chosen not to undertake any comparative trials of high dose ranitidine with omeprazole. Any decision to suspend clinical trials with omeprazole has not been supported by valid reasons and seems to be derived from data of Burlinson et al suggesting that omeprazole is genotoxic.6 We were surprised to learn that Professor Langman perceives that the data of Burlinson et al await full explanation.6 The methodology used in that study has been shown to be invalid by independent investigators, and the results cannot be reproduced.7`9 The conclusions reached in that study by the Glaxo Research Group are crucially dependent on there being a pure population of non-dividing gastric epithelial cells after the digestion process. It should therefore be clearly understood that independent investigators using this method have found a mixed population of cells heavily contaminated with actively dividing cells and cells from the middle portions of gastric glands. Furthermore, is Professor Langman aware that Burlinson et al now acknowledge that their assay is not a valid measure of genotoxicity?'° There is no evidence to support the notion that omeprazole is genotoxic, and we contend that the questions raised by the previous work of Burlinson et al are now satisfactorily resolved.9' Clearly, increased vigilance is both necessary and commendable after any new drug is introduced into clinical practice. Unlike Professor Langman, we have not had the opportunity to appraise fully the Committee on Safety of Medicines' adverse event data, which apparently relate to headache, rash, and diarrhoea with omeprazole. In widespread comparative trials (now including more than 25 000 patients), however, the profile of side effects with omeprazole was no different from that with placebo or the H2 antagonists.4 Worldwide clinical experience with omeprazole now includes more than 15 million patient treatments. As this experience grows the applications of this drug in the management of patients with acidpeptic disease will continue to increase because of its demonstrably superior efficacy with unquestionable short term safety. COLIN W HOWDEN
STEPHEN HOLT Division of Digestive Diseases and Nutrition, University of South Carolina School of Medicine, South Carolina 29203, United States I Langman MJS. Omeprazole. BM7 1991;303:481-2. (31 August.) 2 Jones DB, Howden CW, Burget DW, Kerr GD, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987;28:1120-7. 3 Howden CW, Hunt RH. The relationship between suppression of acidity and gastric ulcer healing rates. Alimentary Pharmacology and Therapeutics 1990;4:25-33. 4 Holt S, Howden CW. Omeprazole: overview and opinion. DigDis Sci 1991;36:385-93. 5 Bate CM, Keeling PWN, O'Morain CA, Wilkinson SP, Mountford RA, Temperley JM, et al. A comparison of omeprazole and cimetidine in reflux oesophagitis. Symptomatic, endoscopic and histological evaluations. Gut 1989;30:A1493-4.
[Abstract.] 6 Burlinson B, Morriss SH, Gatehouse DG, Tweats DJ. Genotoxicity studies with gastric acid inhibiting drugs. Lancet 1990;335:419. 7 Scott D, Reuben RA, Zampighi G, Sachs G. Cell isolation and genotoxicity assessment in gastric mucosa. Dig Dis Sci 1990;35:1217-25. 8 Wright NA. DNA synthesis and genotoxicity. Digestion 1990;47 (suppl 1):24-30. 9 Holt S, Zhu Z-H, Powers RE. Observations on a proposed measure of genotoxicity in rat gastric mucosa. Gastroenterology 1991;1O1:650-6. 10 Burlinson B, Morriss S, Gatehouse DG, Tweats DJ, Jackson MR. Uptake of tritiated thymidine by cells of the rat gastric mucosa after exposure to loxtidine or omeprazole. Mutagenesis 1991;61:11-8. 11 Holt S, Powers RE, Howden CW. Antisecretory therapy and genotoxicity. DigDis Sci 1991;36:545-7.
SIR,-Professor M J S Langman's editorial is subtitled "For recurrent peptic ulcers and severe oesophageal reflux disease."' It is clear to me as a general practitioner that, as with other innovative drugs, omeprazole is prescribed overzealously and often irrationally. Although my experience is obviously anecdotal I BMJ VOLUME 303
5 OCTOBER 1991
suspect it may be representative. Two patients with dyspeptic symptoms who I referred to (different) gastroenterologists returned after endoscopy bearing requests for me to prescribe omeprazole. The first time I obliged; the second time I substituted an H2 antagonist. The symptoms of both patients were subsequently relieved completely with H2 antagonists. Letters to both consultants elicited replies to the effect that H2 antagonists would have been appropriate first line treatment in these two patients, who both had previously untreated reflux oesophagitis. A parallel situation occurs with hypercholesterolaemia, for which-on the basis of a single measurement-patients are all too often prescribed lipid lowering agents rather than being given dietary advice followed if appropriate by a rational prescription of a lipid lowering agent. By rational I mean necessary, effective, economical, and of proved safety. Doctors in general should avoid the temptations and pressures to prescribe the most powerful available agent and be content with one that is simply "good enough." If we fail to do this we face the risk of protocols for prescribing being imposed from outside. R HARRINGTON
Thame, Oxfordshire OX9 3JZ I Langman MJS. Omeprazole. BM_ 1991;303:481-2. (31 August.)
SIR,-It is more than a trifle discomfiting to find that Professor M J S Langman has failed to grasp the basic issues in the debate about the putative genotoxicity of omeprazole.' Burlinson et al at Glaxo did not report "that pretreatment with omeprazole initiated proliferation in the superficial zone" (for example, the rat stomach).2 They claimed that omeprazole induced unscheduled DNA synthesis in non-proliferating superficial cells, presumably after damaging DNA-quite a different concept. It is also unfortunate that Professor Langman did not indicate that things have moved on since the initial claim by Glaxo. Holt et al have shown definitively that the Burlinson method is badly flawed in that there is serious contamination of the so called "non-proliferating" surface cells with proliferating cells undergoing semiconservative DNA synthesis.' Appropriate controls showed no evidence of unscheduled DNA synthesis. Possibly more importantly, Burlinson et al have published what amounts to a retraction of their method as a genotoxic assay: they show, instead, that the method detects ordinary semiconservative DNA synthesis and that omeprazole stimulates this.4 Interestingly, Fraser et al find this effect confined to the original Glaxo rat strain, the PFK rat.5 It thus seems that omeprazole may stimulate cell proliferation in the stomach of at least one rat strain, possibly through stimulating release of gastrin. This is a totally different proposal: it is not indicative of genotoxicity and is a property shared with other antiulcer drugs, as we have shown for
misoprostol.' Incidentally, we ourselves have found that the Burlinson method is inappropriate for measuring unscheduled DNA synthesis, although these experiments have not yet been published.7 It is thus fairly clear that Glaxo's claim, based on the data of Burlinson et al, does not hold water. There has, however, been a claim, from other workers, that omeprazole induced unscheduled DNA synthesis in a rat stomach in vitro assay (C Furihata and T Matsushima, meeting of the European Mutagenesis Society, 1990 (abstract P213)) unfortunately, it proved impossible to suppress semiconservative DNA synthesis totally in this assay, and the marginal rise in tritiated thymidine incorporation can readily be explained by an induction of normal cell proliferation, which would not be detected in the unsuppressed experiments because of the large confidence intervals.
So what can be concluded from this curious affair? That overinterpretation of inappropriately planned experiments occurred is beyond doubt; it is also clear that partial suppression of experimental data was evident in the initial report.2 We shall probably never know the reasons behind such preemptive publication. But the problem of quality control of questionable data and its implications for the standards of certain pharmaceutical companies' in house research does obtrude. R GOODLAD N A WRIGHT
Department of Histopathology, Royal Postgraduate Medical School, London W12 ONN I Langman MJS. Omeprazole. BM 1991;303:481-2. (31 August.) 2 Burlinson B, Morris SH, Gatehouse DG, Tweats DJ. Genotoxicity studies of gastric acid inhibiting drugs. Lancet
1990;335:419. 3 Holt S, Zhao-Hua Z, Powers RE. Observations on a proposed measure of genotoxicity in rat gastric mucosa. Gastroenterology
1991;101:650-6. 4 Burlinson B, Morriss SH, Gatehouse DG, Tweats DJ, Jackson MR. Uptake of tritiated thymidine by cells of the rat gastric mucosa, after exposure to loxtidine or omeprazole.
Mutagenesis 1991;6:11-8. 5 Fraser AG, Debram GS, Dhillon AP, Pounder RE. Variation in rat strain affects gastric mucosal proliferative response to
antisecretory drugs. Gastroenterology 1991;100:A66. 6 Goodlad RA, Madgwick AJ, Moffatt MR, Levin S, Allen JL, Wright NA. Effects of insoprostol on cell migration and transit in the dog. Gastroenterology 1990;98:90-5. 7 Goodlad RA, Lee C, Sarraf CE, Alison MR, Wright NA. Genotoxicity, omeprazole, unscheduled DNA synthesis. Gut (in press).
Confidentiality taken to the extreme SIR,-I wish to express my concern at a hitherto unforeseen consequence of the recently introduced regulations arising out of the Human Fertilisation and Embryology Act 1991. I recently received what amounts to a letter before action from a patient concerning treatment that I had provided. Being aware of the constraints that the act places on me with regard to confidentiality,' 2I sought advice from the Human Fertilisation and Embryology Authority on whether I was permitted to seek advice from the Medical Defence Union. The authority informed me that the act absolutely prevented me from doing so. General discussions with lawyers subsequently have confirmed this prohibition. I am advised that I am unable to seek any legal help other than on the basis of anonymised fact, nor will I be able to defend myself in a court of law if I am sued for any reason if it involves treatment of infertile patients. This applies even if the treatment was provided before the act came into force. The same would apply if I was to be brought before a disciplinary committee of the General Medical Council. As a consequence of this, legal advisers have informed me that they believe that all clinics and practitioners who continue to provide fertility treatment in licensed centres are placing themselves in a similar position until such time as the Department of Health has resolved this problem. In the light of this, we would seem to be unable to continue our work. The Human Fertilisation and Embryology Authority is fully aware of the consequences of this anomaly but is at present unable to advise me of any way in which I could defend myself in this or any other case that might be brought against me or any colleague in a similar position in the future. My legal adviser is aware of no other person in the United Kingdom who is in the potential position of having an action brought against him but who is absolutely prevented from defending himself in a court of law. I consider it my duty to my colleagues who also provide licensed infertility treatment to point out to them this anomaly of the Human Fertilisation and Embryology Act so that they may also be aware of their vulnerability. I cannot believe that when 851
parliament passed this act it intended removing the inalienable right of a person to defend himself in a court of law. Needless to say, the act must be amended soon in order to allow doctors to protect themselves. PETER R BRINSDEN
Yelling, Cambridge PE19 4SD 1 Brinsden P. A tax on infertility? BMJ 1991;303:309. (3 August.) 2 Campbell C. A tax on infertility? BMJ 1991;303:714. (21
September.)
SIR,-Professor Colin Campbell's response' to Mr Peter Brinsden's previously expressed concerns2 are helpful. To most infertile couples and to many medical practitioners, however, the new controls on fertility practice seem quite absurd. Of course the Human Fertilisation and Embryology Authority has to work with an imperfect act as best it can, but why is the act so imperfect? The public will wonder how it is possible for an act to reach the statute book when it has the following results. Firstly, it prevents fertility specialists from communicating with referring doctors and other colleagues as this is positively dangerous and quite contrary to the clear recommendations of the General Medicasl Council. It seems that there has been a gross error in the parliamentary draughtsmanship which was originally intended to protect the confidentiality of patients who have donated gametes but which has been applied to all patients receiving fertility treatment. It would be helpful if this was acknowledged to be the case so that amendments may be made, allowing normal doctor to doctor communications to be restored. The Human Fertilisation and Embryology Authority acknowledges that the act requires a change in communication practice, but the suggestions made in its code of practice provide only an imperfect, circuitous, and inefficient system. What is required is for the relevant clauses of the act to be amended. Secondly, it results in infertile patients having to pay, albeit indirectly, to a centre's costs in order to have a child because of the means of raising revenue for the Human Fertilisation and Embryology Authority's administration, when it financially costs nothing to have an abortion. Surely it would have been fairer to have funded the authority's expenses totally from central sources. Mr Brinsden may rightly complain that his centre's annual levy of £40 000 will have to be passed on to patients, but at least the Bourn Hallam Clinics have the financial backing of Aeres Serono, a multinational pharmaceutical company. What cushion is there for NHS units or totally independent centres such as ours? Thirdly, it prevents the further use of stored donor sperm for couples who have previously had one child from a given donor because that donor then refuses to have his name and date of birth held by the authority, which was previously not required. It is all very well now to consider that there might be a transitional period of six months for the use of undesignated sperm, but why was this not considered long ago, and why should other patients be denied this option after this suggested cut off time if they have already reserved the same donor for a second pregnancy? Professor Campbell, speaking at a meeting earlier this year, emphasised that he did not wish to see the Human Fertilisation and Embryology Authority become a bureaucratic organisation, and yet these and other issues clearly indicate this risk. We should reflect why we are in such a state seven years after parliament received the Warnock report. IAN CRAFT
London Fertility Centre and Medicraft Services, London WIN 1AF 1 Campbell C. A tax on infertility? BMJ 1991;303:713-4. (21
September.) 2 Brinsden PB. A tax on infertility? BMJ 1991;303:309. (3 August.)
852
Papaveretum in women of childbearing potential SIR,-The recent recommendation by the Committee on Safety of Medicines that products containing papaveretum should be avoided in women of childbearing potential' has provoked a defensive reaction from some anaesthetists2 and variable responses from others.3 The manufacturers have not yet written to doctors. Papaveretum is a mixture of opiate alkaloids whose components have been determined by history rather than good science. Most users of papaveretum are unaware of what they are actually prescribing, and the kinetics and metabolism of some of Ihe constituents are poorly described in normal subjects and unknown in the critically ill. Outside the United Kingdom and a handful of other countries morphine is the injectable opiate of choice. I am not aware of any convincing evidence that papaveretum provides superior analgesia to morphine. Like the anaesthetists of Reading,2 until recently I regularly used papaveretum (because it is slightly cheaper than morphine); our division of anaesthesia decided, however, that to use papaveretum for some patients and morphine for others would be a recipe for chaos, and we therefore decided not to use papaveretum in the department. The transition to morphine has been smooth and largely without problems. Papaveretum is now obsolete and of questionable safety and would not receive a licence if it was a new medicine. Morphine is a safe and equivalent alternative. If we allow papaveretum to be used for some patients and not for others we run the risk of confusing our nurses and house officers. It is only a matter of time before someone (probably a child) receives an overdose. Rather than persist in this limbo of partial acceptability, the manufacturers of products that contain papaveretum should voluntarily withdraw them. J R SNEYD
Department of Anaesthesia, Manchester Royal Infirmary, Manchester M 13 9WL I Committee on Safety of Medicines. Genotoxicity of papaveretum and noscapine. Current Problems 1991 June;No 30. 2 Allen S, Marshall Barr A, Bird J, Brock PJ, Ewart MC, Hall R, et al. Papaveretum in women of childbearing potential. BMJ
1991;303:647. (14 September.) 3 Warwick JP, Spittal MJ, Hunter SJ. Papaveretum in women of childbearing potential. BMJ 1991;303:647-8. (14 September.)
From audit to quality and beyond SIR,-You do not need to be either a cynic with regard to audit or someone who dodges audit to be slightly sceptical about Drs Fiona Moss and Richard Smith's editorial on medical audit': it is an excellent example of whistling to keep your spirits up and, like most such pieces, is shot through with unsupported claims and assertions. Audit, we are told, "can be done without the large samples often needed for research and without large computerised databases." Yes, of course it can, in certain strictly limited circumstances: I submit that the confidential inquiry into perioperative deaths and similar local or regional exercises have been doing this for several years. It is not helpful, however, for the authors to castigate doctors who undertake feeble exercises such as case note review, clinical presentations, or meetings on deaths and discharges because for many clinicians this is all that they can do. The fact remains that, in vast areas of medical practice, including most of general internal medicine, we have no means of measuring outcome. To test adherence to guidelines on treatment, such as the recently published recommendations on asthma, or to measure surrogate indicators of
outcome, such as glycated haemoglobin or cholesterol concentration in people with diabetes, is no doubt a valuable exercise, but it still leaves enormous areas of practice uncovered. To answer even very simple questions such as "How effective is rehabilitation physiotherapy after stroke in our hospital?" or "Should all patients admitted to a medical ward have a routine chest x ray examination?" requires an enormous commitment in terms of staff, time, and technology; complex questions about the effectiveness of what we do in terms of relieving symptoms, quality of life, or independence are much more daunting. Enthusiasts for medical audit should understand that audit will win few friends if it seeks simply to answer mundane questions about the process of delivery of care and ignores the much more crucial questions about outcome. ROGER A FISKEN
Friarage Hospital, Northallerton, North Yorkshire DL6 IJG 1 Moss F, Smith R. From audit to quality and beyond. BMJ 1991;303:199-200. (27 Jluy.)
SIR,-The editorial by Drs Fiona Moss and Richard Smith entitled "From audit to quality and beyond" was revealing in ways not intended by the authors. ' While making the point that mere clinical observation could not be relied on to guarantee standards and determine policy the authors remarked that audit could be usefully carried out without "the large samples often needed for research and without large computerised databases." In other words, audit equals bad research. Large enough sample sizes to test a hypothesis, as well as objective ratings, unbiased measures, a prospective design, and long enough follow up, are not mere academic niceties. They are basic necessities if important questions related to service are to be answered satisfactorily. Why should an audit of treatment X be any more persuasive than a doctor's impressions if the evaluation would not have met the standards of, say, the BM3r? Is the new journal Quality in Health Care going to accept papers of "audit quality" or will it insist on "research quality" articles? It is unfortunate that the audit buzzword is attracting resources from departments of health all over the country. A few figures about rising attendance at a clinic plus a consumer satisfaction questionnaire can, under the guise of audit, be used to justify increased resources. Unfortunately, a proper unbiased, well designed, and reproducible evaluation of the service is apt to be given a high rating by a grant giving body and an apologetic letter saying that funds are not available. This issue is particularly relevant to the study of chronic illness, including psychiatric disorders. Determining factors relating to outcome is complicated by heterogeneity and sensitivity to social circumstances. To do this large samples, computerised databases, and probably full time researchers are needed. Turning busy clinicians into reluctant and haphazard researchers will do nothing to improve their patients' care and could be positively misleading. A S DAVID
Department of Psychological Medicine, King's College Hospital, London SE5 9RS 1 Moss F, Smith R. From audit to quality and beyond. BMJ 1991;303:199-200. (27 July.)
AUTHOR'S REPLY,-Dr David and Dr Fisken raise some important questions about the relation between medical audit and research which touch on the discussion about uncertainty in medical practice. The outcome of many clinical interventions is not well understood, and so much of clinical practice is unduly influenced by clinicians'
BMJ
VOLUME
303
5
OCTOBER
1991
STEPHEN HOLT Division of Digestive Diseases and Nutrition, University of South Carolina School of Medicine, South Carolina 29203, United States I Langman MJS. Omeprazole. BM7 1991;303:481-2. (31 August.) 2 Jones DB, Howden CW, Burget DW, Kerr GD, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987;28:1120-7. 3 Howden CW, Hunt RH. The relationship between suppression of acidity and gastric ulcer healing rates. Alimentary Pharmacology and Therapeutics 1990;4:25-33. 4 Holt S, Howden CW. Omeprazole: overview and opinion. DigDis Sci 1991;36:385-93. 5 Bate CM, Keeling PWN, O'Morain CA, Wilkinson SP, Mountford RA, Temperley JM, et al. A comparison of omeprazole and cimetidine in reflux oesophagitis. Symptomatic, endoscopic and histological evaluations. Gut 1989;30:A1493-4.
[Abstract.] 6 Burlinson B, Morriss SH, Gatehouse DG, Tweats DJ. Genotoxicity studies with gastric acid inhibiting drugs. Lancet 1990;335:419. 7 Scott D, Reuben RA, Zampighi G, Sachs G. Cell isolation and genotoxicity assessment in gastric mucosa. Dig Dis Sci 1990;35:1217-25. 8 Wright NA. DNA synthesis and genotoxicity. Digestion 1990;47 (suppl 1):24-30. 9 Holt S, Zhu Z-H, Powers RE. Observations on a proposed measure of genotoxicity in rat gastric mucosa. Gastroenterology 1991;1O1:650-6. 10 Burlinson B, Morriss S, Gatehouse DG, Tweats DJ, Jackson MR. Uptake of tritiated thymidine by cells of the rat gastric mucosa after exposure to loxtidine or omeprazole. Mutagenesis 1991;61:11-8. 11 Holt S, Powers RE, Howden CW. Antisecretory therapy and genotoxicity. DigDis Sci 1991;36:545-7.
SIR,-Professor M J S Langman's editorial is subtitled "For recurrent peptic ulcers and severe oesophageal reflux disease."' It is clear to me as a general practitioner that, as with other innovative drugs, omeprazole is prescribed overzealously and often irrationally. Although my experience is obviously anecdotal I BMJ VOLUME 303
5 OCTOBER 1991
suspect it may be representative. Two patients with dyspeptic symptoms who I referred to (different) gastroenterologists returned after endoscopy bearing requests for me to prescribe omeprazole. The first time I obliged; the second time I substituted an H2 antagonist. The symptoms of both patients were subsequently relieved completely with H2 antagonists. Letters to both consultants elicited replies to the effect that H2 antagonists would have been appropriate first line treatment in these two patients, who both had previously untreated reflux oesophagitis. A parallel situation occurs with hypercholesterolaemia, for which-on the basis of a single measurement-patients are all too often prescribed lipid lowering agents rather than being given dietary advice followed if appropriate by a rational prescription of a lipid lowering agent. By rational I mean necessary, effective, economical, and of proved safety. Doctors in general should avoid the temptations and pressures to prescribe the most powerful available agent and be content with one that is simply "good enough." If we fail to do this we face the risk of protocols for prescribing being imposed from outside. R HARRINGTON
Thame, Oxfordshire OX9 3JZ I Langman MJS. Omeprazole. BM_ 1991;303:481-2. (31 August.)
SIR,-It is more than a trifle discomfiting to find that Professor M J S Langman has failed to grasp the basic issues in the debate about the putative genotoxicity of omeprazole.' Burlinson et al at Glaxo did not report "that pretreatment with omeprazole initiated proliferation in the superficial zone" (for example, the rat stomach).2 They claimed that omeprazole induced unscheduled DNA synthesis in non-proliferating superficial cells, presumably after damaging DNA-quite a different concept. It is also unfortunate that Professor Langman did not indicate that things have moved on since the initial claim by Glaxo. Holt et al have shown definitively that the Burlinson method is badly flawed in that there is serious contamination of the so called "non-proliferating" surface cells with proliferating cells undergoing semiconservative DNA synthesis.' Appropriate controls showed no evidence of unscheduled DNA synthesis. Possibly more importantly, Burlinson et al have published what amounts to a retraction of their method as a genotoxic assay: they show, instead, that the method detects ordinary semiconservative DNA synthesis and that omeprazole stimulates this.4 Interestingly, Fraser et al find this effect confined to the original Glaxo rat strain, the PFK rat.5 It thus seems that omeprazole may stimulate cell proliferation in the stomach of at least one rat strain, possibly through stimulating release of gastrin. This is a totally different proposal: it is not indicative of genotoxicity and is a property shared with other antiulcer drugs, as we have shown for
misoprostol.' Incidentally, we ourselves have found that the Burlinson method is inappropriate for measuring unscheduled DNA synthesis, although these experiments have not yet been published.7 It is thus fairly clear that Glaxo's claim, based on the data of Burlinson et al, does not hold water. There has, however, been a claim, from other workers, that omeprazole induced unscheduled DNA synthesis in a rat stomach in vitro assay (C Furihata and T Matsushima, meeting of the European Mutagenesis Society, 1990 (abstract P213)) unfortunately, it proved impossible to suppress semiconservative DNA synthesis totally in this assay, and the marginal rise in tritiated thymidine incorporation can readily be explained by an induction of normal cell proliferation, which would not be detected in the unsuppressed experiments because of the large confidence intervals.
So what can be concluded from this curious affair? That overinterpretation of inappropriately planned experiments occurred is beyond doubt; it is also clear that partial suppression of experimental data was evident in the initial report.2 We shall probably never know the reasons behind such preemptive publication. But the problem of quality control of questionable data and its implications for the standards of certain pharmaceutical companies' in house research does obtrude. R GOODLAD N A WRIGHT
Department of Histopathology, Royal Postgraduate Medical School, London W12 ONN I Langman MJS. Omeprazole. BM 1991;303:481-2. (31 August.) 2 Burlinson B, Morris SH, Gatehouse DG, Tweats DJ. Genotoxicity studies of gastric acid inhibiting drugs. Lancet
1990;335:419. 3 Holt S, Zhao-Hua Z, Powers RE. Observations on a proposed measure of genotoxicity in rat gastric mucosa. Gastroenterology
1991;101:650-6. 4 Burlinson B, Morriss SH, Gatehouse DG, Tweats DJ, Jackson MR. Uptake of tritiated thymidine by cells of the rat gastric mucosa, after exposure to loxtidine or omeprazole.
Mutagenesis 1991;6:11-8. 5 Fraser AG, Debram GS, Dhillon AP, Pounder RE. Variation in rat strain affects gastric mucosal proliferative response to
antisecretory drugs. Gastroenterology 1991;100:A66. 6 Goodlad RA, Madgwick AJ, Moffatt MR, Levin S, Allen JL, Wright NA. Effects of insoprostol on cell migration and transit in the dog. Gastroenterology 1990;98:90-5. 7 Goodlad RA, Lee C, Sarraf CE, Alison MR, Wright NA. Genotoxicity, omeprazole, unscheduled DNA synthesis. Gut (in press).
Confidentiality taken to the extreme SIR,-I wish to express my concern at a hitherto unforeseen consequence of the recently introduced regulations arising out of the Human Fertilisation and Embryology Act 1991. I recently received what amounts to a letter before action from a patient concerning treatment that I had provided. Being aware of the constraints that the act places on me with regard to confidentiality,' 2I sought advice from the Human Fertilisation and Embryology Authority on whether I was permitted to seek advice from the Medical Defence Union. The authority informed me that the act absolutely prevented me from doing so. General discussions with lawyers subsequently have confirmed this prohibition. I am advised that I am unable to seek any legal help other than on the basis of anonymised fact, nor will I be able to defend myself in a court of law if I am sued for any reason if it involves treatment of infertile patients. This applies even if the treatment was provided before the act came into force. The same would apply if I was to be brought before a disciplinary committee of the General Medical Council. As a consequence of this, legal advisers have informed me that they believe that all clinics and practitioners who continue to provide fertility treatment in licensed centres are placing themselves in a similar position until such time as the Department of Health has resolved this problem. In the light of this, we would seem to be unable to continue our work. The Human Fertilisation and Embryology Authority is fully aware of the consequences of this anomaly but is at present unable to advise me of any way in which I could defend myself in this or any other case that might be brought against me or any colleague in a similar position in the future. My legal adviser is aware of no other person in the United Kingdom who is in the potential position of having an action brought against him but who is absolutely prevented from defending himself in a court of law. I consider it my duty to my colleagues who also provide licensed infertility treatment to point out to them this anomaly of the Human Fertilisation and Embryology Act so that they may also be aware of their vulnerability. I cannot believe that when 851
parliament passed this act it intended removing the inalienable right of a person to defend himself in a court of law. Needless to say, the act must be amended soon in order to allow doctors to protect themselves. PETER R BRINSDEN
Yelling, Cambridge PE19 4SD 1 Brinsden P. A tax on infertility? BMJ 1991;303:309. (3 August.) 2 Campbell C. A tax on infertility? BMJ 1991;303:714. (21
September.)
SIR,-Professor Colin Campbell's response' to Mr Peter Brinsden's previously expressed concerns2 are helpful. To most infertile couples and to many medical practitioners, however, the new controls on fertility practice seem quite absurd. Of course the Human Fertilisation and Embryology Authority has to work with an imperfect act as best it can, but why is the act so imperfect? The public will wonder how it is possible for an act to reach the statute book when it has the following results. Firstly, it prevents fertility specialists from communicating with referring doctors and other colleagues as this is positively dangerous and quite contrary to the clear recommendations of the General Medicasl Council. It seems that there has been a gross error in the parliamentary draughtsmanship which was originally intended to protect the confidentiality of patients who have donated gametes but which has been applied to all patients receiving fertility treatment. It would be helpful if this was acknowledged to be the case so that amendments may be made, allowing normal doctor to doctor communications to be restored. The Human Fertilisation and Embryology Authority acknowledges that the act requires a change in communication practice, but the suggestions made in its code of practice provide only an imperfect, circuitous, and inefficient system. What is required is for the relevant clauses of the act to be amended. Secondly, it results in infertile patients having to pay, albeit indirectly, to a centre's costs in order to have a child because of the means of raising revenue for the Human Fertilisation and Embryology Authority's administration, when it financially costs nothing to have an abortion. Surely it would have been fairer to have funded the authority's expenses totally from central sources. Mr Brinsden may rightly complain that his centre's annual levy of £40 000 will have to be passed on to patients, but at least the Bourn Hallam Clinics have the financial backing of Aeres Serono, a multinational pharmaceutical company. What cushion is there for NHS units or totally independent centres such as ours? Thirdly, it prevents the further use of stored donor sperm for couples who have previously had one child from a given donor because that donor then refuses to have his name and date of birth held by the authority, which was previously not required. It is all very well now to consider that there might be a transitional period of six months for the use of undesignated sperm, but why was this not considered long ago, and why should other patients be denied this option after this suggested cut off time if they have already reserved the same donor for a second pregnancy? Professor Campbell, speaking at a meeting earlier this year, emphasised that he did not wish to see the Human Fertilisation and Embryology Authority become a bureaucratic organisation, and yet these and other issues clearly indicate this risk. We should reflect why we are in such a state seven years after parliament received the Warnock report. IAN CRAFT
London Fertility Centre and Medicraft Services, London WIN 1AF 1 Campbell C. A tax on infertility? BMJ 1991;303:713-4. (21
September.) 2 Brinsden PB. A tax on infertility? BMJ 1991;303:309. (3 August.)
852
Papaveretum in women of childbearing potential SIR,-The recent recommendation by the Committee on Safety of Medicines that products containing papaveretum should be avoided in women of childbearing potential' has provoked a defensive reaction from some anaesthetists2 and variable responses from others.3 The manufacturers have not yet written to doctors. Papaveretum is a mixture of opiate alkaloids whose components have been determined by history rather than good science. Most users of papaveretum are unaware of what they are actually prescribing, and the kinetics and metabolism of some of Ihe constituents are poorly described in normal subjects and unknown in the critically ill. Outside the United Kingdom and a handful of other countries morphine is the injectable opiate of choice. I am not aware of any convincing evidence that papaveretum provides superior analgesia to morphine. Like the anaesthetists of Reading,2 until recently I regularly used papaveretum (because it is slightly cheaper than morphine); our division of anaesthesia decided, however, that to use papaveretum for some patients and morphine for others would be a recipe for chaos, and we therefore decided not to use papaveretum in the department. The transition to morphine has been smooth and largely without problems. Papaveretum is now obsolete and of questionable safety and would not receive a licence if it was a new medicine. Morphine is a safe and equivalent alternative. If we allow papaveretum to be used for some patients and not for others we run the risk of confusing our nurses and house officers. It is only a matter of time before someone (probably a child) receives an overdose. Rather than persist in this limbo of partial acceptability, the manufacturers of products that contain papaveretum should voluntarily withdraw them. J R SNEYD
Department of Anaesthesia, Manchester Royal Infirmary, Manchester M 13 9WL I Committee on Safety of Medicines. Genotoxicity of papaveretum and noscapine. Current Problems 1991 June;No 30. 2 Allen S, Marshall Barr A, Bird J, Brock PJ, Ewart MC, Hall R, et al. Papaveretum in women of childbearing potential. BMJ
1991;303:647. (14 September.) 3 Warwick JP, Spittal MJ, Hunter SJ. Papaveretum in women of childbearing potential. BMJ 1991;303:647-8. (14 September.)
From audit to quality and beyond SIR,-You do not need to be either a cynic with regard to audit or someone who dodges audit to be slightly sceptical about Drs Fiona Moss and Richard Smith's editorial on medical audit': it is an excellent example of whistling to keep your spirits up and, like most such pieces, is shot through with unsupported claims and assertions. Audit, we are told, "can be done without the large samples often needed for research and without large computerised databases." Yes, of course it can, in certain strictly limited circumstances: I submit that the confidential inquiry into perioperative deaths and similar local or regional exercises have been doing this for several years. It is not helpful, however, for the authors to castigate doctors who undertake feeble exercises such as case note review, clinical presentations, or meetings on deaths and discharges because for many clinicians this is all that they can do. The fact remains that, in vast areas of medical practice, including most of general internal medicine, we have no means of measuring outcome. To test adherence to guidelines on treatment, such as the recently published recommendations on asthma, or to measure surrogate indicators of
outcome, such as glycated haemoglobin or cholesterol concentration in people with diabetes, is no doubt a valuable exercise, but it still leaves enormous areas of practice uncovered. To answer even very simple questions such as "How effective is rehabilitation physiotherapy after stroke in our hospital?" or "Should all patients admitted to a medical ward have a routine chest x ray examination?" requires an enormous commitment in terms of staff, time, and technology; complex questions about the effectiveness of what we do in terms of relieving symptoms, quality of life, or independence are much more daunting. Enthusiasts for medical audit should understand that audit will win few friends if it seeks simply to answer mundane questions about the process of delivery of care and ignores the much more crucial questions about outcome. ROGER A FISKEN
Friarage Hospital, Northallerton, North Yorkshire DL6 IJG 1 Moss F, Smith R. From audit to quality and beyond. BMJ 1991;303:199-200. (27 Jluy.)
SIR,-The editorial by Drs Fiona Moss and Richard Smith entitled "From audit to quality and beyond" was revealing in ways not intended by the authors. ' While making the point that mere clinical observation could not be relied on to guarantee standards and determine policy the authors remarked that audit could be usefully carried out without "the large samples often needed for research and without large computerised databases." In other words, audit equals bad research. Large enough sample sizes to test a hypothesis, as well as objective ratings, unbiased measures, a prospective design, and long enough follow up, are not mere academic niceties. They are basic necessities if important questions related to service are to be answered satisfactorily. Why should an audit of treatment X be any more persuasive than a doctor's impressions if the evaluation would not have met the standards of, say, the BM3r? Is the new journal Quality in Health Care going to accept papers of "audit quality" or will it insist on "research quality" articles? It is unfortunate that the audit buzzword is attracting resources from departments of health all over the country. A few figures about rising attendance at a clinic plus a consumer satisfaction questionnaire can, under the guise of audit, be used to justify increased resources. Unfortunately, a proper unbiased, well designed, and reproducible evaluation of the service is apt to be given a high rating by a grant giving body and an apologetic letter saying that funds are not available. This issue is particularly relevant to the study of chronic illness, including psychiatric disorders. Determining factors relating to outcome is complicated by heterogeneity and sensitivity to social circumstances. To do this large samples, computerised databases, and probably full time researchers are needed. Turning busy clinicians into reluctant and haphazard researchers will do nothing to improve their patients' care and could be positively misleading. A S DAVID
Department of Psychological Medicine, King's College Hospital, London SE5 9RS 1 Moss F, Smith R. From audit to quality and beyond. BMJ 1991;303:199-200. (27 July.)
AUTHOR'S REPLY,-Dr David and Dr Fisken raise some important questions about the relation between medical audit and research which touch on the discussion about uncertainty in medical practice. The outcome of many clinical interventions is not well understood, and so much of clinical practice is unduly influenced by clinicians'
BMJ
VOLUME
303
5
OCTOBER
1991
