(To read the linked documents in this article you must have the program Acrobat Reader.)
2007-02-28
Creating a market – long lines and ADHD drugs
Government agencies should be impartial and conduct their affairs with objectivity, for the good of citizens. Conflicts of interest should be handled. Different vested interests should not be allowed to direct the handling of the taxpayers’ money for their own profit.
The above rules are often adhered to – but definitely not by agencies having to do with psychiatry and pharmaceutical companies.
Below is an example from Sweden.
It is about creating a market for ADHD drugs. It is about a national agency (the National Board of Health and Welfare) transferring public funds to a psychiatric authority to invest in areas profitable for the pharmaceutical companies.
(The documents linked to are in most cases from Freedom of Information Act (FOIA) requests, in quite some instances given out first after court decisions.)
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No one likes long lines. And if these long lines are preventing persons from getting “necessary treatment” it is really bad. If the long lines are a result of lack of resources then the handling must of course be to give resources.
So how would it be for a pharmaceutical company, about to market a new ADHD drug, to cooperate with psychiatric authorities and front groups (“patient groups”) and use the dislike of long lines in their marketing efforts?
First they would need to sell the new “disorder”: They would claim that the condition was common and serious; they would check the resources and how long time it would take to get a diagnosis (as it is a new invention it would of course take long time); they would announce on all channels that there were no resources available and that the lines to get the diagnosis – and “necessary treatment” – were very, very long.
And we have the marketing strategy for ADHD, and more recently for “adult ADHD”, for the pharmaceutical companies Eli Lilly (Strattera) and Janssen (Concerta).
Eli Lilly invested 1 million Swedish crowns (around 130 000 dollars) in the front group Attention (the Swedish equivalent to CHADD in the US) in 2004-2005 [1] Contract. 100 000 of these crowns were invested in “research” by a university in Sweden. And the result of this research was predictable: There are long lines and few resources for the diagnosis of “adult ADHD”, and pharmacological treatment for ADHD must be made available.
This was announced in media as a research project conducted by Attention and the university, while in actual fact it was a project directed by Eli Lilly. Lilly wrote the project and gave instructions to the university. A request per the FOIA to get the research instructions submitted by Lilly to the university was turned down. Lilly denied the university the right to reveal the data and wrote: “The reason for this is that our competitors could find the construction of the project and its methodology interesting, and that this knowledge for them could mean that the competitive situation would change to our disadvantage.” [2] Lilly letter In other words, this project was purely a marketing scheme aimed at bettering the competitive situation for Lilly on the ADHD market.
On radio, in television and in newspapers, all over the country, the long lines were bemoaned. Politicians stood up and said that suffering patients should not have to wait for years for diagnosis and treatment. Lilly and other pharmaceutical companies interested in the ADHD market were pleased.
And so, in November 2005, the National Board of Health and Welfare, together with the “psychiatric coordinator” Anders Milton (in the Ministry of Health and Social Affairs), launched a 1 year long project to make sure that all county councils (taking care of the medical services in the Sweden) would diagnose and treat “adult ADHD”.
2 million Swedish crowns were set aside for the project and paid to the well-known ADHD authority Dr. Björn Kadesjö [3] Contract. No declaration of conflicts of interest was written and submitted to the Board – as should have been done according to the strict rules existing.
Maybe it would have been embarrassing to reveal the following extreme conflicts of interest:
Kadesjö was a member of Eli Lilly’s Strattera Advisory Board, a marketing group for Strattera, up to the point of the contract with the National Board of Health and Welfare. Three days after the project was started he resigned from this position [4] Resignation The task and purpose of the Advisory Board is made clear in a written agreement with Lilly: “The members will get access to medical facts and insight into the strategy around the marketing of Lilly’s drugs in the neuropsychiatric field.” [5] Agreement
Kadesjö led Eli Lilly’s clinical trials of Strattera in Sweden when the contract with the National Board was written. He
continued to lead these trials. Strattera was not approved for children or adults in Sweden (later approved for children in April 2006). Lilly had invested 3 200 000 Swedish crowns (32 000 per child) in the national trials and wanted to see results – that the trials smoothed the way for the approval of Strattera. In the beginning of 2005 Kadesjö signed a Confidentiality Agreement with Lilly promising to keep quiet. He should if someone asked questions “promptly notify Lilly and shall not disclose any information without Lilly’s prior written consent” [6] Confidentiality. This was not anything new for Kadesjö, who already in 2002 had signed a similar agreement with Lilly [7] Confidentiality. Thus Kadesjö was bound by Confidentiality agreements with Lilly during his earlier projects for the National Board of Health and Welfare, which included guidelines for school health and a national project about ADHD (2004). When Kadesjö reports on his current project in March, the data related to Strattera are approved beforehand by Eli Lilly.
Kadesjö was and is responsible for the quality of Eli Lilly’s courses about ADHD in Sweden [8] Quality control. Officially these courses should take up only ADHD. But of equal importance is the marketing of drugs, especially Strattera (not approved in the country when these courses started). One of Lilly’s course representatives wrote a mail to Kadesjö in 2005 and said that he needed help to put together the “presentational material for Strattera” so that they released “a material that is in concord with you specialists”.
Kadesjö was also a member of Lilly’s Advisory Board for the European marketing project EINAQ (European Interdisciplinary Network for ADHD Quality assurance) and is still a member according to the web site [9] EINAQ.
In the application to the Ethics Review Board for the clinical trial of Strattera (October 2004) there was a question about risks for the 100 children (research subjects). Kadesjö wrote that Strattera was “very well researched and well tolerated by most patients” [10] Application
No risks or dangers were listed for the children. The risks were made even less by inclusion of the fact that 1 175 000 persons already had taken Strattera. The only serious adverse effect communicated to the parents (in the parent information, an attachment to the application) was that Strattera “can cause liver damage in very rare cases”.
If we jump 2,5 years ahead in time, when Kadesjö is about to report on his project from the National Board of Health, we find him as lyrical about ADHD drugs in a newspaper article as he was in the application to the Ethics Review Board. And praise Lilly and other pharmaceutical companies, for this is what Kadesjö is saying about the miraculous effect these drugs have on adults: “They can think more clearly and maybe for the first time read a book.” (No ADHD drug is approved for adults. If an official representative for a pharmaceutical company would say the things Kadesjö is saying – and marketing the drugs to groups for which they are not approved – it would lead to fines and lawsuits.) Kadesjö wants these drugs for adults and says: “Pharmaceutical companies must therefore become better at showing that these drugs also work for adults.” [11]
Both the Ethics Review Board and the readers of the newspaper got a well-arranged picture of reality.
The facts are that it was not at all unknown for Lilly, at the time of the application to the Ethics Review Board (end 2004), that Strattera causes several very serious harmful effects. The drug had at that point been on the market in the US for two years and many reports about adverse effects had been submitted to the company.
When the harmful effects from Strattera were summarized by the British medical agency MHRA in September 2005 (published December 2005), it was shown that 300 spontaneous reports about suicidality (20 completed suicides), 766 reports about heart disorders and 172 about liver injury had been submitted; in the report the wording “large number of psychiatric reactions reported” is also used (p. 23) [12] Report. All these reports did not suddenly arrive in 2005, the majority of them were known to Lilly when the company together with Kadesjö turned in the application to the Ethics Review Board. But the known harmful effects were “forgotten” in the application. This is normally called lying or in legal language, fraud.
In September 2005 Lilly was also forced to issue a so-called black box warning (most serious warning text) that Strattera could lead to increased risk for suicidality in children [13] Article
And when FDA finally did an analysis of Lilly’s data about Strattera things turned even worse. The FDA assessors investigated primarily the connection between ADHD drugs (amphetamines and Strattera) and psychotic conditions, violence and suicidality. For Strattera it was reported 992 cases of aggression and violence, 360 cases of psychosis or mania, and 399 cases of suicidality. Quite some of the reports about psychosis with hallucinations concerned children aged ten years or less. As clearly pointed out in the FDA document 80-90
percent of the cases with psychotic reactions and violent behaviour in connection with treatment did not have a prior history of such behaviour. In other words, the behaviour was a result of the “treatment” [14] Report (It should be noted that it is generally estimated that only 1-10 percent of the actual adverse effects are reported.)
Björn Kadesjö’s clinical trial of Strattera on children in Sweden was completed in 2006. The results were immediately classified by the Medical Products Agency (MPA) in Sweden. No data are released about this study. Kadesjö and the psychiatrists involved in the study all have Confidentiality agreements with Lilly; they keep quiet and say nothing that can harm the company.
But Kadesjö was also signing as responsible director in the application for Christopher Gillberg’s clinical trial of Strattera on adults in Sweden. This trial was financed with public funds. Thus the Medical Products Agency could not make the results secret, as in Kadesjö’s trial on children, financed by Lilly.
So how well did the results from this study match Kadesjö’s lyrical words about ADHD drugs in media?
The final report from November 2006 and earlier data show that 95 percent of the persons enrolled ended the study in advance – 75 percent due to security risks [adverse effects or no/insufficient effects]! [15a] Report 1 [15b] Report 2
The trial had been ongoing since February 2004 and was unique in that it should test the long term effects of Strattera. Per the application to the Ethics Review Board one should test the drug on 40 adults during 18 months, to see if “the possible positive effect remains”, and study “negative side effects short term and long term…” (p. 3). It was emphasized: “The treatment of AD/HD is in most cases ongoing for many years.” (p. 2) [16] Application
Only 24 persons were enrolled (of the 40 planned for). 4 of these persons did not start. Remained 20.
The primary result: 40 percent (n=8) of the test subjects had to end the study in advance due to adverse effects from the drug.
The next result: 35 percent (n=7) ended the study in advance due to bad or no effect from the drug (“insufficient effect after a certain time”).
The other persons ending the study (n=4) did not come to their next visit or ended on own initiative for other reasons (this can and should of course also be seen as a bad effect of the drug).
And last: “One patient has completed the whole study.”
The 40 percent (n=8) taken out of the study due to adverse effects suffered from: liver injury, thyroid gland injury, aggression/hostility, depression, high blood pressure, subjective feelings of discomfort.
In other words, a catastrophe!
But pharmaceutical companies have taken the art of selective publishing to new heights as exemplified in this article in the medical journal PLoS Medicine [17] Article. With help of professional ghostwriters even this study can be given a positive description. But the above are the results that have leaked out. And they are catastrophic.
What will Björn Kadesjö say about this to the National Board of Health and Welfare?
Janne Larsson
Writer
[1] Contract Eli Lilly – Attention, http://jannel.se/lilly-attention/lilly.attention.pdf
[2] Eli Lilly, mail to the University of Linköping June 20, 2005, http://jannel.se/lilly-attention/Lilly.project.linkoping.PDF
[3] The National Board of Health and Welfare Uppdragskontrakt, November 2005, http://jannel.se/kadesjo.milton.uppdrag.nov.05.PDF
[4] Kadesjö, mail to Eli Lilly, November 4, 2005, http://jannel.se/advboard.strattera.PDF
[5] Lilly, Hägglöf, Agreement for consultation, November 11, 2004. http://jannel.se/refs_strattera_trial/hagglof_lilly_advisory_board.PDF
[6] Lilly, Kadesjö, Confidentiality agreement, February 8, 2005
http://jannel.se/lilly-attention/kadesjo.lilly.05.pdf
[7] Lilly, Kadesjö, Confidentiality agreement, November 26, 2002,
http://jannel.se/lilly-attention/kadesjo.lilly.02.pdf
[8] ADHD-education, EINAQ, http://www.lilly.se/terapiomraden/adhd/lakar_einaqutb.html
[9] EINAQ Resources http://www.einaq.org/faculty.php3
[10] Lilly/Kadesjö, Ansökan om etikprövning, (Application for ethics approval), October 29, 2004, submitted to the Ethics Review Board in Gothenburg December 9, 2004.
http://jannel.se/lilly-attention/kadesjo.lilly.clinical.trial.strattera.pdf
[11] Smålandsposten, Samverkan krävs för att möta vuxna med ADHD, Februari 5, 2007, http://www.smp.se/article/773076_101-0-0-0
[12] MHRA, Preliminary Assessment Report Strattera, December 9, 2005, (on the web site of the MHRA first in May 2006), http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=433&within=Yes&keywords=strattera
[13] Associated Press, Lilly to Add Suicide Warning to ADHD Drug Label, September 29, 2005, http://health.dailynewscentral.com/content/view/0001711/61/
[14] FDA, Psychiatric Adverse Events Associated with Drug Treatment of ADHD: Review of Postmarketing Safety Data, published March 3, 2006,
http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210b_11_01_AdverseEvents.pdf
[15] Gillberg/Råstam/Cederlund, Slutrapport, (Final Report) November 2006. [15a] Gillberg/Råstam/Cederlund, Angående klinisk läkemedelsprövning, 11 oktober 2005, (Report to the MPA) http://jannel.se/refs_strattera_trial/report_clinicaltrial_strattera_adults__051011.pdf
[15b] Gillberg/Råstam/Cederlund, Angående klinisk läkemedelsprövning (atomoxetine hydrochloride) ref nr: 2002/74152; (Report to the MPA) April 25, 2006 http://jannel.se/refs_strattera_trial/rapport%202006-04-25.PDF
[16] Gillberg/Kadesjö, Ansökan till forskningsetikkommittén vid Göteborgs universitet, (Application to Ethics Review Board in Gothenburg) November 29, 2002, arrived Januari 14, 2003. http://www.jannel.se/refs_strattera_trial/application_gillberg_strattera_ethics_committee.PDF
[17] Richard Smith, Medical Journals are an extension of the marketing arm of pharmaceutical companies, Public Library of Science, May 2005,
http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0020138
27.09.2008