Open Letter To Professor Kent Woods MHRA - Strattera

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The text below in PDF on http://jannel.se/letter.mhra.strattera.jan08.pdf

Open letter to: Professor Kent Woods

Chief Executive

Medicines and Healthcare products Regulatory Agency - MHRA

January 2, 2008

The ADHD drug Strattera – actions needed now

This letter gives updated information about the harmful effects of the

ADHD drug Strattera. It should be of great interest to the MHRA

management, considering the promise: " …we take any necessary action to

protect the public promptly if there is a problem. " [1]

In this case there is definitely a " problem " , and it cannot have been

properly communicated to the MHRA management. Shouldn't the " problem " ,

that there exists " compelling evidence " that the drug causes serious

harmful effects in many children, have been acted upon, if the

management had been aware of it?

I hope the data below will repair the lack of information and get

responsible officials to investigate further and ACT for the safety of

children.

------------------

For the years 2004-2006 there have been 31,835 adverse reactions for

Strattera reported to the FDA (where Strattera was the primary suspect

drug) in 9,250 individual cases (with duplicate reports excluded) [2].

This puts Strattera as number three among most reported psychiatric drugs.

For the purpose of causality assessment it should definitely be

observed that Strattera is in the lead – number 1 – as regards notes

about positive dechallenge/rechallenge (*see note) in the reports to

the FDA about psychiatric drugs:

In 1,562 unique cases – in 17% of the 9,250 cases – it was noted the

subsequent disappearance of the adverse reaction(s) when medication

was ceased (1,556 cases) and/or a reappearance of the adverse

reaction(s) when medication was resumed (227 cases) [5]. (I suppose

the MHRA finds the linked document of great value for the purpose of

causality assessment. It contains highlighted data about suicidality –

with 92 cases, 1/3 of the cases reported, of which could be said: When

Strattera was stopped the child didn't any longer want to kill

himself/herself.)

The total number of unsorted adverse reactions reported

internationally for Strattera between November 2002 (when Strattera

was approved) and March 2006: " During this reporting period, a total

of 23,132 spontaneous adverse event reports of atomoxetine

[strattera], representing 58,048 adverse events, were collected by the

MAH [Market Authorization Holder; Eli Lilly]. " [6] Updating this

figure with the number of reports mentioned in Periodic Safety Update

Reports number 7-8, covering the periods May 2006 – May 2007, one gets

a total of 61,220 adverse events in 25,034 reports for Strattera [7].

Once again: A total of 61,220 adverse events in 25,034 reports up to

May 2007.

* dechallenge: withdrawal of a product from the patient's therapeutic

regimen; positive dechallenge: partial or complete disappearance of an

adverse event after withdrawal of the product; rechallenge:

reintroduction of a product suspected of having caused an adverse

event following a positive dechallenge; positive rechallenge:

reoccurrence of similar signs and symptoms upon reintroduction of

product. [3]

" Recovery after medicine withdrawal [dechallenge] is an important

pointer to a causal relationship…recurrence on rechallenge is strongly

suggestive that the medicine was responsible. " [4]

Despite " compelling evidence " for a causal association between

Strattera and treatment emergent symptoms of psychosis or mania – no

action by the MHRA

The word " promptly " , in the MHRA promise about necessary actions,

refers to the manifestation of the ability of the agency to respond

without delay or hesitation in case of a problem. This should be

compared to the extreme ineffectiveness and inability to act described

below.

In January 2006 MHRA described " a problem " of magnitude with

Strattera. The agency had found out that there was a " large number of

psychiatric reactions reported " for the drug [8]. The conclusion in

the Strattera – Risk: Benefit Assessment Report (p. 23) was: " Due to

the large number of psychiatric reactions reported (the majority of

which are unlisted), in September 2005 the MHRA requested the MAH

[Market Authorization Holder] to perform a cumulative review of all

psychiatric disorders reported for atomoxetine. The MAH is currently

performing the review and it is anticipated that it will be available

during " [deleted in document]. " The actual number of " psychiatric

reactions reported " was at that time 10,988 (as stated in Annex 4 to

the report) [9].

A cumulative review was however never done. But in March 2006 the FDA

published its report over some of the psychiatric reactions reported

from ADHD drugs, Psychiatric Adverse Events Associated with Drug

Treatment of ADHD: Review of Postmarketing Safety Data, for the

Pediatric Advisory Committee meeting, March 22, 2006 [10]. In that

report it is stated that Eli Lilly (for the period January 2000 – June

2005; Strattera was approved and marketed first November 2002) had

received 360 reports of psychosis or mania (p. 14). FDA had received

292 reports.

The conclusion was reached that the FDA review " presents compelling

evidence for a likely causal association between each of these four

drugs [strattera/amphetamine drugs] and treatment emergent onset of

signs and/or symptoms of psychosis or mania, notably hallucinations,

in some patients. " (p. 17)

It is stated: " These data show that some patients, including some with

no identifiable risk factors, can develop drug-related signs or

symptoms of psychosis or mania, such as hallucinations, at usual doses

of these drugs. "

It is stated: " Positive rechallenge (i.e., recurrence of symptoms when

drug is re-introduced) is considered a hallmark for causality

assessment of drug-induced adverse effects. Cases which include a

positive rechallenge were reported by the Sponsors for each of the

drugs included in this analysis. "

It is stated: " a substantial proportion of psychosis-related cases

were reported to occur in children age ten years or less, a population

in which hallucinations are not common. " And: " The occurrence of such

symptoms in young children may be particularly traumatic and

undesirable, both to the child and the parents. "

As the MHRA is well aware of, only a fraction of the actual adverse

effects occurring are reported; it's estimated to be 1-10 percent.

The MHRA did not in any visible way act on the data in the FDA report.

But the agency in some way finally found that Eli Lilly had not done

or submitted the requested " cumulative review over psychiatric

disorders reported for atomoxetine " , and in August 2006 the agency

requested Eli Lilly to submit the same data set that, more than one

year earlier, was submitted to the FDA and formed the basis for the

FDA report (part Strattera) presented in March 2006.

Next, someone at the agency decided that no cumulative review was

needed from Eli Lilly – the MHRA did neither, despite now having the

necessary data, do its own analysis of the information submitted.

Nothing was done with these data. Instead the agency wrote: " The

safety of Strattera, including review of all serious psychiatric

reactions, is considered on an ongoing basis in the periodic safety

update reports… Our own assessment of subsequent periodic safety

updates satisfied us that the issue of psychiatric reactions could be

appropriately monitored through these updates and there was not a

requirement for a separate and cumulative review of psychiatric

reactions with Strattera. " [11] This was really a magic trick –

suddenly the need for a full cumulative review of all the 10,988

psychiatric reactions reported had disappeared!

And so we come to March 2007, when, very late, the Periodic Safety

Update Report (PSUR) for Strattera, for the period May 27, 2005 –

November 26, 2005, was finalized. In the PSUR it is stated (p. 61)

under the heading Conclusions: " the MAH [Marketing Authorization

Holder; Eli Lilly] is requested … to perform cumulative reviews of all

reported cases of hallucinations, mania, agitation, and psychotic

reactions with a view to adding these to section 4.8 of the SPC

[summary of Product Characteristics] should there be evidence of a

causal association between these events and atomoxetine treatment. "

[Emphasis added] [12]

The circle was closed. More than a year after it was stated in the

Strattera – Risk: Benefit Assessment Report from January 2006, that a

cumulative review was needed for the " large number of psychiatric

reactions reported " (a review that was never done), the conclusion was

reached again that a cumulative review was needed for a main part of

these reactions.

The question was sent to the MHRA: How come the MHRA is not accepting

the conclusions of the FDA assessors in the report presented March

2006, but instead requests Eli Lilly to do a cumulative review of

basically the same data already reviewed by the FDA? And the answer

was: " Changes to European product information are based on assessment

by EU regulators, agreement between members states and in line with

legal requirements about product information, not on conclusions of

FDA assessors. " [13]

All the cases of positive dechallenge/rechallenge noted for psychotic

behaviour and mania in the FDA report, all the " compelling evidence " –

meaning evidence you cannot resist – " for a likely causal association

between " Strattera and " treatment emergent onset of signs and/or

symptoms of psychosis or mania, notably hallucinations " – were simply

neglected by the MHRA.

A later request per the Freedom of Information Act to see the " request

letter " sent to Eli Lilly to get the cumulative review done is

answered in the following way: " …the responses to PSUR requests are

normally submitted in a subsequent PSUR. "

One and a half year after the " large number of psychiatric reactions "

was mentioned by the MHRA as needing an urgent review, the review was

still not done – and of course, no actions were taken. No warnings

were issued in Europe. The " compelling evidence " for a causal role for

Strattera in inducing psychosis or mania in children, as mentioned by

the FDA assessors, was not acted upon – and, to make it even worse,

the whole thing was turned back to Eli Lilly, the manufacturer, so

that they maybe one day in the future could submit their analysis of

the causal role of Strattera in inducing psychosis and other severe

psychiatric reactions. Should we expect that Eli Lilly would find

" compelling evidence " for Strattera causing these effects? Having read

the analyses and conclusions by Eli Lilly in the PSURs I can clearly

state that Lilly not one single time admits a causal role for

Strattera in inducing harmful effects. Lilly will always refer to " the

underlying disease " , " concomitant medication " , " confounding factors " –

even if the harmful effects are tenth of thousands there will never

for Lilly be a case where the drug caused the effect!

Can the " actions " by the MHRA, described above, be seen as an example

of the principle

" … we take any necessary action to protect the public promptly if

there is a problem " ?

And now we have arrived at the time for the publication of the latest

Periodic Safety Update Report (number 8) for the period 27/11

2006-26/5 2007 – the 4th of December 2007. It's two years after the

MHRA published its finding about the " large number of psychiatric

reactions reported " for Strattera, it's almost two years after the FDA

report was published, and it's one and a half year after the MHRA got

the full data set that the FDA report was based on.

What do we find about hallucinations, mania and psychotic reactions in

this recently finalized report? We find on page 12 the assessor's

comment: " The MAH has recently been asked to perform a cumulative

review of all spontaneously reported cases of 1) mania, 2) psychotic

disorders and 3) hallucinations. " [7]

Still, 2 years after the original conclusion about the need for an

urgent review of " the large number of psychiatric reactions " for the

drug, there is no such review done – and on top of this the assessor

uses the word " recently " to describe when the request for these key

reactions was made. In the very late 5th PSUR (for the period May 27,

2005 – November 26, 2005, finalized March 2007) it was stated that a

cumulative review of all cases of hallucination, mania and psychotic

reactions should be done " with a view to adding these " to the warning

section in the SPC for the drug. But with extreme delays and

ineffectiveness the situation in present time is that no such review

is done.

This means that parents and doctors in Europe are still not told about

" the compelling evidence " for drug induced hallucinations and mania.

They cannot find anything about what is mentioned in the FDA approved

label for Strattera, under the heading Emergence of New Psychotic or

Manic Symptoms, page 7: " Treatment emergent psychotic or manic

symptoms, e.g., hallucinations, delusional thinking, or mania in

children and adolescents without a prior history of psychotic illness

or mania can be caused by atomoxetine at usual doses. If such symptoms

occur, consideration should be given to a possible causal role of

atomoxetine, and discontinuation of treatment should be considered. "

[14] [Emphasis here.] And this text has been in place since August 29,

2006 [14]. The text should be compared to the UK SPC for Strattera

where nothing is mentioned about the fact that Strattera can cause

hallucinations, delusional thinking, or mania [15].

It must be said that the FDA is an agency out of control, subject to

Congressional investigations for its lack of ability to protect US

citizens from serious harmful effects of prescription drugs. That the

MHRA in this case falls far behind the FDA in ability and willingness

to protect patients is probably the most scathing criticism that can

be given to the agency.

The forgotten 700 cases of psychomotor hyperactivity

In an earlier letter I referred to PSUR 5 (finalized in the beginning

of 2007). In that PSUR the MHRA assessors took up the subject of

Movement Disorders, and included psychomotor hyperactivity (pages

54-55). The assessors criticize Eli Lilly and the following incredible

information is given: " … the MAH is requested to provide further

clarification as to the criteria used for determining that the 700

reported cases of psychomotor hyperactivity were related to an

exacerbation of the underlying ADHD which resulted in exclusion of

these cases from this review. " [12]

What could be understood from this was that Eli Lilly had received 700

reports that the company classified as reports of " psychomotor

hyperactivity " and that these were excluded from the analysis, with

the explanation that they only were a sign of " exacerbation of the

underlying ADHD " .

This was remarkable in several ways. First of all the 700 reports

would, considering the accepted rate of underreporting, represent an

actual incidence of between 7000 and 70 000 cases. Secondly, accepting

for a moment that ADHD is a valid medical disorder comparable to

diabetes – which of course it isn't, based as it is only on subjective

views, lacking any confirmable physical abnormality – this would mean

that Lilly said that the " medication " (Strattera, supposed to be

comparable to insulin) worsened the hyperactivity it was supposed to

positively affect (induced more hyperactivity).

Even more serious, the effects in these cases were probably another

example of misclassification by the MAH (as in the famous example

where pharmaceutical companies for many years misled the medical

agencies and the public about the suicide risk with antidepressant

drugs – classifying suicidal behaviour as " emotional lability " , thus

hiding the actual drug induced suicidality). What Eli Lilly classified

as " psychomotor hyperactivity " (an exacerbation of ADHD) should most

likely, in many cases, be classified as drug induced agitation, mania

or hypomania.

The MHRA was asking Eli Lilly to do an analysis of these 700 reported

cases, after the company had withheld this obviously sensitive

information and classified it as " exacerbation of the underlying

ADHD " . The natural solution should have been for the agency to request

all data about this security risk, followed by an independent review

of the data. But this was not done – and as expected nothing is

mentioned in the later PSURs – finalized December 4, about this

matter. A clever guess would be that Lilly didn't provide any further

clarification and that the MHRA forgot to ask – again.

------------------

In order to help the agency with its safety work the following

information can also be given:

The FDA review of psychosis or mania, aggression/hostility and

suicidality was based on data up to June 2005. The updated figures for

Strattera up to December 2006 for reports about psychotic

reactions/mania submitted to FDA are 340; for suicidality 378 and for

aggression/hostility 688. As can be seen in the

dechallenge/rechallenge summary [5] a large proportion of these

reactions have disappeared after withdrawal of the drug – pointing

again to the causal role of Strattera in inducing these reactions.

Finally it should be noted that a total of 870 reported cases of

suicidality and self-injurious behaviour in connection with Strattera

" treatment " have been collected internationally, up to May 2007,

according to data in PSURs. And the response from the MHRA assessor in

the latest PSUR (p. 22)? " Suicide-related events are listed reactions.

These reports do not raise any new issues… " [7a] No action taken. In

other words – these harmful reactions are already known, so just

continue to count!

I would be happy to know what the MHRA management now intends to DO to

protect children from these harmful effects.

Yours sincerely,

Janne Larsson

Reporter – investigating psychiatry

Snöbollsgränd 22

129 45 Hägersten

Sweden

janne.olov.larsson@...

References:

[1] MHRA, About us, http://www.mhra.gov.uk

[2] Reports for Strattera 2004-2006 http://www.psychdrugdangers.com/

(search: Strattera).

[3] FDA, Definitions,

http://www.fda.gov/medwatch/report/cberguid/define.htm

[4] Medsafe NZ, Causality Assessment of Suspected Adverse Medicine

Reactions,

http://www.medsafe.govt.nz/Profs/adverse/causality.asp

[5] Psychdrugdangers, Strattera (Atomoxetine) Dechallenge/Rechallenge,

http://www.psychdrugdangers.com/Strattera%20Suicidal%20Ideation.html

[6] Eli Lilly, Main Report, for Periodic Safety Update Report (PSUR)

6, page 105, period 27 November 2005 through 28 May 2006,

http://jannel.se/Mainreport_p105.pdf

[7] MHRA, Periodic Safety Update Report (PSUR) 7, Periodic Safety

Update Report (PSUR) 8, both finalized December 4, 2007; [7a] excerpt

PSUR 8 http://jannel.se/PSUR8.excerpt.pdf

[8] MHRA, Strattera (atomoxetine) - Risk: Benefit Assessment, January

2006; CHM AD HOC EXPERT ADVISORY GROUP ON STRATTERA (ATOMOXETINE),

page 23; since May 05, 2006 published on the MHRA web site, search

word: Strattera, http://www.mhra.gov.uk

[9] Eli Lilly, Annex 4 to Strattera (atomoxetine) - Risk: Benefit

Assessment, January 2006, pages 1-2 http://jannel.se/Annex4-page%201-2.pdf

[10] FDA, Psychiatric Adverse Events Associated with Drug Treatment of

ADHD: Review of Postmarketing Safety Data, released March 3, 2006.

http://www.fda.gov/ohrms/dockets/AC/06/briefing/2006-4210b_11_01_AdverseEvents.p\

df

[11] MHRA, answer FOI request, November, 2006

http://jannel.se/mhraanswer.nov06.pdf

[12] MHRA, Periodic Safety Update Report 5, May 27, 2005 – November

26, 2005, finalized March 2007, pages 2, 54-63,

http://jannel.se/PSUR5.excerpt.pdf

[13] MHRA, answer FOI request, May 25, 2007,

http://jannel.se/mhraanswer.pdf

[14] FDA, Approved label Strattera,

http://www.fda.gov/cder/foi/label/2007/021411s019lbl.pdf

Strattera, earlier label August 29, 2006,

http://www.fda.gov/cder/foi/label/2006/021411s018lbl.pdf

[15] Electronic Medicines Compendium, Strattera SPC, latest revision

January 23, 2007, http://emc.medicines.org.uk/ (search: Strattera)