From [Janne Larsson]
To: info@mhra.gsi.gov.uk
cc: dhmail@dh.gsi.gov.uk nice@nice.org.uk
Open letter to Professor Kent Woods, Chief Executive, MHRA
July 29, 2007
The MHRA’s failure to ACT to protect children from being harmed by the ADHD drug Strattera
This is not a request for information or documents per the Freedom of Information Act.
It is a protest against the MHRA’s failure to ACT to protect children from being harmed by the ADHD drug Strattera. It is a protest against the MHRA’s failure to fulfil its promise to the public, as stated on its web site:
“…we take any necessary action to protect the public promptly if there is a problem.” [1]
There are – as the agency is well aware of – many problems with the ADHD drug Strattera. But where is the “necessary action to protect” the children?
Let me point out some good examples of problems and lack of action:
· In the beginning of 2006, the MHRA found out that there was “large number of psychiatric reactions reported” for the ADHD drug Strattera [2]. 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).
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 [3]. In that report it is, for example, 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).
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 one year earlier was submitted to the FDA (and from which the FDA report from March was written).
Next someone at the agency decided that no cumulative review was needed – the MHRA did not, despite now having the necessary data, do its own analysis of the information submitted by Lilly. 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.” This was really a magic trick by the agency – suddenly the need for a full cumulative review of all the 10 988 psychiatric reactions reported had disappeared!
And so we come to the end of March 2007, when, very late, the so-called Public 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.”
The circle is 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 all the “large number of psychiatric reactions reported” (a review that was never done), the conclusion is reached again that a cumulative review is needed for 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 above [the report from 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.”
A recent request per the Freedom of Information Act to see the “request letter” sent to Eli Lilly to get the cumulative review is answered in the following way: “…the responses to PSUR requests are normally submitted in a subsequent PSUR.”
In summary: One and a half year after the “large number of psychiatric reactions” was mentioned by the MHRA as needing an urgent review, no review is done – and of course, no actions are taken. No warnings are 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, is not acted upon – and, to make it even worse, the whole thing is 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?
Can the “effective 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”?
· In the above mentioned Public Safety Update Report the MHRA assessors took up the subject of Movement Disorders, and included psychomotor hyperactivity (pages 55-56). 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.”
What could be understood from this is 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 were only signs of “exacerbation of the underlying ADHD”.
This is remarkable in several ways. First of all the 700 reports would, considering the accepted rate of underreporting, represent an actual incidence of at least 7000 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 says 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 are 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.
So Eli Lilly – who had already excluded these vital data from their “review” of Movement Disorders – was only requested to “provide further clarification” as to why these data had been withheld. The company was not ordered to submit the data so that the MHRA could do its own evaluation of the information. And as of July 20 no clarification had been submitted. According to information from the MHRA this was not even expected. Instead these data should hopefully be available for review in a later Public Safety Update Report.
In summary: The MHRA finds already in the beginning of the year that Eli Lilly has excluded vital security data about Strattera, but does not order the company to immediately submit the withheld information to the agency. Instead the agency asks Lilly to explain why the data were withheld – but does not expect to get an answer to the question. The matter is handled according to “normal procedures”, which means that it will hopefully be covered in a later safety report (if Lilly has answered by then).
What about “…we take any necessary action to protect the public promptly if there is a problem”?
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Other information, known to the MHRA, has shown that up to May last year 23 132 reports about harmful effects of Strattera were submitted internationally, in which 58 048 different adverse effects were described.
What will need to happen for the MHRA to withdraw this destructive drug from the market? Or what will need to happen for the agency to do something effective to protect children from being harmed by the drug?
Yours sincerely,
Janne Larsson
Reporter – investigating psychiatry
Sweden
