Coleg Meddygaeth Prifysgol Cymru University of Wales College of Medicine
Adran Meddygaeth Seicolegol / Department of Psychological Medicine
Adran Cymru y Gogledd / North Wales Department
Pennaeth Adran / Head of Department
Yr Athro /Professor Michael J. Owen
Bangor
Dr. D. Healy (Cyfarwyddwr)

Dear  Mr Milburn,

It is almost four months since I wrote to you on the question of missing suicidal act data from trials of olanzapine.

Several days ago a copy of Parliamentary Health Magazine came in my post, edited by Dr Ian Gibson MP. It appears heavily sponsored by Lilly who produce olanzapine. Attempting to capitalise on the publicity for the movie "A Beautiful Mind", the magazine features a Lilly advertisement with Russell Crowe/John Nash. It now seems clear that Nash never had olanzapine or any other antipsychotic for the last 20 or 30 years.

Another Janssen advert features a child. For anyone who has any knowledge in the field, this image links up with a large scale series of clinical trials that Janssen and Lilly have been doing in children with risperidone and olanzapine – children who don’t in fact have schizophrenia.

My first question for you is whether there are any centres participating in olanzapine studies in either children or adults in the UK? If there are any centres, it seems abundantly clear, based on the scenario I outlined to you in my previous letter, that none of the subjects entering these studies could be giving informed consent, as the investigators are not in a position to elicit informed consent from subjects they enrol. The fact that some ethics committee may have approved such a study would, of course, not be an adequate response to this new situation. Should ethics committees be briefed on the new situation? If your department has already foreseen this problem, have you taken any steps to manage the problem?

My concern on this issue stems from the fact that 6 years ago I chaired a Roundtable Meeting for the British Association for Psychopharmacology on the issue of the use of psychotropic drugs in children. I wrote up the recommendations from this meeting and these were published. This was a meeting in which senior regulators from the United States and Europe were involved as well as professors of child psychiatry from a number of European countries, North America and the UK. My concern in promoting this meeting was to ensure that children who could benefit from psychotropic drug treatment would be enabled to gain access to treatment. Only six years ago the climate of the times were such that children were at a real risk of not getting effective drug treatment for their conditions.

If you read the proceedings of the meeting, it will become clear to you that there is in principle no need for any drug studies in children for either antipsychotics or for treatments for OCD for example. Research that is conducted in children or adolescents with such conditions will only produce a situation in which a drug company gains a license to vigorously promote their treatment for these conditions. It will not produce a situation in which clinicians then become able to use these drugs.

There are only two things that clinicians could conceivably learn from such studies. First, that paradoxically a treatment, which works in adults doesn’t work in children. Second, that there are particular toxicities in children that need to be factored in to any risk benefit assessment as regards treatment in children. In return for this right to create the conditions in which children who may well not need the treatments are more likely to end up on drug treatment, the very least market authorisation holders could be expected to do would be to make available critical safety data that arise from such studies.

Against this background, consider the studies conducted several years ago by Pfizer in children who had OCD, which were the basis for Pfizer applying for and receiving a license to market sertraline for OCD in children here and elsewhere in Europe. In these studies there were 248 subjects enrolled altogether, 187 in an OCD arm of the studies and 61 in an allied mixed depression/OCD arm.

If you chase the scientific literature in which these studies were reported you will only find reference to one suicidal act on sertraline. However Pfizer’s expert report, submitted to the FDA in response to FDA questioning about rates of suicidal acts in these trials, makes it clear that there were in fact at least six children who became suicidal on sertraline.

Pfizer go to great efforts to justify these six suicidal acts. First they claim that four of these occurred in the 44 children who were apparently depressed. This however gives a 1 in 11 rate of suicidal acts on sertraline in children who were depressed, which is a 20-fold higher rate of suicidal acts than appear in the sertraline treated adult literature.

Pfizer claim suicidal acts are common in children who are depressed anyway. They are not this common. But if suicidal acts were this common in depressed teenagers, a conundrum arises. One of the justifications that Pfizer offer for treatment with sertraline is that treatment will reduce suicide rates. If, however, there are any cases of suicidal acts averted by treatment with sertraline, given the figures for suicidal acts that come out of these trials, there must logically have been an even higher rate of suicide provocation that is initially apparent from the data.

In the OCD arm of the trial, two children made suicidal acts on sertraline versus one apparently on placebo. In the case of other studies it is clear that Pfizer have been prepared in 50% of cases to label as placebo suicidal acts, acts that in fact occurred during the washout period of clinical trials, which were therefore not true placebo suicidal acts. Can you establish whether this placebo suicidal act occurred during the washout period of clinical trials or not?

Against this background, can I ask you whether there are any studies being conducted with SSRIs in children in the country? Can I also ask you to determine whether the investigators conducting these studies are informed as to the rates of suicidal acts recorded in the only other studies submitted to regulators? If these investigators are not so informed, can I ask you what you intend to do about the situation?

You realise that I am not asking you to inform the many clinicians who will be using these drugs in clinical practise, who will almost certainly not be informing patients or their parents appropriately.

One of the methods for investigators to keep themselves informed is of course to submit a Freedom of Information request to the FDA. Few clinicians in the UK are probably aware that it may be necessary for them to regularly access this invaluable mechanism for safeguarding the health and interests of British patients. Can I ask whether you think it would be timely, in the light of the studies outlined in this letter and the missing data from these studies, to inform UK clinicians about the procedures by which they might make FOI requests? Can I ask whether your department has ever given any consideration to the issue of who should fund such requests?

However, to return to the olanzapine studies, in the case of the studies lodged with the FDA, it is not possible to access the relevant data, as FDA reviews of this drug do not contain the data. The scientific literature furthermore is no use to anyone. In the case of olanzapine, all the authors on studies involving Lilly drugs are typically Lilly personnel. The literature is of doubtful use in the case of risperidone or other novel antipsychotics as for example the lead investigator in many of these studies has since been jailed for a series of dodgy practices related to the recruitment of subjects to these very trials.

My question, which remains unanswered from my previous letter to you, is whether you think this situation is in fact legally incompatible with prescription only arrangements? As no request for data or proprietary information of any sort was put forward in the previous letter, I did not cover the letter with a request to have the question raised handled under the Code of Practice. I am aware of your inability to access the data I seek. Given the lack of response to my letter, however, I would like you to regard this question and the other questions posed in this letter as matters to be answered under the Code of Practice.

As regards Parliamentary Health Magazine it was dispiriting to see the House of Commons used as marketing copy for pharmaceutical companies. Can I ask you where the idea for this magazine came from? What is the level of pharmaceutical company sponsorship of the magazine? Have companies managed to leverage any public monies into funding this exercise? What fees do Dr Gibson or other members of the editorial board get for their role in fronting the exercise? What fees do contributors get for writing the pieces? Who exactly wrote the pieces in the Lilly supplement? By writes, I mean what the person in the street would regard as writing - that is who writes the first draft of the pieces.

Yours sincerely,

David Healy MD FRCPsych

Director, North Wales Department of Psychological Medicine   (Honorary Consultant Psychiatrist)

Uned Hergest, Ysbyty Gwynedd, Bangor, Gwynedd LL27 2PW

Ffôn: (01248) 384452 Ffacs: (01248) 371397

Hergest Unit, Gwynedd Hospital, Bangor, Gwynedd LL27 2PW

Tel: (01248) 384452 Fax: (01248) 311397

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