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superior non-inferirity
- Stephen J Senn (1 June 2003)
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22 May 2003 Neuron article1on Alzheimer: 'valid research' or a 'drug company propaganda'?
- Alexei R. Koudinov (1 June 2003)
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Who actually wrote the research paper? How to find it out.
- Susanna T Rees (12 June 2003)
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Drug Advertising in "The Patient Issue"
- Paul B Borrelli (13 June 2003)
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Re: Who actually wrote the research paper? How to find it out.
- Adam Jacobs (19 June 2003)
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Not just the doctors who need to disentangle
- Graham P Beck (20 June 2003)
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Would Dr Beck advertise a drug about his person if I paid him 20p?
- Richard Smith (21 June 2003)
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Re: Re: Who actually wrote the research paper? How to find it out.
- Susanna T Rees (26 June 2003)
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Editing and Peer Review
- Ali Poostchi (25 August 2003)
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Stephen J Senn, Professor of Pharmaceutical and Health Statistics Department of Statistical Science, University College London, London WC1E 6BT
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Richard Smith is wrong to imply that equivalence trials are particularly poorly handled by the pharmaceutical industry. Both sides of the regulatory divide have been closely involved in research into methods for analysing such trials and there was a stream of such papers during the 1980s and early 90s describing difficulties with such trials. A paper I rather like, in fact I wrote it myself, has a title that says it all 1. At the time I was working for Ciba-Geigy. In 1996, a review paper, whose authors all now work in the pharmaceutical industry, appeared in the British Medical Journal2. This is a useful account but does no more than report features that were already well known and applied within the pharmaceutical industry. The International Conference on Harmonisation leads in this area, with guidelines on statistical analysis and on choice of control group3 4. Nor does one have to look far to find examples outside the industry where such issues should have been handled better. An example of how not to do non-inferiority5 appeared in the British Medical Journal in 1994 (analysis by multiple p-values, failure to find a difference taken as proof of equivalence and no accounting for random effects)6. In fact, it is precisely because the regulators have long realised the difficulties with non-inferiority studies that they have placed such stress on placebo-controlled trials, a stress which Richard Smith also appears to criticise. I would maintain that the superior handling of non- inferiority has been found within the industry. References 1. Senn SJ. Inherent difficulties with active control equivalence studies. Stat. Med. 1993;12(24):2367-75. 2. Jones E, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: The importance of rigorous methods. Br. Med. J. 1996;313(7048):36-39. 3. International Conference on Harmonisation. Statistical principles for clinical trials (ICH E9). Stat. Med. 1999;18:1905-1942. 4. International Conference on Harmonisation. ICH harmonised tripartite guideline: choice of control group and related issues in clinical trials: International Conference on Harmonisation, 2000:1-35. 5. March L, Irwig L, Schwarz J, Simpson J, Chock C, Brooks P. n of 1 trials comparing a non-steroidal anti-inflammatory drug with paracetamol in osteoarthritis. Br. Med. J. 1994;309(6961):1041-5; discussion 1045-6. 6. Senn SJ, Bakshi R, Ezzet N. n of 1 trials in osteoarthritis. Caution in interpretation needed [letter; comment]. Br. Med. J. 1995;310(6980):667. Competing interests: Stephen Senn is a consultant to the pharmaceutical industry, used to work for Ciba-Geigy and has shares in Novartis, the company that makes one of the drugs compared in the paper by March et al that he has just criticised. His book, Dicing with Death, like that of Richard Smith, will be published by Cambridge University Press later this year and, like Smith, he will be promoting his book vigorously. |
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Alexei R. Koudinov, seniour research scientist, editor Rus Acad Med Sci; Neurobiol Lipids
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I appreciate this week's BMJ theme issue on the relationship between doctors and the drug industry, because it is extremely timely for my own field of Alzheimer's disease research. Last week I and my colleagues were digesting May 22, 2003 Neuron (a major neursocience journal published by Cell press) article [ 1 ] and associated editorial coverage [ 2 ] on a validity of the Alzheimer's amyloid-based therapy (read 'amyloid cascade hypothesis'). I and others found that “the title and some of the conclusions of this
study are not yet justified” [ 3 ]. Moreover, the authors
provided apparently false statement that “they have no competing financial
interests related to Elan/Wyeth-Ayerst”, a vaccine maker, creating a rationale
to consider the article "a bias in favor of the expired amyloid dogma-based
Alzheimer’s therapy approach" [ 3 ].
This week BMJ editorial is confident that "journals are caught between publishing the most relevant and valid research and being used as vehicles for drug company propaganda." In light of the above I wonder to which category the latest Neuron articles on Alzheimer's disease [ 1, 2 ] belong to. I believe that many neuroscientists are puzzled, too, especially because similar question was earlier discussed (at the Nature Medicine [ 4 ; also see 'message to remember' ], The Wall Street Journal [ 5 ], and the Boston Phoenix [ 6 ]) for the consensus recommendations for the post-mortem diagnosis of Alzheimer's disease by the NIH National Institute on Aging [ 7 ], a key citation of the Neuron study [ 1 ]. I hope that my letter to the editor of Neuron [ 3 ] and the letter bibliography will make this puzzle easy. Sincerely, Alexei Koudinov, MD, PhD
Competing financial interests: I do not
have any competing financial interest. I aim free information dissemination
and an unbiased development of Alzheimer's neuroscience. I observe the
Society
for Neuroscience Guidelines
for Responsible Conduct Regarding Scientific Communication.
References: 1. Hock C, et al. Report: Antibodies against b-Amyloid Slow Cognitive Decline in Alzheimer's Disease Neuron. 38, 547-554 (22 May 2003) [ PubMed ]. 2. Winblad B, Blum KI. Preview: Hints of a Therapeutic Vaccine for Alzheimer's? Neuron. 38, 517-8 (22 May 2003) [ PubMed ]. 3. Koudinov AR. Hasta la vista, amyloid cascade hypothesis, OR will academic dishonesty yield Alzheimer's cure? AAAS SAKE KE. Published online May 26, 2003 [ FullText ]. 4. Editorial. Taking more interest in conflict. Nat Med. 5, 713 (1999) [ PubMed ] [ FullText ]; Birmingham K, Ready T. Conflict-of-interest problems lead to policy changes. Nat Med. 5, 717-8 (1999) [ PubMed ] [ FullText ]. 5. Waldholz M, King RT, Jr. Did ties to Alzheimer's test maker sway NIH report? The Wall Street Journal. (30 Nov 1998) [ FullText ]. 6. Ready T. Science for Sale: A Harvard researcher stands to profit from a product he "independently" reviewed for the National Institutes of Health. The Boston Phoenix. (29 April 1999) [ FullText ]. 7. The National Institute on
Aging, and Reagan Institute Working Group on Diagnostic Criteria for the
Neuropathological Assessment of Alzheimer's Disease. Consensus recommendations
for the post-mortem diagnosis of Alzheimer's disease. Neurobiol. Aging.
18,
S1-S2 (1997) [ PubMed
].
Competing interests: None declared |
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Susanna T Rees, Care Assistant CH66 1QL
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In reply to the BMJ theme issue of 31st May 2003 (Vol 326 issue 7400) “Time to untangle doctors from drug companies.” Until the end of 2002, I worked for a medical writing agency as an editorial assistant. I believe that the agency I worked for generally has standards of practice that are consistent with best practice within the industry. I write to you about the broader issues associated with general practices in the industry. It is my perception that there is consistently a high turnover in staff throughout all branches of the pharmaceutical industry. It is also my perception that the effect of this is that there is often a lack of consistent follow-through on how the pharmaceutical industry acquires data, monitors it, processes it, validates it. Medical writing agencies go to great lengths to disguise the fact that the papers and conference abstracts that they ghost-write and submit to journals and conferences are ghost-written on behalf of pharmaceutical companies and not by the named authors. There is a relatively high success rate for ghost-written submissions - not outstanding, but consistent. One standard operating procedure I have used states that before a paper is submitted to a journal electronically or on disk, the editorial assistant must open the File Properties of the Word document manuscript and remove the names of the medical writing agency or agency ghost-writer or pharmaceutical drug company, and replace these with the name and institution of the person who has been invited by the pharmaceutical drug company (or by the agency acting on its behalf) to be named as lead author, but who may have had no actual input into the paper. Quality-assurance auditors vet the standard operating procedures of the agency I worked for. I am surprised that these auditors, presumably following government guidelines, do validate such a procedure, which is actually in place in order disguise the true authorship from the editorial boards of journals. This area seems very blurred. This practice is contrary to the principles of openness and transparency of the scientific method. The full file history of every Word document may be retrieved, using a Texteditor or a Hexeditor. It is impossible to change that history or to disguise who actually created the Word document or the name of the organisation of origin. Office applications can reveal the full chronology of authors, file paths, file names, file amendments, and details of the computers used. Text, graphics or tables that have been inserted into a Word file will contain the full history of the document that they were extracted from. Technical effort is required to identify this information[1,2]. Such a check might be made prior to peer-review, using an original file, saved onto disk by the authors and included as part of the submission package to the journal. Even this check may not be exhaustive or conclusive: for example, where a file has been exported into .RTF format, much of the original file history may be lost. A Word document that has been exported into .RTF format and subsequently back into .DOC format, may possibly lose much of its original Word file history. RTF offers a “track changes” option, so it may be possible to view the entire text-editing history of a Word document that has been exported into .RTF format. A file that has been exported into .PDF format will have lost its entire history. On-line submission of ghost-written papers and abstracts to journals and conferences is done from the agency computer or sometimes from the offices of the pharmaceutical company. Do journals and conference organisers always try to identify the organisation that actually submitted the electronic file? An internet engine search on the authors of a paper will quickly reveal whether these names are closely linked to pharmaceutical drug companies, to their products or publicity materials. The interests of the pharmaceutical industry lie at the heart of many current, urgent debates: GM food, anti-depressants and their side-effects, and others. We need to ask: Who wrote this paper? Who did this research? Are the objectives of this research genuinely impartial? Is this process fully transparent? Independent authorship and impartiality are the cornerstones of scientific research. The pharmaceutical giants are using the tools of scientific research as a marketing tool. I believe that these marketing practices are damaging the authority and effectiveness of pharmaceutical research. With thanks to Doro Mücke-Herzberg References (1) PC-Welt (German language publication) 1999(7):242-243. “Verborgene Infos” (trans: Hidden information) Springer T, Apfelböck H. (2) c’t (German language publication) 2002(3):172-175. “Dokumente durchleuchtet: Was Office-Dateien verraten können” (trans: Documents under the X-ray: what Office files can tell you) Rost M, Wallisch A. Competing interests: None declared |
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Paul B Borrelli, General Practice Principal Salisbury SP5 3JP
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I imagine that all your readers of the "Patient Issue" of the BMJ relished the irony of having Pharmaceutical Adverts in a magazine designed to be read by patients containing a debate on "direct" advertising to patients. Competing interests: None declared |
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Adam Jacobs, Director Dianthus Medical Limited, London SW19 3TZ
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I agree with Susanna Rees that the practices of the medical writing agency that she used to work for are ‘contrary to the principles of openness and transparency of the scientific method’, but they are certainly not consistent with best practice within the industry. The recently published guidelines on Good Publication Practice (www.gpp-guidelines.org) give guidance on best practice for papers written by professional medical writers on behalf of the named authors. One of the things they state specifically is that ‘the contribution of the medical writer should be acknowledged’. Clearly, taking heroic measures to remove all evidence of the medical writer’s involvement is going very much against these guidelines. The standard operating procedures of Rees’s former company were no doubt written before the guidelines were published. I hope they will now be revised in light of the guidelines. In my own company, we would never try to hide our involvement as professional medical writers. Indeed we have on occasion liaised with the journal on behalf of the authors. However, the extent to which our involvement is transparent is not always entirely under our control: sponsors, authors, and journal editors all have their part to play too. I urge all those involved in papers written by professional medical writers to respect the principles of transparency and openness. Competing interests: My company provides ghostwriting services. I am also vice president of the European Medical Writers Association, which represents the interests of professional medical writers. |
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Graham P Beck, Consultant Anaesthetist New Cross Hospital Wolverhampton WV10 0QP
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So we have yet another politically correct leader from the BMJ. I am frankly offended as a doctor that you feel free pens will influence my prescribing. Please refer to the recent patient issue of the BMJ. Facing page 1294 is a full page advertisement - 'why not order an extra copy for your waiting room, only £5'. Now turn over the page - a full page advertisement sponsored by GlaxoSmithKline for your patient to read. There are many more drugs advertised in this journal, many in a format that I don't think I've seen in the 'doctor's BMJ'. So please tell me that the extra copies have the advertisements removed. Whilst you are prepared to declare your conflict of interest at the end of this leader, I think it's all a bit too rich! Competing interests: None declared |
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Richard Smith, Editor BMJ
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Dr Beck is one of those remarkable people who has complete insight into his own motivations. Unfortunately I'm not. He says that he is not influenced by free pens, and I accept that. The pharmaceutical companies are giving him these free gifts out of the goodness of their hearts. They expect no return--despite their duty to their shareholders to maximise profits. I wonder if Dr Beck would be willing to walk around for a year advertising the BMJ about his person if I paid him 20p? That's what companies are achieving with their free pens. And has Dr Beck considered the effect on patients? Might they wonder--as he leans over the anaesthetise them--why he is advertising a particular drug? Might some of them worry for an instant that he has been influenced by the free pen, even though he knows that he hasn't? Richard Smith, Editor, BMJ Competing interests: I am the editor of the BMJ and accountable for all it contains and its finances |
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Susanna T Rees, Care Assistant CH66 1QL
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It is encouraging to see that voluntary guidelines on Good Publication Practice for pharmaceutical companies (www.gpp-guidelines.org) have been proposed, and that there is interest from some parts of the pharmaceutical industry. I note however that many names are not on the list of those who have signed up. What incentives are there for the pharmaceutical companies and the medical writing agencies to sign up? Do these guidelines go far enough? Are these voluntary guidelines sufficient to ensure that pharmaceutical research is not inappropriately influenced by marketing initiatives? Competing interests: None declared |
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Ali Poostchi, PRHO Surgery Derriford Hospital, Plymouth
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Richard Smith notes that pharmaceutical advertising is often misleading. The quality of papers in the BMJ is largely maintained through the process of editing and peer review, and it seems strange that the drug adverts are exempted from this. Perhaps the BMJ should consider following the Lancet’s lead and employ an editor solely to maintain the quality of its adverts. Competing interests: None declared |
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