Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Doctors & Patients are Too Stupid?
- Verna E. Radcliffe (15 September 2002)
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Patient's raw determination returned Alosetron (Lotronex) and not Pharmaceutical $$
- Jeffrey D. Roberts (15 September 2002)
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Author's response
- Michel Lièvre (16 September 2002)
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How Sad
- Bud Hodorowski (17 September 2002)
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Writer has own agenda
- Jeffrey D. Roberts (18 September 2002)
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Lotronex - a true lifesaver
- Diana F. Hoyt (18 September 2002)
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IBS Hardly "Benign"
- Michelle A Yard (18 September 2002)
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Organic causes of the "irritable bowel syndrome".
- Richard G Fiddian-Green (18 September 2002)
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IBS, ileostomy dysfunction and intussusception
- Richard G Fiddian-Green (21 September 2002)
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"Irritable bowel syndrome" and peptic ulceration
- Richard G Fiddian-Green (21 September 2002)
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A new model for peer review
- Emmet J Andrews (29 September 2002)
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What, really, is the problem?
- Robert H. Palmer (1 October 2002)
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Verna E. Radcliffe, Author/Petition to FDA & GSK for the Return of Lotronex 1212 Mohawk Lane, St. Joseph, Michigan 49085
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Amazing! "The [FDA] agency would now rather provide the best information for patients and doctors to make their own decisions than to make the decisions in their name." Another one who feels patients and their own doctors don't have brains enough to determine appropriate care. Why don't we just close all medical schools then, and put the doctors to work as veterinarians? Misinformation such as this article prattled about by the ignorant cause harm to many. Much more than a case of constipation. Sincerely, Verna Eileen Radcliffe |
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Jeffrey D. Roberts, President & Founder IBS Self Help Group Toronto, Canada M4N 3R1
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Michel Lièvre, I read with great disappointment your editorial in BMJ 2002;Sept. 14 about Alosetron. In particular your depiction of the Irritable Bowel Syndrome Self Help Group as a recipient of pharmaceutical funding is wholly inaccurate. The IBS Self Help Group was established in 1987 to aid individuals suffering from this chronic illness. After Lotronex was removed from the market in 2000, members established the Lotronex Action Group, a grassroot organization, with no pharmaceutical or corporate affiliation. Neither the IBS Self Help Group nor the Lotronex Action Group has ever received any funding from pharmaceuticals. The banners which you allude to in your editorial were quite obviously webpage hotlinks and not sponsored banners. Your characterization that the Lotronex Action Group somehow conducted a Drug Voice survey is also wholly inaccurate. Our personal convictions that Alosetron is a safe drug are backed by our own personal experiences.That is clearly documented in our testimony to the FDA in April 2002. Perhaps you do not think ANYBODY can have good intentions without putting a price tag on it. Jeffrey D. Roberts, B.Sc. President & Founder IBS Self Help Group Co-Founder & Coordinator Lotronex Action Group Email: jeffrey.roberts@ibsgroup.org Url: http://www.ibsgroup.org |
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Michel Lièvre, Associate Professor Clinical Pharmacology Unit, Faculté de Médecine Laënnec, rue Guillaume Paradin, 69008 Lyon, France
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I am sorry Mr Roberts felt being personally attacked in my editorial about alosetron for IBS. I have no doubts about his sincerity and good intentions. I only suggested that it may be difficult for such an organization as the IBS self help group to be really independent. The IBS self help group needs money to be an effective organization. It can be read on the Group's Web site that "Our site offers sponsorship opportunities for quality companies offering patients, caregivers and healthcare professionals, appropriate help, services and products". The term "companies offering products" seems to correspond to the definition of pharmaceutical companies. When on the same site everyone can find the banners of 3 drug companies that are developing or marketing drugs for the treatement of IBS, it may be concluded that these companies are probably sponsors of the group. It is particularly so because no list of past and present sponsors can be found on the Web site. Transparency is of an utmost importance when one wants to claim its independence. That's the reason why journals like the BMJ ask contributors to declare any conflict of interest they may have (I have myself declared some). Even if the presence of drug companies banners on the IBS self help group web site does not prove that these companies are actually sponsors of the group, the banners point to sources of information that are obviously biased. In my opinion, this is equivalent to advertising for these companies, be it free, and the visitors of the IBS self help Group site may deduce that the Group validates the information given by these drug companies sites. I never pretended that the Lotronex Action Group had commissioned a Drug Voice survey on Lotronex, but it is a mere fact that the results of such a survey were used by the LAG as an argument in favor of the reintroduction of Lotronex on the market. There may be some thoughtlessness to present without warning results that may be biased. Therefore, the Lotronex Action Group and the IBS self help Group would gain much from increased transparency and caution. In fact, I fully approve the empowerment of patients, and I think self help groups or any kind of patient associations are useful and necessary. But the corrolary is that patients must receive a really independent and unbiased information. There is a French saying that reads "Chacun voit midi à sa porte", meaning that we only consider things from our own point of view. A severely distressed patient will usually tend to highly prioritize the benefits against the risks, but this attitude may well change in case of severe adverse effect of the treatment. It would have been fair to ask the opinion of patients who had a surgical operation following the use of Lotronex, as well as that of patients who experienced "life changing benefits". Unfortunately, those who died are now silent. The concerns I expressed in my editorial are firstly those of a plain citizen who has not been spared from the burden of "benign" disease (a bilateral osteoarthritis of the hips is nothing nice to live with). Secondly, my concerns are those of a member of the French drug evaluation agency, who feels it is his duty to help making good decisions regarding licensing of new drugs, with the most difficult task to fulfill: assessing the risk / benefit ratio. The European Agency for the Evaluation of Medicinal Products (EMEA) [1] has issued "points to consider on the evaluation of medicinal products for the treatment of irritable bowel syndrome". This draft concludes "As IBS is a benign syndrome, the safety of any therapeutic intervention is paramount" and "it is necessary to have long-term safety data (12 months) in adequate numbers". This also my opinion, and the facts do not plead in favor of Lotronex in this regard. Michel Lièvre [1] http://www.emea.eu.int/ |
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Bud Hodorowski, IBSer Rep 13512 Sunshine Valley Rd, Grass Valley, CA 95945
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It is sad that Michel Lièvre does not understand IBS and the Lotronex story. Too many times, a person's ignorance perpetuates ignorance in society. In Michel's editorial he states, " irritable bowel syndrome, a benign though unpleasant disorder." For many IBS suffers that may be the case, but for some it goes way beyond that. For my wife, before Lotronex, she would spend two, three or four days at a time, three or more times a month, lying in the fetal position holding her gut with Hydrocodone doing nothing to help, praying for relief. IBS took away about 70% of her quality of life. For her it was a devasting and debilitating illness. Lotronex gave her the biggest part of her quality of life back immediately. The gut pain attacks came far less frequently, didn't last as long and were less in severity when they did occur. She's just one example of the many who suffer in that most severe range. It's just unfortunate that so many don't truly understand how devastating this illness can be and how effective Lotronex is. IBS is not always an "unpleasant disorder" .... It is a terrible and devastating illness with no known cure and, for many, a life long sentence. Lotronex and risk versus reward .... It's a no-brainer for us. One last thing: Michel feels that we must be protected from ourselves. I resent the mentality that doctors and patients are incompetent in making wise health decisions. I can assure you that my wife and I are well educated when it comes to IBS and Lotronex. There's also other incorrect information, but ...... Enough! Too bad he'll probably never realize how far off base he is in his editorial. |
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Jeffrey D. Roberts, President & Founder IBS Self Help Group Toronto, Canada M4N 3R1
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The fact is that neither the IBS Self Help Group nor the Lotronex Action Group have ever in the past or present received any funds from a pharmaceutical organization. We thank you for your suggestions about our claim to independence but we don't need a writer with their own agenda to question our integrity. |
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Diana F. Hoyt, Sales Manager OM5, Atlanta, Ga. USA 30361
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In response to the article written by Monsieur Lievre, I must share my comments from someone whose life was changed drastically by this unique drug. For those of us with severe IBS-D, this was truly a wonder drug and the opportunity for many of us to lead a semi-normal life after years of suffering. Imagine what life would be like for you should you have to worry at every moment that you will have an excrutiatingly painful bout of diarrhea, with no warning, and soil yourself in front of the world. This is what life is like on an hourly basis with severe IBS-D. I have had "accidents" in my car, at my desk in the office, on a deserted street - I have thrown my soiled clothes in the closest garbage and cried all the way home. My life is ruled by this disease. And it affects every member of my family, and every person that knows me. So believe me, I was ecstatic to hear that there might be a drug developed to address my disease. To hear that FINALLY after almost 30 years (this began at 15 - I am 43 now) the real cause of IBS was being explored and minds would be forever changed. I knew this was important for my life. Within 1 week of taking Lotronex, I was cured. My emotional fears were still there, but the physical transformation was incredible. I used Lotronex for almost 18 months with no side effects whatsoever. And it truly did change my life. I became a part of the Lotronex Action Group by accident. I do not surf the web, do not spend hours on the internet, but when Lotronex was pulled from the shelves, I was devastated and my husband and I turned to the internet to see if anyone had any ideas. There I found similar people with the same wonderful results and the same devastation at losing the only drug that helped them. If we had choices...if there was any other medication that would work, I would consider that. But Lotronex was the first of its kind - the first time that anyone looked outside the norm for an answer to my suffering. I was one of the patients that spoke out at the FDA meeting in Washington to beg for Lotronex's return. I have no connection to any drug company, I paid all my own expenses and was happy to do so. It was the hardest thing I have ever done but I would gladly stand before 200 people again and bare my soul if it meant the return of such a life altering drug. I understand your concerns but believe me, when you suffer from such a debilitating disease, you are willing to accept possible consequences in exchange for quality of life. Doctors need to educate their patients on the risks, the warning signs, and how to take control of their own lives by being informed patients. I am responsible for my life and will gladly accept the risks, and until you offer me something with the same reward, I will continue to do so. As I said in my speech, "quality of life is the issue here and as you can see from my story, a life without Lotronex is a miserable existence". |
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Michelle A Yard
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Only someone who has never soiled themselves in public would call this IBS benign. I am a professional woman who found herself trapped in a meeting when an IBS attack hit. I think you can imagine my horror. I now work from home as a freelance writer at a substantial reduction in income. That's hardly the result of a benign syndrome. I could list the many medications I tried, the many diet modifications I underwent, but I'm sure you would discount those. Lotronex gave me back the life I had. There are medications for incontinence, erectile disfunction and other relatively benign problems. (IBS affects the sex life too.) None of them will kill the body. They may, however, kill the spirit. I'll take my chances, moderate my dosage as my body indicates and take back a normal life. |
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Richard G Fiddian-Green, None None
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Although my experience is undoubtedly skewed by the majority of cases I saw in my academic surgical practice being referred to me almost exclusively by gastroenterologists, I cannot recall ever having seen a patient who had what is called the "irritable bowel syndrome" (1). I have encountered many patients who have had symptoms similar to those described in the irritable bowel syndrome. The cause was invariably an intermittent obstruction. In most instances the intermittent obstruction was caused by faecal impaction and in one case by undigested Asulphadine tablets having a ball-valve effect above a mechanical obstruction. The causes of the mechanical obstruction included Crohn’s disease, carcinoma, diverticular disease, radiation enteritis, ischaemic enteritis, adhesions and anal stenosis. Phytobezoar were a cause of intermittent obstruction seen when gastrectomy was routinely performed for peptic ulcer disease. It may still be a cause in edentulous patients. Other causes included intermittent obstruction from an intermittent volvulus in children and on one occasion the intermittent obstruction of the small bowel of a medical student whose small intestine became intermittently incarcerated in a paraduodenal hernia.. The commonest cause of the symptoms of the "irritable bowel syndrome", especially in those with evidence of atherosclerotic disease and the aged, might be chronic gastrointestinal ischaemia (2,3). Gastrointestinal tonometry provides the means to make an accurate diagnosis of chronic gastrointestinal ischaemia especially if measurements are made during the provocative stimulus such as feeding or exercise (3,4,5,6,7,8,9). Administering alosetron, which may cause ischaemic colitis, to patients thought to have the irritable bowel syndrome without first excluding the presence of chronic gastrointestinal ischaemia would seem most unwise (1). Given the risk of developing ischaemic colitis when taking alosetron it might be appropriate not only to exclude the presence of chronic gastrointestinal ischaemia before administering the drug but also to repeat the investigations after the administration of the drug to be sure that it is not causing chronic ischaemia. The bottom line is that no single cause of the “irritable bowel syndrome” has been identified. Treatment of this condition with alosetron should be reserved for symptomatic patients in whom all organic causes of their symptoms have been excluded. This is very difficult to do especially in the case of an intermittent volvulus and of incarceration in an internal hernia. In these cases the diagnosis may only be excluded at laparotomy. Conflict: I once had a tangible financial interest in gastrointestinal tonometry. 1. Lièvre M. Alosetron for irritable bowel syndrome. BMJ 2002; 325: 555-556 2. Fiddian-Green RG, Stanley JC, Nostrant T, Phillips D. Chronic gastric ischemia. A cause of abdominal pain or bleeding identified from the presence of gastric mucosal acidosis. J Cardiovasc Surg (Torino). 1989 Sep-Oct;30(5):852-9. 3. Fiddian-Green RG. Provocative test for chronic mesenteric ischemia. Am J Gastroenterol. 1992 Apr;87(4):543. 4. Fiddian-Green RG, Amelin PM, Herrmann JB, Arous E, Cutler BS, Schiedler M, Wheeler HB, Baker S. Prediction of the development of sigmoid ischemia on the day of aortic operations. Indirect measurements of intramural pH in the colon. Arch Surg. 1986 Jun;121(6):654-60. 5. Schiedler MG, Cutler BS, Fiddian-Green RG. Sigmoid intramural pH for prediction of ischemic colitis during aortic surgery. A comparison with risk factors and inferior mesenteric artery stump pressures. Arch Surg. 1987 Aug;122(8):881-6. 6. Fiddian-Green RG, Gantz NM. Transient episodes of sigmoid ischemia and their relation to infection from intestinal organisms after abdominal aortic operations. Crit Care Med. 1987 Sep;15(9):835-9. 7. Faries PL, Narula A, Veith FJ, Pomposelli FB Jr, Marsan BU, LoGerfo FW. The use of gastric tonometry in the assessment of celiac artery compression syndrome. Ann Vasc Surg. 2000 Jan;14(1):20-3. 8. Kolkman JJ, Groeneveld AB, van der Berg FG, Rauwerda JA, Meuwissen SG. Increased gastric PCO2 during exercise is indicative of gastric ischaemia: a tonometric study. Gut. 1999 Feb;44(2):163-7 9. Kolkman JJ, Groeneveld AB. Occlusive and non-occlusive gastrointestinal ischaemia: a clinical review with special emphasis on the diagnostic |
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Richard G Fiddian-Green, None None
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In addressing the organic causes of the “irritable bowel syndrome(IBS) I overlooked the important lessons to be learned from the pathogeneisis of ileostomy dysfunction. Ileostomy dysfunction is characterised by severe abdominal cramps, constipation relieved by watery diarrhoea mixed with lumps of vegetable matter, and an increased volume of ileostomy output. These symptoms are very similar to those described by Lievre and patients with what has been diagnosed as IBS (1-4). In the absence of recurrent Crohn’s disease the obstruction is virtually always caused by intermittent mechanical problem at or adjacent the stoma. Patients who are given a well placed and properly fashioned Brooke ileostomy have an unlimited capacity to eat food in any form often gaining tens of pounds in weight within weeks of surgery. Some foods, such as nuts, may cause induce a liquid output and others, such as popcorn, a thickened output. Patients identify these foods, which may be different in different patients, very quickly and learn to avoid those that cause them problems. Once on a regular diet the ileostomy output has a mushy consistency and a volume of about 600mls to 700mls a day. The commonest cause of ileostomy dysfunction, i.e stomal obstruction, I have encountered is stenosis due to fibrosis at the mucos-cutaneous junction. This is usually the product of an ileostomy performed without primary muco-cutaneous anastomosis as was the custom before I acquired the large surgical referral practice for inflammatory bowel disease at the University of Michigan. The next most common was mucosal intussusception at the facial margin, invariably caused by the suturing of the wall of the ileum to the fascia. The least common is a twist in the terminal ileum at the peritoneal margin, usually caused by poor fixation of the terminal ileal mesentery in eliminating the possibility of an internal hernia. ( An intermittent internal hernia in an inadequately closed paraileal gutter is another cause of intermittent obstruction). I have not encountered “pouchitis” after an ileo-anal anastomosis with or without the formation of a J-pouch. Abdominal cramps, watery diarrhoea, urgency and incontinence, similar to that sufffered by patients with IBS, are said common in these patients (3,4). This condition is, I believe, analogous to ileostomy dysfunction and caused by an anastomotic stenosis. Indeed I enountered a patient with intermittent constipation and diarrhoea urgency and incontinence who had had an ileoanal performed years earlier in the late sixties or early seventies, long before Lester Martin’s report on his use of the Svensen in children with ulcerative colitis. She had a very tight stricture. Digital dilatation under anaesthesia resolved all of her symptoms completely. From that moment on I trained all patients on whom I had constructed an ileo-anal or colo-anal anastomosis to dilate themselves regularly for life to insure that they never developed a significant anastomotic stricture. In some cases patients found it necessary to dilate themselves weekly to prevent stricturing especially in the first months after surgery. More often patients found it sufficient to dilate themselves every month or two. Some patients found it unnecessary to dilate themselves. I believe it is this practice that has been responsible for the absence of clinically significant “pouchitis” in my patients. Those gastroenterologists who have not been able to resist the urge to look inside the pouch and take biopsies have on occasions found histological changes and bizarre bugs consistent with the diagnosis of “pouchitis”. “Pouchitis” is I believe a clinical diagnosis and not a histological or bacteriological diagnosis. Establishing the presence of a significant obstruction in a patient with an ileostomy can be extremely difficult especially in the case of mucosal intussusception which is rarely seen on contrast studies performed either from above or below. The mucosal prolapse, usually responsible for the intussusception, tends to come and go. Eliminating all possible causes of obstruction by revising the ileostomy invariably relieves the patient of his/her symptoms of ileostomy dysfunction. Intussusception is most commonly seen in children who have never had an operation. These patients behave very similarly to patients with IBS (2). The condition in young children is thought to be caused by hypermotility. It is possible that it might be initiated by by a focus of mucosal oedema or enlarged Peyer’s patch induced by contact with an ingested food product,or viral or bacterial infection. In older children and adults intussusception is usually caused by a polyp. Intussusception in patients who have never had surgery is another of the many organic causes that need to be excluded in making a diagnosis of IBS. It too is a clinical diagnosis that is extremely difficult to either prove or disprove radiologically. Finding a tender tube-shaped palpable mass, which might be tender, during an attack of pain or seeing one on a contrast CT scan may establish the diagnosis. I wonder if all the organic causes I have listed have been excluded in the patients who have described their distressing symptoms (2,3,4). In so doing it should be noted that mucosal oedema, a possible cause of intussusception, is a classic feature of the relatively benign and reversible episodes of ischaemic colitis. It is called “thumb printing” from its radiographic appearances. It might alternatively be caused by an allergic reaction to an ingested product of food. 1. Lièvre M. Alosetron for irritable bowel syndrome. BMJ 2002; 325: 555-556. 2 Hodorowski B. How sad. bmj.com, 16 Sep 2002 3. Hoyt DF. Lotronex – a true lifesaver. bmj.com, 17 Sep 2002 4. Yard MA. IBS Hardly “Benign”. bmj.com, 17 Sep 2002 |
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Richard G Fiddian-Green, None None
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The carcinoid syndrome, caused by the release of abnormally large amounts of serotonin from carconoid tumours, causes flushing, abdominal cramps, diarrhoea, occasionally intestinal ischaemia and even ischaemic strictures in the small intestine, and cardiac lesions. It may progress slowly or rapidly. Serotonin receptor antagonists relieve patients of their symptoms in the carcinoid syndrome (1) in addition to patients with the "irritable bowel syndrome" as reported in this editorial. Serotonin is usually present in large amounts in the gut and, like other gut hormones, is released principally into the lumen of the gut(2). The presumption is, therefore, that it exerts its actions from within the gut lumen, from within the portal circulation, and/or systemically. If so abdominal cramps and diarrhoea are likely to be topical effects, flushing a regional and/or systemic effect and the cardiac lesions a systemic effect. If patients with the "irritable bowel syndrome" do not have one of the many organic causes I have listed for their symptoms and their symptoms are relieved by a serotonin receptor antagonist might the irritiable bowel syndrome be an early manifestation of the carcinoid syndrome? In which case the episodes of intestinal ischaemia that have developed after being placed upon a serotonin receptor antagonist might be the consequence of the progression of the carcinoid syndrome rather than a complication of the drug. Indeed some of these patients might even have carcinoid tumours. I once proposed that duodenal and gastric ulcers were different manifestations of a common disease and that all peptic ulcers were the product of an abnormal release of gastrin, a gut hormone also released primarily into the lumen of the gut (3). I still believe this is the case and that H pylori is a secondary factor rather than than the primary cause of the ulcers as others have proposed. Might the "irritable bowel syndrome" and peptic ulceration have a common cause? Might that cause even be smoking? 1. Wymenga AN, Vries EG, Leijsma MK, Kema IP, Kleibeuker JH. Effects of ondansetron on gastrointestinal symptoms in carcinoid syndrome. Eur J Cancer. 1998 Jul;34(8):1293-4. 2. Hopkinson GB, Hinsdale J, Jaffe BM. Contraction of canine stomach and small bowel by intravenous administration of serotonin. A physiologic response? Scand J Gastroenterol. 1989 Oct;24(8):923-32. 3. Fiddian-Green RG, Is peptic ulceration a hormonal disease? Lancet. 1977 Jan 8;1(8002):74-7 |
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Emmet J Andrews, Surgical Registrar Our Lady' Hospital Navan, Co. Meath, Ireland.
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The arguments of flawed analysis, bias and collusion in the debate regarding the Food and Drug Administration (FDA) with regard to Alosetron1,2 are similar to those in the recent debate regarding peer review3. Although it could be concluded that the two methods of assessing medical information have flaws, the notable observation is that one system is professional, the other is amateur. While the FDA performs a crucial role in the regulation of drugs and medical devices, the content of the medical literature is of no lesser importance. Indeed the FDA requires information that has been through the peer review process in determining it’s decisions and evidence based medicine recommends that clinical decisions are based on the results of clinical trials as presented through the medical literature4. There must therefore be confidence that what the medical literature contains is accurate and unbiased both in what is published and in what is not. This puts significant obligation on editors and reviewers to perform their jobs with due diligence and integrity but there is evidence that this is not always the case5. It begs the question: why is the peer review system still amateur? Perhaps the FDA or the patent review system are models that could be applied to the peer review process. They have specified criteria for submission, defined timeframes for reviewing applications, a resubmission system, and full feedback from the multidisciplinary review personnel. A similar centralised professional body, national or international, could act as a reviewing agency for all medical journals for all medical articles. It could then allocate the article to the most appropriate journal depending on the potential impact and interest level. This would eliminate the need for repeated submission to different journals and speed the time to publication. This would of course require significant alteration to the current system. Funding issues, appropriate personnel, and not least the support of journals and editors would need to be investigated. But the need to re -engineer the peer review process has never been greater given its importance and the current limitations of the system. The medical literature has enormous significance to healthcare and should probably be treated as a more valuable resource with greater investment. References: 1. Moynihan R. Alosetron: a case study in regulatory capture, or a victory for patients' rights? BMJ 2002; 325: 592-595. 2. Lièvre M. Alosetron for irritable bowel syndrome BMJ 2002; 325: 555- 556. 3. Bacchetti P. Peer review of statistics in medical research: the other problem. BMJ 2002;324:1271-1273. 4. Sackett DL, Richardson WS, Rosenberg W, Haynes RB. Evidence-based medicine: how to practice and teach EBM. Churchill Livingstone, London, 2000. 5. Goldbeck-Wood S. Evidence on peer review scientific quality control or smokescreen? BMJ 1999; 318: 44-45. |
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Robert H. Palmer, Medical Director Forest Laboratories, New York NY 10022
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EDITOR - The discussions of alosetron and irritable bowel syndrome in the September 14 issue of BMJ were extremely disappointing because the quantitative estimates of risk are unreliable; those cited appear to have been based on reports of events for which causality has not been established. Dr. Lievre1 cites an incidence for severe constipation of "1 in 1000 patients treated for 6 months", and extrapolates to suggest that if two million patients received alosetron, "it might result in 2000 cases of severe constipation" (emphasis added). As quoted by Dr. Thomas Permutt of the FDA, (p. 100 of the FDA transcript, ref. 3), the incidence of severe constipation with alosetron was 11 in approximately 11,000 patients. However, the incidence with placebo was 3 in approximately 3,000 patients, also 1 in 1000, so it can not be inferred that treatment of two million patients would "result" in 2,000 cases. What we need to know, and what was not discussed in any of the articles in this issue, is the absolute risk increase associated with the use of alosetron. This would lead to the more relevant calculations of the number needed to treat in order to result in one of the complications associated with alosetron, and the 95% confidence intervals on those numbers. Dr. Permutt pointed out problems with comparing incidences from controlled trials, and referred to the importance, therefore, of post- marketing surveillance data. As discussed repeatedly by authors from the FDA and elsewhere, and affirmed by Dr. Ann Mackay of the FDA Office of Drug Safety on p. 111, reference 3, the spontaneous reporting system may have great value in identifying signals, but it is useless in assessing incidence rates. Among other reasons, this is because the issue of causality is not addressed. This fact is repeatedly glossed over in the BMJ articles. Mr. Moynihan2 cites "113 cases of serious complications of constipation....and at least seven deaths assessed as probably linked to the drug" (emphasis added). These same numbers are quoted by Dr. Mackay, in reference 6, (p. 116-117), with the comment that "association with Lotronix can not be reasonably excluded". This is a far cry from being "probably related". As Dr. Lievre certainly knows, the French have a complicated and arduous method of evaluating the probability of causality for individual spontaneous reports, but no such rigor is required in the US. Submission of a report is, per se, sufficient to qualify an event as "possibly related", and to have it included in these numbers. In summary, the magnitude of the risk involved with alosetron appears to be still unknown. It may be small or it may be large, but evidence- based medicine requires that we recognize how the numbers were derived, and what the limits of uncertainty are. Even the quoted statement by GlaxoSmithKline2 of a "five-fold increase in the risk of developing ischemic colitis" is not very helpful, absent the absolute risk, the number needed to treat, and the confidence intervals. Much of the controversy discussed in these articles is meaningless without of a better quantitative understanding of the magnitude of the risks involved. Robert H. Palmer, MD
1. Lievre M. Alosetron for irritable bowel syndrome. BMJ 2002;325:555. 2. Alosetron: a case study in regulatory capture, or a victory for patients' rights? Moynihan R. BMJ 2002;325:592. The author is an employee of Forest Laboratories, Inc. No competing interest. |
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