faced Leigh Thompson, then the chief scientist at Lilly, with this

issue in the course of his deposition in the Wesbecker case:

 

Q: Do you feel that you have an obligation to report the fact that the

German government raised the issue and that it was fully analyzed back in

1984 or '85?

 

A: I would probably call on my legal colleagues to help me interpret it, but

under the current NDA regulation, I think the current NDA regulation does

request information on negative findings by other regulators. But what that

means has never been tested in court in terms of whether that is just a

letter that you receive from the BGA saying we're not going to approve your

drug, or whether it means everything that you talk about in working up

whatever their questions are. I'm not aware that that's ever been resolved.

 

Q: So let me make sure I understand. You feel it is your absolute duty to

report a conversation that you have overheard in the hallway, but you don't

necessarily feel it's your duty to report an issue raised by another

regulatory agency and the analyses that were done by the drug company in

response to that issue being raised?

 

A: Under the FDA laws and regulations, I think you've stated it correctly.

[8]

 

It seems fairly evident what the unacceptable damaging effects were. It is

not clear that the FDA sought or received advice from anyone on this point.

There is no record of what any of these FDA officials made of the testimony

of Joachim Wernicke, a key player at Lilly in steering Prozac through the

FDA who, faced with this very point in the Wesbecker trial, acknowledged

that a mistake had been made.[9]

 

Aside from any interpretations of what these exchanges reveal, there are a

number of datasets that throw light on what might be said about what Lilly

or the FDA can reasonably be said to have done or not done. Following the

public controversy about the risk of suicide induction on Prozac, the FDA

held a hearing in September 1991 that appeared to exonerate Prozac. At this

hearing experts were faced with a selected dataset from Lilly's clinical

trial data.

 

FDA PDAC Hearing Data - 1991

Drug

Patients Suicidal Acts Acts/PEY % Suicides & Suicidal Acts

Prozac

 

1765

 

6

 

0.054

 

0.3%

 

Comparator

 

731

 

3

 

0.043

 

0.4%

 

Placebo

 

569

 

1

 

 

 

0.2%

 

Some years beforehand, in 1985, Lilly had presented a much more

comprehensive set of clinical trial data to the German regulators. One

explanation for the difference in the datasets is that the 1991 set

contained US clinical trial data only. These US trials contained data from a

Dr Cohn, which the FDA had previously adjudged to be unsatisfactory.

 

German Regulatory Data - 1985

Drug

Patients Suicidal Acts Acts/PEY % Suicides & Suicidal Acts

Prozac

 

6903

 

63

 

0.054

 

0.91%

 

Comparator

 

2310

 

15

 

0.043

 

0.65%

 

In this German dataset, Lilly included under the heading of comparator all

data from placebo and other antidepressants with which Prozac was being

compared. These are the tabulated figures that can be found in the

submissions to Germany, but the clinical trial data going with these figures

make it clear that Lilly had miscoded as placebo suicidal acts, acts that

had not occurred on placebo - occurring either in the run in phase of trials

or up to a year after the trial was over[10].

 

When this miscoding is taken into account, the resulting correct set of

figures is as follows:

 

Correct Clinical Trial Data 1985

Drug

Patients Suicidal Acts Acts/PEY % Suicides & Suicidal Acts

Prozac

 

6903

 

63

 

0.054

 

0.91%

 

Comparator

 

2310

 

7

 

0.020

 

0.30%

 

Miscoded

 

 

 

8

 

 

 

 

 

These figures were not presented to the FDA panel hearing on Prozac -

although they were available to the FDA.

 

But in addition to these figures, the FDA was at this point sitting on

figures for suicidal acts from clinical trials of Zoloft and Paxil, of which

panel members were unaware.

 

The data on Zoloft and Paxil subsequently appeared as follows:

 

ZOLOFT & PAXIL - 1991

Drug

Patients Suicides Suicidal Acts % Suicides & Suicidal Acts

Zoloft

Comparator

Placebo

 

2,053

595

786

 

2

0

0

 

7

1

5

 

0.44%

0.17%

0.64%

 

Paxil

Comparator

Placebo

 

2,963

1151

554

 

5

3

2

 

40

12

6

 

1.52%

1.30%

1.44%

 

In fact FDA medical reviews of these data, which are publicly available,

reveal that Pfizer and SmithKline had followed Lilly's example in miscoding

figures for suicidal acts, incorporating under the heading of placebo

suicidal acts that had not occurred on placebo. This reorganizing of the

data had happened after the public controversy about Prozac had blown up,

making it difficult to resist the interpretation that the companies and the

regulators were trying to manage a problem. Adjusting for this leads to the

following table:

 

ZOLOFT & PAXIL - 1990

Drug

Patients Suicides Suicidal Acts % Suicides & Suicidal Acts

Zoloft

Comparator

Placebo

Miscoded

 

2,053

595

786

 

 

2

0

0

0

 

7

1

2

3

 

0.44%

0.17%

0.25%

 

 

Paxil

Comparator

Placebo

Miscoded

 

2,963

1151

554

 

 

5

3

0

2

 

40

12

1

2

 

1.52%

1.30%

0.20%

 

 

 

 

There seem to be three questions for regulators to answer.

 

* First, why did they let SSRI companies miscode the figures for suicidal

acts in this fashion?

* Second, why when data on Prozac were being presented, did the

regulators keep Zoloft and Paxil data out of the frame?

* Third, did they not at any point themselves put these datasets together

and realise that the relative risk of suicidality for these SSRIs in adults

was 2.5 times greater than it was on placebo[11] - exactly the figure we are

now told applies to the risk of suicidality on Paxil in children?

 

 

This data is now over a decade old.

 

David Healy MD MRCPsych

North Wales Department of Psychological Medicine

Hergest Unit

Bangor

Wales LL57 2PW

Tel: 01248-384452

Fax: 01249-371397

------

 

[1]. Depositions of Nick Schulz-Solce and Hans Weber in Fentress Vs Eli

Lilly.

 

[2]. Deposition of W Leigh Thompson in Fentress Vs Eli Lilly July 20th, 21st

& 22nd (1994).

 

[3]. Letter to Max Talbott of Lilly from Robert Temple of FDA on September

9th 1987, in a series of correspondences that followed 88 submissions from

Lilly about Prozac starting in September 6th 1983. Fentress Exhibit Pz1064

290.

 

[4]. Letter from MaxTalbott to FDA, Fentress Exhibit Pz 2027, 1643.

 

[5]. See Fentress trial testimony÷Joachim Wernicke.

 

[6]. Letter from Max Talbott to the FDA, December 4th 1987, Exhibit 10 in

Deposition of N Schulz-Solce in Fentress Vs Eli Lilly.

 

[7]. Memo from Richard Kapit of FDA, Dec 8th 1987, Exhibit 11 in Deposition

of N Schulz-Solce in Fentress Vs Eli Lilly.

 

[8]. Deposition of W Leigh Thompson in Fentress Vs Eli Lilly July 22nd 1994.

 

[9]. Testimony of Joachim Wernicke in Fentress Vs Eli Lilly.

 

[10] Brickler G (1994). Exhibit 1 in the deposition of G Brickler in

Fentress Vs Eli Lilly

 

[11] Healy D (2003). Lines of Evidence on SSRIs and Risk of Suicide.

Psychotherapy and Psychosomatics 72, 71-79.

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