January 6, 2007.
Regarding investigation of “psychiatric reactions” from the ADHD drug Strattera
In the document Strattera (atomoxetine) - Risk: Benefit Assessment, January 2006; CHM AD HOC EXPERT ADVISORY GROUP ON STRATTERA (ATOMOXETINE), now posted on the MHRA website, it was on page 23 said: "Due to the large number of psychiatric reactions reported (the majority of which are unlisted), in September 2005 the MHRA requested the MAH 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 “large number of psychiatric reactions reported” was, to be more exact, 10.988 (as stated in Annex 4 to the above report).
The above-mentioned request was based on the evaluation that the number was “large”, and was in keeping with the purpose of the MHRA to “take any necessary action to protect the public promptly if there is a problem”. But in order to take action a full and swift cumulative review would need to be done.
For some reason nothing happened as regards this review.
Eli Lilly never submitted any review and the agency seemed to have forgotten it ever made the request. First August 4, 8 month later, the MHRA wrote again to Eli Lilly in order get this review. It was said that Lilly should submit it before August 9.
In the letter sent to Lilly it is written that Lilly earlier stated that they “submitted a dataset of psychiatric adverse events from clinical trials and post-marketing experience for Strattera to the FDA in December 2005”.
The MHRA writes: “We had understood that this review was to be submitted to the MHRA when it became available and our risk benefit assessment report reflects this.”
The agency further writes “a complete review of all psychiatric adverse reactions was not included in the risk benefit assessment of Strattera pending completion of the above mentioned cumulative review”.
This means that the MHRA, 8 months after its conclusion that there exist a “large number of psychiatric reactions reported” for Strattera, and its request to Lilly to submit a review over these, finds out that the “dataset of psychiatric adverse events” for Strattera was submitted to the FDA in December 2005.
However the FDA didn’t do a review of these data in its report presented in March 2006. The FDA review is covering the specific areas of psychosis or mania; suicidal ideation and behaviour; aggression and violent behaviour. It does NOT cover the other serious adverse psychiatric events reported for Strattera. Further – as stated on page 7 in the FDA report – the review of the three categories mentioned was done already in September 2005. In other words it covered some specific areas and was not based on the dataset submitted in December.
In the letter from August 4 the MHRA requests “the original and same data package that was submitted to the FDA”.
From this it could be expected that the MHRA – 8 month after the January report, and not having received any cumulative review from Eli Lilly – finally should get in all data about “the large number of psychiatric reactions reported”, to then let an independent group of experts do a full analysis of the data.
Even if this was very far from taking “action to protect the public promptly”, it was absolutely a first step towards protecting the public.
But the surprises in this affair were not over.
Instead of announcing that the agency had commenced its own investigation into the serious safety problem with the drug, the MHRA in November announced that no specific review was needed.
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!
The full data package, (most likely) at last submitted by Eli Lilly (which could form the basis for a full review of these adverse effects from the drug), was not investigated, instead the psychiatric reactions were said to be “considered on an ongoing basis in the periodic safety update reports” [PSURs].
This statement was very easy to make for the MHRA, knowing that officials at the agency would follow the rules of concealment of data, not giving the public the possibility of verifying this statement in the actual documents (from the periodic safety report).
What was not taken into account was that all documents from the periodic safety report had been made public in other countries. In other words the statement done by the MHRA about the “review of all serious psychiatric reactions” done in the periodic safety report could be verified – and it could be verified to be false.
A list of all documents from the periodic safety report was provided to the MHRA and the agency got the opportunity to give the names and pages of the documents where this assessment/review of the "large number of psychiatric reactions reported" was done. The answer to that was that the agency was “unable to provide [me] with the title of the documents or a copy of them.”
In other words they did not exist.
Despite the complete non-existence of documents and pages to refer to, the agency stated in December: “An assessment of psychiatric adverse events associated with Strattera is currently ongoing in the context of the most recent PSUR.”
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Based on the data above I want to get answers to some very specific questions, closely related to the purpose of the agency:
- Did the MHRA actually receive a full dataset of psychiatric adverse reactions from Eli Lilly (with data about the 10.988 reactions) as requested in August 4, 2006?
- Did officials in the agency then decide not to do a full cumulative review of these adverse effects? If so how come officials took this decision, contrary to what was stated in the January document?
- How can the above-mentioned inactions be defended considering the trust put in the agency to “take any necessary action to protect the public promptly if there is a problem”? If they cannot at all be defended, what will be done to prevent similar occurrences in the future?
- Will the MHRA now – when these data have been brought to the attention of senior officials in the agency – take swift action to do a full independent review of “the large number of psychiatric reactions reported” for Strattera?
Yours sincerely,
Janne Larsson,
Writer
janne.olov.larsson@telia.com
