Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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There are bigger issues at stake for the patient, than "business models for individually tailored drugs".
- Hilary Butler (12 December 2003)
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glaxo's drugs don't work.
- dr.manan vasenwala (12 December 2003)
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Here we go again
- Peter Lapinskas (12 December 2003)
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Glaxo was right to bring attention to the 50% who do not benefit from their drugs.
- Richard G Fiddian-Green (13 December 2003)
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Stop equating the medical profession with the drug companies
- Jeremy G Jones (13 December 2003)
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Look at the NNT's of GSK's biggest OTC product line
- John R. Polito (14 December 2003)
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Better drugs without genetic testing?
- Richard G Lanzara (16 December 2003)
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Dichotomania
- Stephen J Senn (18 December 2003)
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Having more than just conventional 'tools in the toolbox' increases job satisfaction
- Becky Hirst (18 December 2003)
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Let the sun shine in
- James G Penston (18 December 2003)
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Correction re: "The Drugs Don't Work" by Richard Smith
- Elizabeth A Mejia-Millan (19 December 2003)
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confusion over plants
- Carolyn J McGhee (14 January 2004)
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Hilary Butler, Freelance Journalist New Zealand 1892
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Dear Sir, You say " it's hard to see the business model for individually tailored drugs. " Very true. After all, maximum profits come from maximum use of drugs, by putting as many backsides on the drug seats as possible, regardless as to whether they work or not. This is the only possible way to satisfy the profit/loss margin for the comapnies, and to keep Wall Street traders happy. But wouldn't it be more to the point, rather than to say that none of this is "new", to ask why it is that patients ~ the ones being offered Glaxo's useless drugs ~ are never told that in all likelihood, they are paying good money, for something far more potentially dangerous than any sugar coated placebo, or the primrose oil now "put to rest"? Don't you think it would be nice, for patients to know the terms and conditions of what is essentially the "Russian Roulette" that Glaxo and others are playing, with their bodies? The bottom line for the people at the coal face, is that, as before, they are never told the full facts about pharmaceuticals. And the negative reaction of the media is exactly what you would expect from people who are representative of the average person, who may well feel, and justifiably so, that they have been sold a lie, both personally, and in the use of their taxes.. The real question then, is, "When is the medical profession, in particular the phamaceutical industry, going to adhere to the same sort of scrutiny and honesty in the claims for, marketing, testing and the use of Glaxo's useless drugs , as they are now attempting to exact over safer alternatives, like vitamins, minerals and other supplements?" You may say that evening primrose has no benefits with regard to skin problems. That may be true. But what about the people who have found it useful for pre menstrual tension? Or any other "female" complaint? Isn't it better that they take evening primrose if it works for them, safety wise, rathan succumb to the tacky, artful repackaging of a certain antidepressive, which had a long list of known side-effects, not to mention addiction problems? The needs and wishes of patients should be what "drives" a doctor to find a solution. But that it appears, is a concept ahead of its time. Regards, Hilary. Competing interests: None declared |
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dr.manan vasenwala, consultant-cardiologist k.k.heart center, aligarh.india
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now, the truth, long suppressed is out. so when are glaxo going to withdraw these useless drugs from the market? or are they coming under a new garb or packing " glaxo's drugs that actually work"? surely there is something fishy in this glaxo announcement which appears to be yet another brazenly bold, innovative marketing device. Competing interests: None declared |
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Peter Lapinskas, Private consultant 26 Deepdene Wood, Dorking, Surrey, RH5 4BQ, UK
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"The BMJ is on difficult ground here...." It most certainly is. The trial which you are quoting tested the effect of high doses of borage oil (BO) on eczema. It indicated that the treatment was ineffective. We already knew that - that's why we used evening primrose oil (EPO). You cannot extrapolate from one oil to another; in fact there is strong evidence in the literature that they behave differently, so this result tells us very little about the effect of GLA and nothing at all about evening primrose oil. Surely this is elementary science? So why are you so keen to jump to the unjustified conclusion that this finally 'proves' that EPO is ineffectual. So keen that you devote two editorials as well as a major article to a treatment which has been delisted, which no one is promoting any more and where the major supporter is dead. It seems to me that you are back in grave-dancing mode. I do wish you would stop. "Yet Williams tells a sorry tale of failures to publish company sponsored trials supposedly showing benefit, unjustified accusations against authors of a study that found no benefit, editorial suppression of criticisms, threats of legal action, and governmental suppression of important data. This can't be a good way to make decisions on drugs. Let the sun shine in." I can't comment on the full litany of accusations because I wasn't party to many of the decisions, but there are a few points I would like to make. David Horrobin was a great believer in open publication. If he could have published the Epogam trials I believe he would. But you have to remember that Epogam did not have patent protection. The only way to protect it from generic competition was to deny competitors access to the trials data so that they could not incorporate it into a licence submission. To publish that data would have been suicide for the company. "unjustified accusations" - how do you know they were unjustified? Is that not an assumption? If they were justified, would that not explain why the work was never published? As an editor, I am sure you would not allow yourself to be deterred from publishing a good piece of research just because the company involved did not like the results. Why do you assume that other editors are made of weaker stuff? For a small pharmaceutical company to threaten legal action against an academic critic is not an obvious course of action - the effect on opinion in the academic community (which it relies upon for research collaboration) is likely to be profoundly counter-productive. It suggests that they considered the work to be very seriously flawed. Certainly no court would support an attempt to suppress genuine scientific endeavour, and the company must have known that. Greater openess of data and trials is a wonderful idea. However, as Scotia found to its cost, it is only practicable in the real world if a company has rock-solid patents. If compulsary publication were to be introduced, unless the current legal framework is amended, it would have the major side effect that only patentable discoveries would ever be researched in the commercial sector. That would rule out a whole raft of potential therapies, to the detriment of patients but to the benefit of the major pharmaceutical companies with large patent departments. Now that David Horrobin is dead, and can no longer defend himself, it is remarkable how many are happy to attack his reputation, who were silent while he lived. There's a word for that, and it's not complimentary. Competing interests: Formerly Seed Production Director at Scotia Pharmaceuticals Ltd |
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Richard G Fiddian-Green, None None
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Effective drugs cost a lot of money to bring to market. In those cases where the drug is revolutionary second and third generation me-too drugs can capture market share and even displace the original product. It is appropriate, therefore, for drug companies to charge high prices especially if generic manufacturers are permitted to undercut them in lesser developed countries and send them back to the US as Canada is doing. Cost-effectiveness is heavily dependent upon administering the right dose to the right patient. To do this with a new drug requires an intimate understanding not only of the pathophysiology of the disease being treated but also of the pharmacology. The product inserts are for their defense lawyers and dummies and seldom include the information necessary to prescribe the drug effectively and therefor cost-effectively. The reality is that this is most likely to occur in the hands of those actively engaged in the practice of medicine in tertiary referral academic medical centers. The further removed clinicans are from this kind of environment the less likely the medication prescribed will be given in the right dose and for the right reason and therefore cost-effectively. Hence the common practice of changing the medications being prescribed after being re- evaluated in such in such a center. Might the real point that Glaxo has made be that doctors do not get it right nearly as often as they should and that charging high prices is a win-win situation for them. It decreases the likelihood of the drug being abused by doctors and giving the company a bad name at the same time as generating profits in the order of those from less critical prescibing in a larger group of patients. Lesser developed countries would make far better use of their limited funds if they improved the quality of their practices. I am all too familar with nurses in these environments sleeping on duty and having a very variable interest in patient welfare and limited clinical skills. Expensive magic bullets have little or no place in these environments because the chances are they would be abused to the degree that they did bankrupt the health services in those countries. This issue came up with Centoxin some ten years ago because of the fear, loudly voiced in British editorials, that approval would bankrupt the NHS. Wrong. Even at $5,000 a treatment the drug could have reduced the costs of care substantialy provided it and other effective drugs had been prescribed for the right reasons and ineffective treatments were withheld. I strongly suspect that the retraction of the paper was politically inspired. Pity. The chances are the drug, since withdrawn, could have saved many lives and done so cost-effectively. Glaxo was right to draw attention to the issue. It is the doctors that are at fault. Competing interests: None declared |
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Jeremy G Jones, Specialist in Rheumatology and Rehabilitation Medicine Queen Elizabeth Hospital, Rotorua, New Zealand
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I do wish individuals like Butler would stop equating the pharmaceutical companies with the medical profession. In this age of political correctness the medical profession has, long ago, had to stop equating cranky, bitter, axe grinding feminists with the makers and purveyors of expensive, largely useless, "natural", "organic" and alternative products. This is because, as I am sure that Butler will agree, the association is but a gross generalisation. So too is the association between drug company and medical profession. The sooner such prejudices are put aside, the sooner we can start to address the marketing of both orthodox and heterodox substances and treatments in a such a way that the consumer is able to make an informed decision about whether she chooses to partake of the treatment or not. Competing interests: I am a member of the medical profession who has no links with manufacturers of drugs or other therapies be they useful or useless. |
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John R. Polito, Director WhyQuit.com Charleston, SC 29464
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It isn't just a matter of some GSK products having extremely low NNTs but in the case of its biggest selling over-the-counter (OTC) product line, smoking control, which generated £378 million in 2002, NNTs of well over 100. GSK’s marketing of nicotine replacement therapy (NRT) impliedly asserts that each time a quitter relapses while using NRT that their odds of success increase with a subsequent NRT attempt. "Smoking is a hard habit to break. In fact, many former smokers say they tried to quit three or four times before they were successful," one GSK NRT website asserts. [1] "Many people who quit permanently only do so after many attempts," says a UK GSK NRT website.[2] Although I hope we are each deeply troubled that GSK continues to hide OTC NRT's 93% six-month meta-analysis relapse rate from smokers - as found in March 2003 by its own consultants [3] - GSK is committing a much bigger sin than simply keeping consumers in efficacy darkness. Contrary to its above implied assertions, GSK has known since 1993 that the relapse rate for second time NRT users increases to 100%.[4] Smokers only muster the confidence to make a mad dash for freedom about once every three years. Yes, the school of hard-quitting-knocks can eventually teach them the true power of one puff of nicotine but the only lesson flowing from encouraging them to again spend that priceless period of confidence toying yet again with nicotine is that GSK profits were more important than life itself. Five quick questions for any GSK representative. Why do you continue to hide OTC NRT's 93% midyear relapse rate, its 100% second time use relapse rate, and that 36.6% of all nicotine gum users are chronic long-term users?[5] If OTC NRT's six month relapse rate is 93% what is its one year relapse rate? Where did you get the nerve and license to assert to the word that a cold turkey quitter's natural and historic quitting success rate of 10% at six months and 5% at one year have now dropped to just 3% at six months and to some obviously lower undisclosed rate at one year?[6] How do you sleep at night? John R. Polito [1] GSK's "I need relapse help" webpage - http://www.committedquitters.com/relapse_help/index.htm [2] NiQuitin CQ - "Quitting" http://www.niquitin.co.uk/uk/html/SN0300000.htm [3] Hughes, JR, Shiffman, S, et al., A meta-analysis of the efficacy of over-the-counter nicotine replacement . Tobacco Control, March 2003;12:21-27 - free full text link http://tc.bmjjournals.com/cgi/content/full/12/1/21 [4] Tonnesen P, et al., Recycling with nicotine patches in smoking cessation. Addiction. 1993 Apr;88(4):533 - abstract link http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8485431&dopt=Abstract [5] Shiffman S, Hughes JR, et al, Persistent use of nicotine replacement therapy: an analysis of actual purchase patterns in a population based sample, Tobacco Control 2003 November; 12: 310-316 - abstract link http://tc.bmjjournals.com/cgi/content/abstract/12/3/310 [6] Polito, Is cold turkey quitting more productive and effective than nicotine replacement therapy - http://whyquit.com/whyquit/A_Cold_Turkey.html Competing interests: Director of www.WhyQuit.com an abrupt nicotine cessation forum |
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Richard G Lanzara, President Bio Balance, 30 Wesy 86th St. NY, NY 10024
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Recently, Dr. Allen Roses, vice-president of genetics at GlaxoSmithKline (GSK), said that fewer than half of the patients prescribed drugs actually derived any benefit from them (Reuters). This raises a few issues that should be openly addressed. Why? How? and what can be done? First to the why. Dr. Roses' explanation would suggest that because of our inherent genetic variation, as many as fifty percent of us would not benefit from the clinically prescribed dosages of many drugs. This suggests that the problem could entail multiple problems that have often been overlooked or have gone previously unconsidered. Although it is the new trend to consider that one day we will all get genetic testing to determine our susceptibility, or lack thereof, to various medicines, we should all pause at this juncture and question the consequences, unintended or otherwise, of such a course. Personally, I believe that there are better methods to address this issue, which relates to the second and third questions of how and what can be done to correct it. One of the overlooked perils of drug development is the occurrence of desensitization, which is also called tolerance, fade, tachyphylaxis or down-regulation. At one time or another, we all have experienced the gradual loss of drug effectiveness with continued use. Many in the industry believe that by selecting the proper dosage regime drug-receptor desensitization can be minimized or prevented. Rightly or wrongly, they create a tightrope that patients and doctors must walk when utilizing the proper dosages and types of medications. This may affect anywhere from 30 to 50 percent of all pharmaceuticals and be a fertile area for drug development and improvement in the future. Given some of the disturbing reports that have shown upwards of 90,000 cases per year of reported medical errors in the US alone [1], the production of safer drugs should be a top priority in the pharmaceutical field. Yet why haven't the major companies done more to produce safer drugs? A partial explanation would be that it is much more expensive to ensure safer drugs, but an alternative explanation may be that they lack the technology to understand and correct the problem. Certainly, the major companies would want the safest product on the market. This would not only make sense from a medical standpoint, but a marketing one as well. Safer drugs require that all of the variables of drug development be evaluated and adjusted for the greatest number of people using these medications. Surprisingly, the safest drugs may come from using agonist/antagonist combinations in ways to prevent, diminish or control drug-receptor desensitization. This would be analogous to creating designer partial agonists in ways that have been previously overlooked, but would offer a new technology for enhancing the safety and efficacy of many pharmaceuticals [2,3]. I believe that this approach would produce better drugs without the need for extensive genetic testing. References 1 Kohn, L.T. et al., eds (2000) Institute of Medicine Report - To err is human : building a safer health system. National Academy Press, Washington, D.C. 2 Lanzara, R. (2003) Agonist/antagonist combinations at the beta-1- adrenergic receptor for preventing receptor desensitization. The Chemweb Preprint Server (http://preprint.chemweb.com/medichem/0302002) 3 Lanzara, R. (2003) Compositions to enhance the efficacy and safety of bio-pharmaceutical drugs. US Pat. 6,593,094 Richard Lanzara
Competing interests: None declared |
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Stephen J Senn, Professor of Statistics Department of Statistics, University of Glasgow, G12 OSA
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Sir, The recent fuss over drugs and minority response plumbs new depths in the misunderstanding of treatment response. Neither you, nor Dr Rogers, nor anybody else, has any idea whether or not Glaxo SmithKline's drugs work in only a minority of patients, because nearly all trials that anybody runs, despite misleading research you have published to the contrary1 2, are incapable of determining who does and does not respond to treatment. Imagine a group of patients suffering from asthma and treated with placebo and showing, as is commonly found to be the case, a wide variation in FEV1 at outcome. Now randomly select half of these patients and add 300ml to their values. Now compare the 50% you selected to the 50% you have not. You will find a considerable overlap between the 'treated' and the 'untreated' group. Some results under placebo will be higher than some under active treatment, yet, by construction, every patient given active treatment in this thought-experiment has had a benefit of 300ml. How do we know that this does not happen in clinical trials? Of course, where genuine binary outcomes are involved, instead of continuous ones wastefully dichotomised to feed the numbers needed to treat sausage machine3 4, then one could often argue, if one did not stop to think, that only a minority of patients would benefit. You did not seem to believe this was the case, however, when, at the end of June, you hailed the most important BMJ in fifty years5. How quickly opinions change. Whatever will be called for next? The withdrawal of seatbelts from motorcars on the grounds that only a minority of cars are involved in crashes? References 1. Guyatt GH, Juniper EF, Walter SD, Griffith LE, Goldstein RS. Interpreting treatment effects in randomised trials [see comments]. British Medical Journal 1998;316(7132):690-3. 2. Senn SJ. Individual Therapy: New Dawn or False Dawn. Drug Information Journal 2001;35(4):1479-1494. 3. Grieve AP. The number needed to treat: a useful clinical measure or a case of the Emperor's new clothes? Pharmaceutical Statistics 2003;2(2):87- 102. 4. Hutton JL. Numbers needed to treat: properties and problems (with comments). Journal of the Royal Statistical Society A 2000;163(3):403-419. 5. Smith R. Editor's choice: The most important BMJ for 50 years? British Medical Journal 2003;326. Competing interests: The author is a consultant to the pharmaceutical industry |
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Becky Hirst, Specialist Registrar Palliative Medicine St Luke's Hospice Sheffield S11 9NE
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Editor – my increasing realisation that drugs don’t work on most patients(1) is part of what led me to abandon General Practice in favour of Palliative Medicine. Few would disagree that opiates are effective for managing pain – audits of the WHO guidelines for oral opioids in cancer pain is that two-thirds of patients achieve good or moderate pain relief(2) . I was unable to find any calculations of numbers need to treat (NNT) for this on recourse to my usual source of this type of information - Bandolier (www.jr2.ox.ac.uk/bandolier). However, a 10mg intramuscular dose of morphine in acute postoperative pain had an NNT of 2.9 for at least 50% relief over 4 to 6 hours compared with placebo(3), and other interventions for acute pain show similarly low NNTs(2). There is already a class of ‘drugs’ which tailors treatments to individual patients; a well chosen homeopathic remedy can have staggering effects although like conventional therapies it doesn't work in everybody. There have been no NNT calculations done for studies in homeopathy that I could find, but in a survey of 100 consecutive inpatients at Glasgow Homeopathic Hospital, of the 77 who responded 75% reported moderate to significant improvement or cure of presenting complaint with only 6% reporting deterioration in symptoms (personal communication). The low rate of adverse effects is also notable. For many doctors, the evidence regarding homeopathy remains mixed and the debate about will no doubt continue. However, as a conventional physician with homeopathy as an extra ‘tool in my toolbox’ the difference I can make to my patients’ lives and symptoms remains a source of immense professional satisfaction. (1) Editor’s Choice BMJ VOL 327 13th December 2003 (2) McQuay H J and Moore R A. Opioid problems, and morphine metabolism and excretion. Bandolier (3) McQuay H J, Carroll, D and Moore R A. Injected morphine in postoperative pain: a quantitative systematic review. Journal of Pain and Symptom Management 1999;17:164-74 Competing interests: Awarded an Alexander Dykes Memorial Scholarship for further studies in Medical Homeopathy 2002-2003 |
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James G Penston, Consultant Physician/Gastroenterologist Scunthorpe General Hospital, Cliff Gardens, Scunthorpe, North Lincolnshire DN15 7BH
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Sir, In the Independent on 8th December, Allen Roses was quoted as saying that “The vast majority of drugs – more than 90% - only work in 30 to 50 per cent of the people.” The enormous media response to this remark should serve as a warning to all those involved in the provision of health care. For many of the most lucrative drugs, the benefits of treatment are of an order of magnitude less than the figures mentioned by the vice- president of genetics at GlaxoSmithKline. For example, less than five per cent of patients receiving long-term treatment with statins are likely to obtain any benefit whatsoever.[1,2] Put another way, of every one million pounds spent on lipid-lowering agents, more than £950,000 is wasted. Imagine the media outcry to such a revelation? But, even these miserably small benefits may be nothing but a fiction, a statistical sleight of hand or – to use the current vernacular – a “sexing-up” of the data by interested parties. For all the accolades bestowed upon large-scale randomised trials, their methodology is deeply flawed and their results are highly questionable.[2,3] Yet, patients continue to be prescribed long-term treatment with expensive drugs with little prospect of benefit, scarce health care resources continue to be squandered, and those with a vested interest in the results of large-scale randomised trials continue to promote their wares to a bemused – if not frankly gullible - medical profession. We are urged to “Let the sun shine in.” [4] If, as it seems, this is a call for honesty and openness, then few would disagree. But, let this honestly and openness extend to the foundations of clinical research. And, of course, let those – including the editor of the BMJ – who endlessly extol the virtues of large-scale randomised trials, bring honesty and openness into the murky world of this flawed methodology. References 1. Freemantle N, Hill, S. Medicalisation, limits to medicine, or never enough money to go around? BMJ 2002;324;864-5. 2. Penston J. Fiction and Fantasy in Medical Research: the Large-Scale Randomised Trial. The London Press. London, 2003. 3. Charlton BG. Fundamental deficiencies in the megatrial methodology. Curr Control Trials Cardiovasc Med 2001;2;2-7. 4. Smith R. Editor’s choice: The drugs don’t work. BMJ 2003;327; 13th December. Competing interests: None declared |
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Elizabeth A Mejia-Millan, Resident DUMC/GSK
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I believe that the statements which you cited are attributable to Allen Roses (not Allen Rogers, my colleague in Medical Information at GSK), GSK's VP of Genetics. Thanks for the correction. Competing interests: None declared |
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Carolyn J McGhee, retired Prince George BC Canada V2N 5L7
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I think Editor Richard Smith cannot be a gardener! Borage and Evening Primrose are not at all the same plant. Competing interests: None declared |
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