Interferon beta in multiple sclerosis

Letters Replacement therapy should be offered to adults with severe growth hormone deficiency Editor—In 1996 adult growth hormone deficiency became a licensed indication for growth hormone replacement therapy. Under most circumstances it is not difficult to identify patients likely to have severe growth hormone deficiency. We screen this cohort and assess their need for replacement therapy. Because of current health economic policies we are unable to provide a supply of growth hormone from the hospital and therefore ask the patient’s general practitioner to do this. We provide a shared care protocol and justification for the therapeutic decision and emphasise that we are happy to supervise the patient’s management while he or she is taking growth hormone replacement. Currently only a fifth to a quarter of our requests for a prescription for growth hormone are met. Some of the general practitioners do not reply or refuse a prescription on medicolegal grounds. In addition, many general practitioners refer the request to their local health adviser, who often misquotes or is ill informed about the Advice to authors We receive more letters than we can publish: we can currently accept only about one third. We prefer short letters that relate to articles published within the past four weeks. We also publish some “out of the blue” letters, which usually relate to matters of public policy. When deciding which letters to publish we favour originality, assertions supported by data or by citation, and a clear prose style. Letters should have fewer than 400 words (please give a word count) and no more than five references (including one to the BMJ article to which they relate); references should be in the Vancouver style. We welcome pictures. Letters should be typed and signed by each author, and each author’s current appointment and address should be stated. We encourage you to declare any conflict of interest. Please enclose a stamped addressed envelope if you would like to know whether your letter has been accepted or rejected. We may post some letters submitted to us on the worldwide web before we decide on publication in the paper version. We will assume that correspondents consent to this unless they specifically say no. Letters will be edited and may be shortened. 600 evidence on the benefits and side effects of growth hormone replacement therapy. Some of these advisers quote an efficacy review, available on the Internet, that is inaccurate, having been prepared 18 months ago, before growth hormone was licensed for adult use and before many data on efficacy were available. Last August I wrote an editorial on this topic for the BMJ.1 My aim was to present a balanced case to cover the available evidence. I tried to develop a therapeutic strategy that would apply to the patients who are most in need. At the same time I was keen to avoid financial waste, being aware that, by endocrine standards, growth hormone is expensive. In the editorial I concluded that a substantial proportion of patients with severe growth hormone deficiency benefit from growth hormone replacement therapy. Thus it is with great regret that I have learnt that a number of health authorities have misconstrued the tenor of my editorial and are using it as an argument against prescribing adult growth hormone replacement. To avoid any misunderstanding I wish to make my position clear: in my view a trial of growth hormone replacement therapy should be offered to patients with severe growth hormone deficiency and considerably impaired quality of life or severe osteopenia; such therapy should be continued in those patients in whom the trial shows benefit. Stephen Shalet Professor Department of Endocrinology, Christie Hospital, Manchester M20 4BX 1 Shalet SM. Growth hormone deficiency and replacement in adults. BMJ 1996;313:314. (10 August.) Interferon beta in multiple sclerosis Reducing frequency and severity of relapses will be of great clinical benefit Editor—Richard G Richards’s editorial on interferon beta in multiple sclerosis deals with the “clinical cost effectiveness” of the drug in the disease, but it lacks a fair balance, emphasising the cost effectiveness and minimising the clinical effectiveness of the drug.1 Richards states that “the studies showed no evidence of any reduction in the more clinically relevant endpoint—the progression of disability, which should be the goal of treatment.” This is his personal judgment and does not reflect the needs and wishes of patients with multiple sclerosis and their families. Multiple sclerosis is a distressing, humiliating, and often long drawn out disease with no cure. For this reason, quality of life, for the patients and their families, is paramount. A drug that can reduce the frequency and severity of relapses, whether or not it diminishes the progression of the disease, will be of great clinical benefit to many patients, improving their situation physically, psychologically, and socially. Surely happiness, feeling better, and increased health have great value. This is what many of us believe that the practice of our profession is about. Alexander Burnfield President, Andover and Winchester branches of the MS Society Terstan Longstock, Stockbridge SO20 6DW 1 Richards RG. Interferon beta in multiple sclerosis. BMJ 1996;313:1159. (9 November.) Current policy is sensible Editor—The NHS Executive’s position on interferon beta allows individual hospital doctors, working within certain parameters, to decide with a patient with multiple sclerosis whether to start treatment with the drug. This sensible standpoint comes in for varying degrees of criticism in three recent articles, mainly on the grounds of health economics.1-3 The authors are all proponents of evidence based policymaking but are happy to assert that an effect on disability is the most important outcome measure in this disease without producing any evidence to support their view. Many people with multiple sclerosis would consider a reduction in the number of relapses to be valuable. We do not withhold treatments that give important symptomatic relief in other conditions, such as cancer, on the grounds that they will not produce long term benefit or cure. In any case, it is not true to say that interferon beta-1b has no demonstrable effect on disability. In one trial, at three years disability (as assessed by the expanded disability scale scoring system) had worsened less in aggregate in the cohort treated with high dose interferon beta than in the cohort treated with placebo.4 The difference was significant. A favourable effect of interferon beta-1b on disability has been shown, albeit less convincingly than might have been wished. Interferon beta-1a delays progression of disability5—though not to Richard G Richards’s satisfaction.2 BMJ VOLUME 314 22 FEBRUARY 1997 Letters Ferner demands that before a drug is available for prescription in the NHS it should be shown to be at least as effective as standard treatment. As no other drug has been shown to reduce the number of relapses in multiple sclerosis I suggest that interferon beta meets this criterion. In Norfolk we have found the maligned pressure groups to be well informed and capable of weighing the evidence for themselves. Many people who might be eligible for treatment have not sought to obtain the drug because of gaps in our knowledge about long term risks and benefits. Fears that resources would be “sucked from elsewhere” have proved unfounded. I believe that current national policy is well balanced and sensible. The dismal discipline of health economics has been put firmly in its place. Such an approach can only ever be an aid to decision making; real life is much more complex and rewarding. C Price Director of primary care Norfolk Health, Thorpe St Andrew, Norwich NR7 0HT 1 2 3 4 5 Ferner RE. Newly licensed drugs. BMJ 1996;313:1157-8. (9 November.) Richards RG. Interferon beta in multiple sclerosis. BMJ 1996;313:1159. (9 November.) Rous E, Coppel A, Haworth J, Noyce S. A purchaser experience of managing new expensive drugs: interferon beta. BMJ 1996;313:1195-6. (9 November.) Paty DW, Li DKB, the UBC MS/MRI Study Group and the Interferon Beta Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI results of a multi-centred, double-blind, placebo-controlled trial. Neurology 1993; 43:662-7. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM. Intramuscular interferon beta-1 a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285-94. undertaking comprehensive postmarketing surveillance in the form of a safety assessment approved by the Medicines Control Agency. We are also funding an extensive programme of clinical studies of interferon beta-1b in different types of multiple sclerosis. Proposals for a national trial of interferon beta in multiple sclerosis, led by the Department of Health’s technology assessment programme, have been postponed indefinitely owing to difficulties in selecting meaningful outcomes measures. The medical director of the NHS Executive subsequently wrote to all regional directors of public health to affirm that, because the national trial had been postponed, “there is no further reason to delay introducing local purchasing policies for beta interferon in line with [executive letter] EL(95)97 and the clinical advice from [the Department of Health’s Scientific Medical Advisory Committee] which accompanied the EL.” Finally, a further assertion made by the articles is that the NHS should not be obliged to pay for new drugs unless they are at least as good as older ones. Interferon beta-1b is the only drug currently licensed for relapsing-remitting multiple sclerosis in Europe and represents the first hope in what was hitherto a therapeutic void. Comparison with other agents is therefore irrelevant. Editor—Two recent editorials and an article all discuss interferon beta.1-3 It is worrying that, in all the discussions about rationing, cost effectiveness, and so on, the benefits of the product to the patient are being overlooked. Interferon beta-1b was shown in the five year pivotal trial in relapsingremitting multiple sclerosis to reduce the rate of severe relapses by one half and the overall relapse rate by one third.4 Studies have highlighted the fact that relapses can have a profound effect on the quality of life of people with multiple sclerosis and their carers (data on file). Additionally, patients who received interferon beta-1b in the pivotal trial showed no increase in total lesion load on magnetic resonance imaging over five years, compared with an increase of about 30% in the placebo group.4 This finding also correlated significantly with progression of disability, adding to the growing body of data supporting such a link. While much emphasis is placed on the alleged lack of knowledge about the side effects of interferon beta-1b and the need for post-licensing monitoring of patients, none of the articles mention that there is now experience of use of interferon beta-1b of up to 10 years in some 50 000 patients world wide. In Britain Schering is also BMJ VOLUME 314 22 FEBRUARY 1997 Jeremy Holmes* Managing director Economists Advisory Group, London W2 1JA0-0 *Jeremy Holmes is an adviser to Schering Health Care, which manufactures interferon beta-1b. 1 Jacqueline C Napier Associate medical director Schering Health Care, Burgess Hill, West Sussex RH15 9NE 3 1 4 2 3 Interferon beta reduces overall relapse rate by one third In 1994 the Economists Advisory Group found that less than 13% of the total annual burden of multiple sclerosis was borne by the NHS. By contrast, nearly 24% of the burden was accounted for by state benefits, including those applying to the provision of social services.4 It is therefore a shame that proposals are being advanced for new drugs in multiple sclerosis (such as interferon beta-1b) to be evaluated simply in terms of the number of stays in hospital that are avoided. Only slightly less alarming is the comment by Richard G Richards that because interferon beta-1b only delays rather than prevents disability “it is unlikely that economic benefits will include avoiding the need for social care.”1 There are real economic benefits in delaying social care, just as there are in delaying hospital care. The first step in quantifying these benefits, however, is to recognise that they exist, and Richards has at least made that admission. The challenge now is for policymakers to take the blinkers off and do the same. 4 Ferner RE. Newly licensed drugs. BMJ 1996;313:1157-8. (9 November.) Richards RG. Interferon beta in multiple sclerosis. BMJ 1996;313:1159. (9 November.) Rous E, Coppel A, Haworth J, Noyce S. A purchaser experience of managing new expensive drugs: interferon beta. BMJ 1996;313:1195-6. (9 November.) IFNB Multiple Sclerosis Study Group. Interferon beta 1b in the treatment of multiple sclerosis: final outcome of the randomised controlled trial. Neurology 1995;45:1277-85. Avoidance of the need for social care should also be taken into account Editor—Recently, two editorials and an article referred to the need to evaluate the cost effectiveness of new drugs.1-3 Disappointingly, despite the advent of total purchasing and disease management, many commentators persist with a blinkered view of resource allocation. The phenomenon of cost shifting in the health service is well recognised and has been likened to a balloon: when you squeeze one part of it another part expands. But the corollary is also true: when you spend money in one area it is responsible to see if this can be justified by savings elsewhere as well as in the area concerned. This logic must now be applied to the social services. Already it is often hard to see the join between these services (provided by local authorities) and those provided under the NHS. For example, in the care of elderly or disabled people where does the role of a home carer stop and that of a care assistant start? In specific chronic diseases such as multiple sclerosis it is even more important to take a holistic view of care because so much of it is provided in the home. 2 Richards R. Interferon beta in multiple sclerosis. BMJ 1996;313:1159. (9 November.) Ferner RE. Newly licensed drugs. BMJ 1996;313:1157-8. (9 November.) Rous E, Coppel A, Haworth J, Noyce S. A purchaser experience of managing new expensive drugs: interferon beta. BMJ 1996;313:1195-6. (9 November.) Holmes J, Madgwick T, Bates D. The cost of multiple sclerosis. Br J Med Econ 1995;8:181-93. NHS Executive issued advice to help NHS plan for introduction of the treatment Editor—Richard G Richards’s editorial mentions guidance issued by the NHS Executive about the purchasing and prescribing of interferon beta for patients with multiple sclerosis.1 2 As signatory to executive letter EL(95)97 (entitled “New drugs for multiple sclerosis”), I thought it might be helpful to outline our aims and to try to correct any misunderstandings. The executive letter was written to support clinical advice about interferon beta-1b issued by the Standing Medical Advisory Committee; this advice had been developed in consultation with the Association of British Neurologists and other professional bodies and after discussions with the Multiple Sclerosis Society and NHS colleagues. The clinical advice drew on published data from clinical trials and aimed to give factual information about interferon beta-lb, including its therapeutic indications and contraindications. Although the NHS Executive had not previously developed guidance of this kind, both documents were issued—with the agreement of several key interests, including the relevant professions and representatives of NHS purchasers—to help the NHS in planning for and managing the introduction of the treatment. 601 Letters There is no instruction to prescribe this—or, indeed, any—treatment. Decisions about treatment in individual cases must always be a matter of clinical judgment. The executive letter and the clinical advice suggest that those decisions should be made only by specialist neurologists (that is, not by general practitioners) to help ensure appropriate targeting of the treatment and to ease monitoring and evaluation of its effectiveness. The executive letter asks purchasers to develop local arrangements for purchasing and prescribing along these lines. Graham Winyard Medical director NHS Executive, Department of Health, Leeds LS2 7UE 1 2 Richards RG. Interferon beta in multiple sclerosis. BMJ 1996;313:1159. (9 November.) Rous E, Coppel A, Haworth J, Noyce S. A purchaser experience of managing new expensive drugs: interferon beta. BMJ 1996;313:1195-6. (9 November.) to work with those managing this complex new situation. In spite of the attempt by the Departments of Health in Britain to ensure the orderly introduction of interferon beta, a year after its licensing there are great disparities in purchasing across Britain. With several other treatments approaching the point at which they will be licensed, we have renewed our request to the departments to do everything possible to restore order. patients’ perspective can no longer be ignored. Evaluation of new drugs in multiple sclerosis will certainly raise even more problems in the future, but the answer lies in the evolution of the use of surrogate markers such as results of magnetic resonance imaging, which correspond better to clinical disability. We have to accept some form of compromise in the degree of certainty of proof and reject the notion of perhaps scientifically more stable absolutes. Peter Cardy Chief executive MS Society, London SW6 1EE Jukka Peltola* Lecturer Tapani Keranen Lecturer Department of Neurology, Tampere University Hospital and University of Tampere, Medical School, PO Box 607, FIN-33101 Tampere, Finland 1 2 Richards RG. Interferon beta in multiple sclerosis. BMJ 1996;313:1159. (9 November.) Rous E, Coppel A, Haworth J, Noyce S. A purchaser experience of managing new expensive drugs: interferon beta. BMJ 1996;313:1195-6. (9 November.) Relapses deserve treatment Some form of compromise must be accepted Editor—Richard G Richards has computed the average reduction in hospital admissions through the use of interferon beta and postulates that “a theoretical relapse free patient would cost up to £1m.”1 This does not bear any relation to reality. The recognised costs of severe and frequent attacks of multiple sclerosis are not simply those of hospital admission but also those to the patient and society through the destruction of family life, employment, and social networks. Similarly, it is an abstraction to suggest that a reduction in the progression of disability is more relevant than a reduction in attacks. Doctors might with advantage put this to patients such as one who describes her relapses to me as “a living hell of pain and confusion”; to one whose mobility was so severely affected during a recent attack that a fall resulted in admission to hospital; or to another whose attacks have now left him jobless. None has received interferon beta, though all are eligible for it. Where is compassion and humanity in this calculation? Relapses deserve treatment, and it is sad to see so much ingenuity spent on maintaining the tradition that multiple sclerosis is untreatable. Richards asks whether the money should instead be spent on other services for patients with multiple sclerosis. Ironically, the handful of multidisciplinary services established for patients with the disease since the licensing of interferon beta have all appeared where the drug is being purchased. The MS Society has worked hard to ensure access to authoritative information and to reduce expectations. As a result, patients in Britain have not made a stampede for interferon beta. We long ago invited purchasers to consult us; we still await Richards’s response. Richards caricatures the MS Society as “an active patient interest lobby” dictating national policy. This theme is repeated in the disparaging cartoon accompanying the paper by E Rous and colleagues, which depicts the society as a pressure group by showing us with a wheelchair.2 This is a travesty of the responsible way in which the MS Society has sought Editor—Richard G Richards presents a critical analysis of clinical trials of interferon beta in multiple sclerosis, focusing on the lack of evidence on the progression of disability.1 This is a fundamental question, but Richards fails fully to grasp the inherent complexities. The trial of interferon beta-lb was constructed to show an effect on the relapse rate; the failure to show an effect on the progression of the disease is thus not surprising.2 When discussing the trial of interferon beta-la,3 which showed an effect on disability when the same expanded disability status scale was used, Richards is not happy to apply the same criteria of judgment and proceeds to attack the scale for “questionable claims” without making any clear reference to the trial of interferon beta-la. Of course the progression of disability is the primary point of interest, but to show it in a clinically unambiguous way is difficult. The external advisory committee for the trial of interferon beta-lb recommended after a two year interim analysis that patients taking placebo and 1.6 MIU should be offered the option of changing to an 8 MIU dose “in an orderly and expeditious manner.”2 The inherent problem is how to justify keeping the patients in a trial once a significant effect has been shown, even though the results do not give answers in a clinically definitive way. This question is more pronounced in the case of a usually progressive disease for which no treatment exists. The use of surrogate markers to replace clinical end points is problematic, but in areas where pressure for new treatments is great surrogate markers have been used—for example, the lowering of CD4 counts in drug trials in AIDS has been accepted as a measure of efficacy.4 Likewise, the data from magnetic resonance imaging in the trial of interferon beta-lb were pivotal in the deliberations of the Food and Drug Administration that led to the drug’s approval in multiple sclerosis.5 Richards is concerned at the influence of an active patient interest lobby, but clinical trials are not carried out in a social vacuum and the 602 *Jukka Peltola is an investigator in a phase III study of recombinant human interferon beta in secondary progressive multiple sclerosis sponsored by Serono. 1 2 3 4 5 Richards RG. Interferon beta in multiple sclerosis. BMJ 1996;313:1159. (9 November.) IFNB Multiple Sclerosis Study Group. Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomised, doubleblind, placebo-controlled trial. Neurology 1993;43:655-61. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM. Intramuscular interferon beta-la for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285-94. Nowak R. Problems in clinical trials go far beyond misconduct. Science 1994;264:1538-41. Goodkin DE. Interferon beta-lb. Lancet 1994;344:105760. New antiepileptic drugs The drugs are not all the same Editor—A G Marson and colleagues’ systematic review of new antiepileptic drugs is unhelpful for two reasons.1 “Regulatory” placebo controlled trials are not suitable evidence for a comparison of new antiepileptic drugs, and, perhaps more importantly, the authors give the erroneous impression that all new antiepileptic drugs are interchangeable. It is hardly surprising that the main positive conclusion of this review is that each of the new antiepileptic drugs has proved more effective than placebo, because most of the studies were designed to show just that.2 In addition, the trials looked at different subsets of patients who had previously been exposed to different antiepileptic drugs; the patients were receiving different relative doses of different (and sometimes interacting) antiepileptic drugs, and often the titration schedules that were used were different from those that were later recommended. For each compound the trials showed superiority over placebo with acceptable tolerability, and the outcome of this exercise was that a product licence was granted for each compound. Comparison among antiepileptic drugs across such a wide range of varied studies is not a proper basis for an evidence based approach to the management of refractory partial epilepsy. A second point is that this is not a horse race, which implies a fair contest among members of the same species. These new BMJ VOLUME 314 22 FEBRUARY 1997 Martin J Brodie Director Epilepsy Unit, Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT 1 2 3 4 Marson AG, Kadir AZ, Chadwick DW. New antiepileptic drugs: a systematic review of their efficacy and tolerability. BMJ 1996;313:1169-74. (9 November.) Brodie MJ. Antiepileptic drugs, clinical trials and the market-place. Lancet 1996;347:777-9. Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med 1996;334:1583-90. Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med 1996;334:168-75. Analysis based on number needed to treat shows differences between drugs studied Editor—A G Marson and colleagues report their systematic review of the efficacy and tolerability of new antiepileptic drugs.1 We wondered, however, what the results would have been if the authors had calculated the number needed to treat instead of odds ratios. The proportion of patients who responded in the placebo arms of the studies ranged from 0% to 19%, whereas the proportion who responded in the active treatment arms ranged from 6% to 54%. Because the proportion who responded in the two arms of each study varied considerably, the absolute benefit of treatment also varied considerably. The number needed to treat takes into account the absolute benefit. Moreover, it is a more meaningful measure than the odds ratio because it addresses both statistical and clinical significance in a way that can easily be interpreted.2 We calculated the number needed to treat in order to get one responder—that is, a patient with a 50% reduction in the frequency of seizures as compared with the baseline (figure 1). The 95% confidence intervals were based on the total number of patients in a BMJ VOLUME 314 22 FEBRUARY 1997 21 18 15 12 9 6 3 at e Ga ba pe nt in Vi ga ba tri n Ti ag ab in e Zo ni sa m id e pi ra m To ot rig in e 0 La m antiepileptic drugs have different, sometimes overlapping, and often multiple mechanisms of action.3 They cannot, therefore, be compared across trials as if they were all angiotensin converting enzyme inhibitors or thrombolytic drugs. Each produced a 50% or greater reduction in partial seizures in under half of the patients studied (depending on the relative doses used in the trial programme), which supports the hypothesis that different pathophysiological changes underlie a range of seizure disorders that are lumped together under the all embracing label of refractory partial epilepsy. Even in patients whose seizures have similar symptomotology the clinical response to the same drug can be very different, which implies that the epilepsies may be even more heterogeneous than is suggested by the complicated classifications of seizures and syndromes published under the aegis of the International League against Epilepsy.4 The challenge for doctors who treat people with epilepsy is to identify the best drug for the individual patient and not to pick winners and losers in a bogus competition. Progress will require a considered, rational programme of clinical and basic research and not automatic homage to the god of meta-analysis. Mean No Letters Fig 1 Mean (95% confidence interval) number needed to treat to get one responder with each of six drugs particular treatment group. Pooled estimates, adjusted for differences in sample size between the studies included, showed figures of the same order of magnitude. The number needed to treat indicates differences in efficacy among the antiepileptics under study, and thus we do not agree with the authors’ conclusion that there is no evidence of such differences. In addition, we ask that the number needed to treat be used in studies of efficacy. A J A Elferink Clinical assessor B J Van Zwieten-Boot Clinical assessor Medicines Evaluation Board, PO Box 5811, 2280 HV Rijswijk, Netherlands 1 2 Marson AG, Kadir ZA, Chadwick DW. New antiepileptic drugs: a systematic review of their efficacy and tolerability. BMJ 1996;313:1169-74. (9 November.) Cook RJ, Sacked DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995;310:452-4. known risks associated with the older antiepileptic drugs has led some authorities to believe that the new drugs may be safer in pregnancy and may in fact be the drugs of choice then. The reality is that the information on which to draw definitive conclusions is not available. In conjunction with the British Neurological Surveillance Unit, we have established a central register to which all patients with epilepsy in the United Kingdom who have taken one of the new antiepileptic drugs while pregnant may be reported. We collect data on the women’s antenatal exposure to the new drug and on the outcome of the pregnancy. Since we set up the register in January 1996 about 10 cases a month have been identified; we estimate that this represents only a small proportion of all pregnancies occurring in women taking the new drugs. We recognise that as the newer antiepileptic drugs gain wider acceptance our current method of ascertaining cases may be insufficient. To maximise the identification of cases we therefore ask all doctors in the United Kingdom to report any such cases to the pregnancy register at the address below. We hope that the data collected through this register, in combination with those collected through all other methods, will eventually permit conclusions to be drawn about the relative safety of the newer antiepileptic drugs in pregnancy. John J Craig Specialist registrar in neurology James I Morrow Consultant neurologist Department of Neurology, Ward 21, Royal Victoria Hospital, Belfast BT12 6BA 1 2 Register of women who take the drugs during pregnancy has been set up Editor—R E Ferner rightly asserts that more careful postmarketing surveillance would make it easier to detect problem medicines.1 Rigorous postmarketing surveillance is especially important in certain groups of patients, such as those often excluded from clinical trials—for example, pregnant women. It is generally accepted that the incidence of congenital malformations in children born to women with epilepsy is two to three times that in children born to women who do not have epilepsy,2 3 this increase being partly a consequence of the recognised teratogenicity of the older antiepileptic drugs. When an antiepileptic drug is started in a woman of childbearing years teratogenicity is therefore an important issue. The potential teratogenicity of the newer antiepileptic drugs is unknown. This is partly due to the exclusion of pregnant or potentially pregnant women from such clinical trials as those systematically reviewed by A G Marson and colleagues.4 In animal toxicology studies an increase in certain malformations has occasionally been noted with some of the new antiepileptic drugs, but overall the results have been encouraging. This in combination with the 3 4 Ferner RE. Newly licensed drugs. BMJ 1996;313:1157-8. (9 November.) Boobis S. The teratogenicity of anti-epileptic drugs. Pharmacol Ther 1978;2:269-83. Kelly TD. Teratogenicity of anti-convulsant drugs.1. Review of the literature. Am J Med Genet 1984;19:413-34. Marson AG, Kadir ZA, Chadwick DW. New antiepileptic drugs: a systematic review of their efficacy and tolerability. BMJ 1996;313:1169-74. (9 November.) Study suggests that under a quarter of patients will still be taking the new drugs after six years Editor—Gilles Mignot rightly comments on the lack of long term studies of new antiepileptic drugs.1 It is difficult to conduct long term randomised clinical trials, and metaanalysis is unlikely to offer the answer. As a result, only systematic observational study with analysis may be able to provide us with the answer. Such a study has been conducted to investigate the time to withdrawal (a function of efficacy and adverse effects) and reasons for withdrawal of gabapentin, lamotrigine, and vigabatrin in five tertiary referral epilepsy clinics: the David Lewis Centre, Manchester Royal Infirmary, the Maudsley Hospital, the National Hospital for Neurology and Neurosurgery (Queen Square and Chalfont), and Walton Hospital. A total of 2701 patients had been identified to be exposed to at least one of the three drugs. Altogether 1326 patients were discarded because the new drugs were started outside the centres, and thus 1375 patients were 603 Estimated cumulative survival Letters Report of research assessment exercise should have focused on British medical schools 1.0 Lamotrigine Vigabatrin Gabapentin 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 5 6 Time (years) Fig 1 Estimated survival functions for time to withdrawal of new antiepileptic drugs in patients with partial epilepsy, by Cox regression, after adjustment for type of epilepsy, age at onset of seizure, previous exposure to other new antiepileptic drugs, and hospital included. Gabapentin was received by 361 patients, lamotrigine by 1050, and vigabatrin by 713. Three (0.8%) patients became seizure free while taking gabapentin, 31 (3.0%) while taking lamotrigine, and 24 (3.4%) while taking vigabatrin. The time to withdrawal from treatments was analysed by Cox regression (with spss for Windows V6). The age at onset of seizures, previous exposure to other new antiepileptic drugs (gabapentin, lamotrigine, or vigabatrin), and the hospital in which the patients were treated were found to be significantly co-related with the time to withdrawal of the new antiepileptic drugs (P < 0.05). Age, sex, and the presence or absence of learning disability and of a suspected aetiology of epilepsy were not significant (P > 0.05). Figure 1 shows the estimated survival functions of time to withdrawal of treatment. The results suggested that less than a quarter of patients with refractory partial epilepsy will still be taking the new antiepileptic drugs after six years. Furthermore, few patients will be seizure free. Sadly, I have to agree with M C Walker and colleagues that the task to improve the prognosis of severe refractory epilepsy has not been accomplished.2 Further studies must be conducted to establish the therapeutic value of these drugs in patients with less severe epilepsy. I thank Dr V Hillier of Manchester University for advice on Cox regression and the hospitals for allowing me to use their patients’ data. Ian C Wong* Research assistant David Lewis Centre,Warford, Near Alderley Edge, Cheshire SK9 7UD *Ian C Wong’s post is wholly funded by GlaxoWellcome, which manufactures lamotrigine. 1 2 Mignot G. Drug trials in epilepsy. BMJ 1996;313:1158. (9 November.) Walker MC, Li LM, Sander JWAS. Long term use of lamotrigine and vigabatrin in severe refractory epilepsy: audit of outcome. BMJ 1996;313:1184-5. (9 November.) 604 Editor—Jackie Cresswell’s news item about the research assessment exercise contains important factual errors.1 Firstly, grade 3a was not the lowest grade in unit of assessment 03 (hospital based clinical subjects, not “hospital based clinical studies”), and unit of assessment 01 is clinical laboratory sciences, not “clinical laboratory services.” Secondly, in the case of King’s College, London, in clinical laboratory sciences the work on immune regulation was flagged because it was judged to stand out because of its higher quality. Thirdly, this was the fourth assessment exercise, not the second as stated. Finally, to highlight the outcome for Bournemouth University, which entered 1.1 full time equivalent staff, seems extraordinary: this outcome is of no particular relevance to the performance of British medical schools, which would seem to be the legitimate interest of the BMJ’s readers. Readers would surely wish to have read a thoughtful analysis, addressing questions such as the research standing of our medical schools and whether the results of the research assessment exercise reflect the widespread concern that has been expressed by the British medical academic community in recent years. Keith Peters Chairman Council of Deans of UK Medical Schools and Faculties, PO Box 138, Leicester LE1 9HN 1 Cresswell J. League tables lead to funding loss. BMJ 1997;314:91. (11 January.) Newly licensed drugs pharmaceutical industry has thus had 15 years in which to undertake randomised trials for these drugs but has failed to do so. Given this, it is surprising that the British Hypertension Society has been unable to obtain support from the industry for a trial comparing the main therapeutic classes of antihypertensive drugs.2 Several new antihypertensive drugs are now being introduced: losartan (an angiotensin II receptor antagonist), nislodopine (a third generation calcium antagonist), and moxonidine (a selective imidazoline receptor antagonist) are three examples. These drugs are marketed for first line use in hypertension, although none has been shown to be effective in reducing morbidity or mortality in hypertension. We could easily enter into a spiral of new unproved drugs being introduced to succeed older “new” drugs (such as captopril and nifedipine) before the older drugs have been shown to be effective. The spiral could continue, with the pharmaceutical industry claiming insufficient time to prove effectiveness at each stage. Clearly, in selected patients the known benefits of treatment with one of the new drugs may outweigh the lack of evidence of effectiveness in hypertension. Angiotensin converting enzyme inhibitors in some diabetic patients are an example of this. A probationary period for new drugs would not delay the early introduction of such potentially beneficial drugs. It would, however, prevent patients being exposed to ineffective or even dangerous treatments for longer than necessary. Liam Smeeth Academic registrar Department of Primary Care and Population Sciences, Royal Free Hospital School of Medicine, University College London Medical School, London NW3 2PF 1 A probationary period is a good idea Editor—R E Ferner calls for newly licensed drugs to be on probation until they have been shown to be at least as effective as existing alternatives in randomised controlled trials.1 The clear need for such a probationary period is supported by examination of the drug treatment for adult essential hypertension. Observational data suggest an increased risk of myocardial infarction and death in hypertensive subjects treated with short acting dihydropyridine calcium antagonists compared with hypertensive subjects receiving other treatments.2 Whether one believes that these data are worrying enough to preclude the drugs’ use or that the drugs’ continued use as first line agents is justified,3 there is clearly an urgent need for randomised controlled trials. Thiazides and â blockers remain the only drug treatments for hypertension proved to be effective in reducing cardiovascular morbidity and mortality. Nifedipine (as Adalat) was licensed for hypertension in 1982, and captopril (as Capoten) was licensed in Britain for the treatment of hypertension in 1981(dates supplied by manufacturers). The 2 3 Ferner RE. Newly licensed drugs. BMJ 1996;313:1157-8. (9 November.) Beevers DG, Sleight P. Short acting dihydropyridine (vasodilating) calcium channel blockers for hypertension: is there a risk? BMJ 1996;312:1143-5. Hanna FW, Peters JR, Rees JA. Evidence for the risk of calcium channel blockers in hypertension was selective. BMJ 1996;313:1259-60. (16 November.) Randomised controlled trials are needed in primary care before new drugs are licensed Editor—I have several points to add to R E Ferner’s editorial about newly licensed drugs; my points relate specifically to the implementation of research findings in primary care.1 Over the past 10 years several advances have had major implications for primary care, where most patients receive most of their continuing care. We have evidence that angiotensin converting enzyme inhibitors decrease morbidity and mortality in heart failure,2 statins reduce mortality in men with ischaemic heart disease,3 the eradication of Helicobacter pylori in patients with peptic ulcer disease reduces the incidence of recurrent disease,4 warfarin reduces the risk of stroke in patients with atrial fibrillation,5 and angiotensin converting enzyme inhibitors delay the progression of nephropathy in diabetic patients with BMJ VOLUME 314 22 FEBRUARY 1997 Letters microalbuminuria. Although we have some evidence that the above treatments decrease morbidity or mortality, or both, we do not know: x how to diagnose conditions in primary care accurately—in particular, heart failure, microalbuminuria, and H pylori infection. We have treatments for conditions that we cannot diagnose properly; x how the results apply to unselected populations—for example, warfarin in the prevention of stroke, or statins in the secondary prevention of coronary heart disease; x the overall cost effectiveness of both diagnosis and treatment in primary care. Randomised controlled trials in primary care are needed to establish the true costs and benefits of innovations in treatment in the context in which they are likely to be used. I agree with Ferner that this should be before drugs receive their full licence and is best done by the NHS rather than by the drug industry. Although randomised trials in general practice are difficult, such trials are the only way that we can be sure that the benefits are real and the adverse reactions are appropriately monitored. Julia Hippisley-Cox Lecturer Department of General Practice, Faculty of Medicine, Medical School, Queen’s Medical Centre, Nottingham NG7 2UH 1 2 3 4 5 Ferner RE. Newly licensed drugs. BMJ 1996;313:1157-8. (9 November.) SOLVD Investigators. Effects of enalapril on survival of patients with reduced left ventricular ejection fractions and congestive cardiac failure. N Engl J Med 1991; 325:293-302. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the 4S study. Lancet 1994;344:1383-9. Forbes GM, Glaser ME, Cullen DJE. Duodenal ulcer treated with Helicobacter pylori eradication: seven year follow-up. Lancet 1994;343:258-60. Sweeney K, Gray DP, Steele R, Evans P. Use of warfarin in non-rheumatic atrial fibrillation: a commentary from general practice. Br J Gen Pract 1995;45:153-8. view of the relative benefits and cost. Furthermore, patients are left with unacceptable uncertainty about their future treatment. Drugs continue to be marketed at the level of prescribers rather than at the level of health authorities. Health authorities counter by applying pressure on prescribers. The result is that many clinicians feel pressurised from three directions: for the best care by patients, for optimal drug treatment by pharmaceutical companies, and for treatment within the budget by health authorities. What do those of us who work on prescribing in health authorities want from the pharmaceutical industry? Firstly, no later than 12 months before a drug is licensed the industry should give us better information on efficacy and cost for those new drugs that will require additional funding. Secondly, prices should reflect real, measured benefit to patients. The pricing of new products out of proportion to additional benefit obliges health authorities to use medical and pharmaceutical advisers to counter company promotions. We should both be promoting clinically cost effective care. Thirdly, companies releasing a drug before it has obtained a licence should do so only with the agreement of health authorities. Finally, when the efficacy of a drug is in doubt we should be able to insist, collectively, on further trials being conducted. This is particularly important when the disease is fatal and patients’ suffering is severe. Health authorities want to know that they are not wasting money prolonging the agony both of those who are treated and of those whose treatment is denied as a result. Jim A G Paris Primary care medical adviser Wesham Park Hospital, Wesham, Near Kirkham, Lancashire PR4 3AL 1 2 “Proportionate benefits” should be made clear Editor—The principle of “proportionate benefits” in determining the use of a drug1 is crucial to a health authority’s management of the drugs budget. It does not, however, feature in many pharmaceutical companies’ marketing strategies—a factor that hinders rather than helps the move towards rational prescribing. High cost treatments of limited efficacy for serious, debilitating, and life threatening diseases are of particular concern. Riluzole has recently been licensed for use in amyotrophic lateral sclerosis.2 The validity of the results of the trial and the efficacy of the drug, in terms of improvement in the quality of life, have been questioned.3 The cost of treatment—£3750 per patient per year—has to be justified against other priorities. Riluzole was released for use before licensing, the cost being met by RhônePoulenc Rorer. Now that a licence has been granted, health authorities are expected to take over the cost. Thus a drug can be launched early, which pre-empts health authorities’ process of taking an objective BMJ VOLUME 314 22 FEBRUARY 1997 3 Ferner FE. Newly licensed drugs. BMJ 1996;313:1157-8. (9 November.) Lacomble L, Bensimon G, Leigh PN, Guillet P, Meininger V, for the Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Dose ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 1996;347:1425-31. Guiloff RJ, Goonetilleke A, Emami J. Riluzole and amyotrophic lateral sclerosis. Lancet 1996;348:336-7. general practice. This would remove doctors’ clinical freedom to prescribe what they consider to be best for patients and suggests that general practitioners are not capable of deciding when to use a new product. By the time Ferner’s suggested monitoring process had been completed and the new medicine given a clean bill of health, further important delays would have prevented the general public from having access to new medicines. It already takes an average of 12 years for a new medicine to reach the market. Ferner’s claim that prescribers are not constrained to use drugs rationally and cost effectively is a further slight on the average prescriber. All general practitioners will confirm that there has been increasing pressure to reduce prescribing costs over the past six years, and generally they have complied. Ferner’s solutions include introducing the cost-benefits of new products into NHS trials. This would inevitably lead to long delays before a product could be used generally, and it is well recognised that, even when good evidence exists for the use of a particular treatment, for the treatment to reach common use takes considerable time. Furthermore, there needs to be a change in the NHS: out of necessity the Department of Health operates on shorter term policies than this suggestion implies. The present system should be maintained and the pharmaceutical industry should encourage all doctors to report adverse reactions. The importance of this responsibility should be emphasised in the undergraduate curriculum. Adding a further hurdle to the already lengthy procedures necessary to make a new medicine available for patients would not benefit them and would also remove doctors’ clinical freedom to prescribe what they consider to be best for their patients. Richard Tiner Director Department of Medicine, Association of the British Pharmaceutical Industry, London SW1A 2DY 1 Doctors should be encouraged to report adverse reactions Editor—In the editorial about newly licensed drugs R E Ferner suggests a further hurdle for pharmaceutical companies to leap before they can market new products— namely, a probationary period.1 The drug industry and regulators already operate a stringent system of randomised controlled trials and reports that have to be completed before a product can receive a marketing authorisation. For every medicine that reaches the market around 10 000 molecules have undergone initial testing in the laboratory. Ferner’s proposal risks stifling innovation as companies would be reluctant to bring products to the market if there was any chance of their being removed after a relatively short period. Ferner suggests that “general use of a newly licensed drug may be undesirable” and indicates that newly licensed drugs should not be available for prescription in Ferner RE. Newly licensed drugs. BMJ 1996;313:1157-8. (9 November.) Peak expiratory flow is a prognostic indicator in elderly people Editor—D J Hole and colleagues report that impaired lung function, as measured by the forced expiratory volume in one second, was an important clinical indicator of the risk of death in men and women aged 45-64 at the baseline of their study.1 When using peak expiratory flow rate as an indicator of lung function in elderly populations we have obtained similar results.2 3 As a part of a large prospective study4 we report here the peak expiratory flow of random people in four elderly birth cohorts (aged 65, 75, 80, and 85) and its correlation with survival over the next five years. A total of 1326 people were examined and followed up for five years. Of these sub605 Letters Table 1 Number of subjects with successful measurements of peak expiratory flow in four birth cohorts and their mean peak expiratory flow by sex and survival over five years Age (years) 65 75 80 85 P Alive 276 44 26 17 Dead 31 19 19 18 Alive 326 119 87 57 Dead 11 32 47 57 <0.001 Alive 477 (111) 447 (116) 432 (90) 375 (75) <0.001 Dead 431 (129) 423 (111) 381 (113) 342 (113) 0.073 <0.001 <0.001 0.138 0.313 Alive 347 (87) 344 (93) 321 (91) 263 (79) <0.001 Dead 324 (112) 255 (83) 257 (82) 247 (76) 0.046 0.408 <0.001 <0.001 0.279 No with successful measurements Men: <0.001 Women: Mean (SD) peak expiratory flow (l/min) Men: P Women: P All subjects: Men 473 (113) 440 (114) 411 (112) 358 (97) <0.001 Women 346 (88) 325 (97) 299 (93) 255 (77) <0.001 <0.001 <0.001 <0.001 <0.001 343 (7) 297 (8) P Both sexes* 395 (4) 369 (7) <0.001 *Mean (SE) values adjusted for sex. jects, 1186 were able to perform a peak expiratory flow test (using a mini-Wright meter) at entry (table 1), and 234 of these died within the follow up period. Data were analysed according to age, sex, height, body mass index (weight/height2), health score (on a visual analogue scale, with 0 = poor health and 10 = excellent health), and survival with analysis of variance, covariance, logistic regression, and the Cox proportional hazard model. The decrease in peak expiratory flow related to age accelerated with age, being 0.7%/year from ages 65 to 75 and about 2%/year thereafter. Peak expiratory flow correlated significantly with the health score (r = 0.288, P < 0.001). Inability to blow successfully into the flowmeter (n = 140) was associated with a threefold increased risk in death in the next five years (50% v 19%; risk ratio after adjustment for age and sex 3.1 (95% confidence interval 2.0 to 4.6)). After age and sex were controlled for the lowest quarter of peak expiratory flow was associated with an almost threefold excess mortality (risk ratio 2.7 (1.9 to 3.9)). When subjects with asthma (n = 56), chronic bronchitis (n = 128), and emphysema (n = 111) were excluded (829 remained alive, 178 died) the risk ratio for death (adjusted for age and sex) associated with a decrease in peak expiratory flow of 100 l/min was 1.27 (1.08 to 1.49). This study shows that the decrease in peak expiratory flow is a good indicator of declining health in the elderly general population. It reflects the strength and condition of respiratory muscles and the degree of airflow limitation in large airways. Our analysis suggests that measuring lung function is useful in assessing the prognosis in elderly populations. Furthermore, measurement of peak expiratory flow may 606 be easier than measurement of the forced expiratory volume for these people. Reijo Tilvis Professor of geriatrics Jaakko Valvanne Physician in chief Sirpa Sairanen Research fellow Anssi Sovijärvi Professor of clinical physiology Helsinki University Central Hospital, FIN-00290 Helsinki, Finland 1 2 3 4 Hole DJ, Watt GCM, Davey-Smith CL, Hart CL, Gillis CR, Hawthorne VM. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ 1996;313: 711-5. (21 September.) Nunn AJ, Gregg I. New regression equations for predicting peak expiratory flow in adults. BMJ 1989;298:106870. Boezen HM, Schouten JP, Postma DS, Rijcken B. Distribution of peak expiratory flow variability by age, gender and smoking habits in a random population sample aged 20-70 years. Eur Respir J 1994;7:1814-20. Lindroos M, Kupari M, Heikkilä J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol 1993;21:1220-5. trial carried out in Boston (which Thornton does mention) was regular audit of outcome at the most senior level in the hospital. The randomised trials conducted so far have clearly shown that active management, even when not introduced in its full form, reduces the duration of labour significantly.3 4 Interest in the effect of active management on caesarean section rates has been stimulated by a sense of frustration among many people at their inability to reproduce the low incidence of caesarean delivery documented from the National Maternity Hospital. Active management was not introduced to reduce caesarean rates, but O’Driscoll et al suggested that it might provide a solution to caesarean section for dystocia,5 which is the root cause of the epidemic of caesarean sections in the Western world. Active management has been introduced in many different practice settings around the world, often producing results similar to those in Dublin. The most successful units have tended to be those that have included the key element of regular audit of outcome. This process was omitted from the trial in Boston, and this was one of several reasons why that trial was unsuccessful in reducing the incidence of caesarean section. The question that Thornton should have asked is why have the randomised trials failed to reproduce the results from Dublin when introduction of the package seems to work so well in different settings? There are two possibilities: one is that a randomised controlled trial is not the best method of assessing this particular approach to the care of women in labour, while the other is that the randomised trials have not tested active management in its totality as practised in the National Maternity Hospital in Dublin. My knowledge of the trials suggests that the latter possibility is the more likely and that the most important component not included has been continuous audit. Peter Boylan Master National Maternity Hospital, Dublin 2, Republic of Ireland 1 2 Active management of labour Continuous audit is the most important component Editor—Active management of labour was developed in the 1960s as a method of preventing prolonged labour.1 Over the subsequent 30 years the approach has been constantly modified and now includes the package described by J G Thornton: antenatal classes, early diagnosis of labour by senior midwives, amniotomy when membranes are intact before the onset of labour or at admission to the delivery ward (70%), selective acceleration of slow labour with oxytocin, personal support in labour by midwives, liberal availability of epidural anaesthesia, and regular rounds by senior obstetricians.2 The one factor that Thornton does not mention and that was not tested in the 3 4 5 O’Driscoll K, Jackson RJ, Gallagher JT. Prevention of prolonged labour. BMJ 1969;ii:477-80. Thornton JG. Active management of labour. BMJ 1996;313:378. (17 August.) Lopez-Zeno JA, Peaceman AM, Adashek JA, Socol ML. A controlled trial of a program for the active management of labor. N Engl J Med 1992;326:450-4. Frigoletto FD Jr, Lieberman E, Lang JM, Cohen A, Barss V, Ringer S, et al. A clinical trial of active management of labor. N Engl J Med 1995;333:745-50. O’Driscoll K, Foley M, MacDonald D. Active management of labor as an alternative to cesarean section for dystocia. Obstet Gynecol 1984;63:485-90. Commitment to low intervention rates with audit of outcomes is important Editor—If active management of labour is to be abandoned because of the results of randomised controlled trials, as J G Thornton suggests,1 what are we left with? Do we simply accept caesarean section rates of over 15% or even 20%? Or should we attempt to examine what it is about units that practise active management that results in low intervention rates? Johnson and Ansell have reported the management of labour at Middlemore BMJ VOLUME 314 22 FEBRUARY 1997 Letters Hospital in South Auckland.2 They have maintained their caesarean section rate below 10%, which is the lowest for such a unit in New Zealand. There is an institutional commitment to a low rate of induction (less than 11%), encouragement of trials of labour whenever possible, and fetal blood sampling if fetal distress is suspected in labour. The unit also operates a protocol for active management of labour in nulliparous women at term. Robson et al, from Pembury Hospital in England, showed that the caesarean section rate could be lowered by a combination of continuous clinical audit, peer review meetings concentrating on management of labour and caesarean sections, as well as attention to progress in spontaneous labour in nulliparous women with early intervention for failure to advance.3 They achieved a reduction in the overall caesarean section rate from 12% to 9.5% with the rate for nulliparous women in spontaneous labour falling from 7.5% to 2.4%. Both results were significant. A similar programme in a private hospital in California resulted in a reduction in the caesarean section rate from 31.1% to 15.4%.4 Perhaps the key ingredient of active management programmes is not the use of early amniotomy and oxytocin but the institutional commitment to low intervention rates with close audit of outcomes. If the low caesarean rates outlined above are the result of the Hawthorne effect entering day to day clinical practice then that is fine: it is the end result that matters. Robert Buist Registrar in obstetrics and gynaecology St Thomas’s Hospital, London SE1 7EH 1 2 3 4 Thornton JG. Active management of labour. BMJ 1996;313:378. (17 August.) Johnson N, Ansell D. Variation in caesarean and instrumental delivery rates in New Zealand hospitals. Aust NZ J Obstet Gynaecol 1995;35:6-11. Robson MS, Scudamore IW, Walsh SM. Using the medical audit cycle to reduce caesarean section rates. Am J Obstet Gynecol 1996;174:199-205. Lagrew DC, Morgan MA. Decreasing the cesarean section rate in a private hospital: success without mandated clinical changes. Am J Obstet Gynecol 1996; 174:184-91. Litigation in obstetrics and gynaecology has increased in Merseyside Editor—Over recent years the incidence of litigation, particularly in obstetrics and gynaecology, has increased dramatically. In 1995 I recorded the time that I spent dealing with in house matters of litigation. From 1 January to 31 December 1995 I spent 110.5 hours of time dealing with litigation issues (correspondence, reports to solicitors, interviews, etc). This amounts to about three working weeks. The vast majority of this time was in the evenings and at weekends and hence was not paid for by the NHS. I work in a large district general hospital, which in 1995 employed five consultants in obstetrics and gynaecology. I have no reason to think that my firm attracted any more litigation than any other or that Arrowe Park Hospital is in any way atypical. If all of my BMJ VOLUME 314 22 FEBRUARY 1997 colleagues spent roughly an equivalent amount of time dealing with their own litigation cases this would amount to about 550 consultant hours a year in this department alone—equivalent to 16 working weeks of consultant time a year. In January 1995 my department had 106 cases of litigation in progress, but in January 1996 it had 146 cases, an increase of 38%. During the year some cases were abandoned or settled while others were started. Obviously, during the year we accumulated new cases at a faster rate than the old ones were resolved. I offer these statistics simply for interest. I do not know how they compare, if at all, with those at other units, but I have no reason to suspect that Arrowe Park Hospital attracts more litigation than similar hospitals elsewhere in Britain. Although I have quantified only my own time involved in this exercise, obviously support staff spend considerable time and effort in managing these complaints. For example, we have a full time clerical officer whose sole task is to manage litigation and complaints for the department. Our secretaries spend an enormous amount of time typing reports, although currently this remains unquantified. The cost to taxpayers is clearly massive. Brian Alderman Consultant obstetrician and gynaecologist Wirral Hospital, Upton, Wirral, Merseyside L49 5PE Pilot trial of integrating pharmacy into primary care in rural areas is needed Editor—The recent white paper on primary care calls for the development of innovative models of care.1 A willingness to consider radical alternatives to established models is explicitly stated: “the government has no preconceived ideas.” An opportunity exists here for rural general practices to pilot a large scale, self funding revolution in the provision of services that would be applicable across the whole of Britain. In so doing it would meet the criteria set out by Mike Pringle.2 While the problems faced by deprived urban areas are often aired, those affecting rural areas are rarely examined. In rural areas both primary care and community pharmacy are hard pressed, to the extent that “essential small pharmacy” subsidies of up to £33 600 a year are available to sustain pharmacies. There is no comparable facility for practices. The benefits of full integration of pharmacy into primary care in rural areas could be shown rapidly, and access for the public to both professions could be assured, probably without the need for any subsidies.3 Though the white paper pays lip service to “bringing pharmacists more closely within the primary healthcare team,” the pivotal folly—separating prescribing and dispensing—continues not to be addressed. Any putative benefits from the separation of the two have been eclipsed by technological change and budgetary imperatives. The predicted savings—£5.5bn over a parliament’s lifetime3 —must be worth, at the very least, a large scale pilot. This is not the time to be timid or to toy with ineffectual half measures. Steven Ford General practitioner Five Stones, Heugh House Lane, Haydon Bridge, Northumberland NE47 6HJ 1 2 3 Secretary of State for Health. Primary care: the future. Choice and opportunity. London: HMSO, 1996. Pringle M. Primary care: choice and opportunity. BMJ 1996;313:1026-7. (26 October.) Ford S, Jones K. Integrating pharmacy fully into the primary care team. BMJ 1995;310:1620-1. Those who believe in alternative theories of AIDS have little room for manoeuvre Editor—In 1984 Robert Gallo declared that he had discovered the virus that was the “probable cause of AIDS.” A team of scientists began working on what they expected to be a cure or vaccine for AIDS within two years. It didn’t happen. Widely publicised and largely unquestioned claims that AIDS was about to devastate the heterosexual world followed. That didn’t happen either. Twelve years and $42bn (£26bn) after the discovery of HIV there is no vaccine, only the possible beginnings of a cure, and limited heterosexual spread confined largely to the third world.1 The collapsed expectations surrounding AIDS made it likely that someone of Peter Duesberg’s stature would continue to pursue his theories, but, for all the misinformation that has surrounded AIDS, HIV still remains the predominant causal factor. Richard Strohman protests too much.2 If Duesberg’s contribution to the scientific literature on AIDS had been without serious flaw then it would have been heard, widely disseminated, discussed, and acted on. Alternatively, Duesberg is victim to a monumental medical conspiracy to avoid the truth. Conspiracy is unlikely: it is not the way medical science works. Duesberg has made some useful contributions to the discussion of AIDS, but he rightly remains peripheral to the debate because ultimately his argument is negative, pedantic, and fundamentally flawed. Strohman argues that the “haemophilia data ... cannot establish correlation or cause.”2 In a recent interview Duesberg made a similar point to me; he protested, “the fact that everybody who eats a tomato dies does not prove that tomatoes are ‘ultimately deadly.’ ”3 True, but if everyone who had eaten tomatoes in the 1970s had died in the 1980s who would eat tomatoes today? Duesberg may be formally correct— correlation does not prove causation—but his stance is infuriatingly narrow. Once all other credible causes have been ruled out, correlation does imply causation. The studies of Darby and Sabin leave little room for manoeuvre by those who maintain that HIV has a non-pathogenic role.4 5 A reasonable response to Duesberg’s negativity would be to concede that until a biochemical mechanism shows the causal role of HIV it would be prudent to keep an eye on other possible influences. In this way 607 Letters Duesberg’s work could be funded peripherally to the larger body of work looking into the mechanisms of HIV. Thus we could “have it both ways,”2 and had we been dealing with anything except AIDS that is surely what would have occurred. not assess the quality of the evidence that was found, and its conclusions do not seem to be evidence based. The menopause may or may not cause depression. This review has not fully examined the evidence and therefore cannot settle the question. Stuart W G Derbyshire Research fellow University of Pittsburgh Medical Center, Department of Radiology, 200 Lothrop Street, Pittsburgh, PA 15213, USA Mark Petticrew Research fellow in health services research NHS Centre for Reviews and Dissemination, University of York, York Y01 5DD 1 2 3 4 5 Derbyshire SWG. WHO criticised for “inflating” AIDS figures. AIDS Analysis Africa 1995;5(6):4-5. Strohman R. Alternative theories about AIDS should not be dismissed out of hand. BMJ 1996;313:1147-8. (2 November.) Derbyshire S. The HIV-Aids heretics. Living Marxism 1996;95:34-6. Darby C. Mortality before and after HIV infection in the complete UK population of haemophiliacs. Nature 1995;377:79-82. Sabin C. Comparison of immunodeficiency and AIDS defining conditions in HIV negative and HIV positive men with haemophilia A. BMJ 1996;312:207-10. Causality, the menopause, and depression Review did not fully examine the evidence Editor—Louise Nicol-Smith’s critical review concludes that there is insufficient evidence to maintain that the menopause causes depression.1 This finding is echoed by Myra S Hunter’s editorial.2 The title of the paper refers to a critical review, but both the discussion section and the editorial refer to it as a systematic review. I am not convinced that the review is systematic, and several major methodological issues concern me. Firstly, the author searched only for evidence that the menopause caused depression; research that showed no association was “not considered.” Non-English language studies also seem to have been excluded. This approach is inconsistent with the ethos of systematic reviews, one of whose strengths is that they are comprehensive. Secondly, the author’s conclusions do not seem to be based on the results of the 17 studies included. These studies are largely ignored in the accompanying text, and from the summary of the studies it is difficult to ascertain what the author thought were the limitations of each individual study. In explanation, the author suggests that discussion of definitions of concepts and of the methodology of the primary studies is inappropriate to this review. This makes me wonder to what extent the review is systematic—or, indeed, critical. The studies included are heterogeneous—published between 1933 and 1995, with depression measured by 21 different methods in 18 different countries in both clinical and non-clinical groups. The assessment of the nature and quality of the evidence is one of the defining characteristics of a systematic review. This requirement is not adequately met by a general application of Bradford Hill’s criteria, and a comprehensive and critical assessment of the evidence from the individual studies would have been appropriate. Nicol-Smith concludes by hoping that the usefulness of an epidemiological systematic review has been shown. Unfortunately, this review had a restricted search and does 608 1 2 Nicol-Smith L. Causality, menopause, and depression: a critical review of the literature. BMJ 1996;313:1229-32. (16 November.) Hunter MS. Depression and the menopause. BMJ 1996;313:1217-8. (16 November.) Author’s reply Editor—Mark Petticrew comments on the methodology of my review. In an earlier version of the review, and in my original thesis,1 I criticised the methods and statistics used in the primary studies reporting positive findings. Because of limitations on space and a comment from a referee that the shortcomings in these studies were equally apparent in studies with negative findings, this section was dropped from the published version. Figure 1 in my paper, showing the inconsistencies in measurements and samples, was considered to be sufficient to carry the argument. This figure shows all the studies that I located with both positive and negative findings. The original popperian null hypothesis, which considered only positive findings, is, however, still valid. This is unclear in the text, and I apologise for the confusion. The search method that I used is clearly stated in the materials and methods section of the paper, and I have not been made aware of any omissions or misrepresentations. I included only English language studies because I was able to obtain the methodological information necessary to classify a study only by close reading of the whole text. An English abstract (when this was present on Medline) was not adequate. While Petticrew and I may not agree on what constitutes a systematic review in a subject with such heterogeneous material as this, I do agree with his comment that “the menopause may or may not cause depression.” I was surprised by Myra S Hunter’s editorial and the BMJ’s presentation of my findings. Even though I had examined a large body of research and had found no evidence that would enable me to discard my null hypothesis (that the menopause does not cause depression), this is not the same as concluding that the menopause is not associated with increased depression. As Bertrand Russell’s well known inductivist turkey found out, despite evidence gained over a number of days and under a variety of weather conditions that his dinner arrived at 0900, his conclusion that he was fed each day at 0900 was dramatically disproved on Christmas Day.2 New guidelines on managing back pain are similar to previous ones Editor—Richard A Deyo’s editorial discusses the Royal College of General Practitioners’ guidelines on the management of acute back pain.1 I am surprised that Deyo makes no reference to similar British guidelines produced by the Clinical Standards Advisory Group and published two years ago.2 It is reassuring that the guidance is so similar, but the absence of new recommendations makes the subheading of the editorial (“limited imaging and an early return to normal activities”) misleading. Although the report by the Clinical Standards Advisory Group was widely accepted, it has not led to widespread changes in practice, and one study of compliance with these guidelines among general practitioners suggested a continuing gulf between what guidelines say ought to happen and what actually happens.3 While disability related to back pain continues to rise, the question remains whether any current guidelines will achieve their aim of reducing chronicity. James Campbell Consultant in musculoskeletal medicine Princess Margaret Rose Orthopaedic Hospital, Edinburgh EH10 7ED 1 2 3 Deyo RA. Acute low back pain: a new paradigm for management. BMJ 1996;313:1343-4 (30 November.) Clinical Standards Advisory Group. Back pain. London: HMSO, 1994. Little P, Smith L, Cantrell T, Chapman J, Langridge J, Pickering R. General practitioners’ management of acute back pain: a survey of reported practice compared with clinical guidelines. BMJ 1996;312:485-8. General practitioners have always been the A-Team Louise Nicol-Smith Psychologist Fururabben 19, N-1345 Østerås, Norway Editor—I was interested in, but surprised by, Liam Farrell’s comment that “general practitioners are the A-Team now.”1 Surely they always have been. I well remember my general practitioner father, as long ago as 1924, being called out of his morning surgery to stop a dog fight. Then, later the same day, he got an urgent call to a convent, where he was taken into the tall Victorian conservatory. On looking up he observed a pair of black stockings and knickers covering some legs sticking down between two of the wooden slats. Viewed from above, there was a perfectly ordinary nun, but, unusually, she was sitting in the middle of a conservatory. She had been cleaning the second storey windows, had slipped, and had been saved from falling further by her voluminous dress. My father sent for the fire brigade to release her; fortunately, examination showed no injury. 1 Alaister Nimmo Retired general practitioner 2A Dovedale Road, London SE22 0NF 2 Nicol-Smith L. Depression and menopause: a systematic review of the literature. Oslo: Department of Psychology, University of Oslo, 1993. (Final thesis.) Chalmers AF. What is this thing called science? 2nd ed. Milton Keynes: Open University Press, 1982. 1 Farrell L. One born every minute. BMJ 1997;314:152. (11 January.) BMJ VOLUME 314 22 FEBRUARY 1997