Pharmacology

To the Editor: On behalf of the Endocrine Society of Australia, I would like to endorse the views expressed by Stockigt that the Therapeutic Goods Administration (TGA)-approved information sources for thyroid-related medications are outdated.1 His examples are compelling evidence that statements within product information (PI) sources are inconsistent with current practice. The consequences of these statements range from confusing to potentially dangerous. The current process for updating PI appears to exclude expert advice from specialist practitioners who are most likely to be aware of recent developments regarding the use of medications specific to their practice. In most areas of medicine, specialist societies representing these practitioners provide an excellent potential “first port of call” for the TGA and suppliers to source expert, evidence-based assistance in updating PI. Certainly, the Endocrine Society of Australia is willing to act in this capacity for endocrine-related drugs, and I would be very surprised if this were not the case for other specialist societies. In summary, a partnership between all parties involved in the provision of quality care is needed to ensure that PI is contemporary and accurate.

Leon A Bach

To the Editor: I concur with Professor Stockigt’s recent article1 outlining the shortcomings of product information (PI) for thyroid-related drugs. I often need to contradict incorrect or even hazardous PI advice given to patients. An example is the consumer medicine information (CMI) available on the MIMS website, the “myDr” service.2 Although Hysone (hydrocortisone, Alphapharm) is often used for cortisol replacement, rather than as anti-inflammatory therapy, much of the CMI makes no distinction between these two uses. This may, in part, underlie the potentially dangerous advice: “Do not take Hysone if you have any infections that are not being treated or are not responding to treatment”.2 This instruction implies that patients should stop taking Hysone when they have an infection; this may be disastrous for those with adrenal insufficiency because it could lead to an adrenal crisis.3 It is necessary to increase replacement dosages in the event of an infection, intercurrent illness or surgery.3 The CMI for Cortate (cortisone acetate, Aspen Pharmacare), the alternative glucocorticoid replacement drug, has similar information: “Do not take CORTATE if you have an uncontrolled infection”.4 In the editorial accompanying Stockigt’s article,5 Dowden acknowledges that PI needs to be kept up to date, but I think that PI and CMI will remain inadequate without expert professional review, in addition to that currently mandated by the Therapeutic Goods Administration. Patients with adrenal insufficiency need reliable information about the replacement medications they take long term. The CMI for these two drugs is in need of urgent revision in the interests of patient safety.

David Torpy

To the Editor: The discussion regarding increased currency and updating of prescription drug information (product information, PI)1 provides on opportunity for insightful and valuable debate. MIMS (a compilation of PI)2 supports any initiatives that result in PI and consumer medicine information (CMI) being updated more regularly, and I would like to clarify MIMS’ specific role in the process. PI is an invaluable information source, but not the only source. Accordingly, MIMS was never intended to be used as a stand-alone resource, without appropriate clinical experience and reference to other resources, where warranted. Although this was not mentioned in Stockigt’s article,1 it is clearly stated on the Foreword page of MIMS annual.2 Stockigt, in various comments he made to the media, observed that his article reviewed only one class of drugs1 — thyroid medication — which has been notable for its lack of new products or information in recent years. Thus, his findings cannot be extrapolated across the entire pharmaceutical database. Dowden’s editorial,3 however, appears to suggest that outdated PI is common. This is an assertion with which MIMS must strongly disagree. One measure of the currency of a medicine information database is the frequency and number of updates. MIMS currently publishes more than 100 changes to PI every month, and has the processes and people in place to make an even greater number of changes more frequently should this information become available. However, ultimately the responsibility for updating PI lies with the pharmaceutical industry, and all changes must be approved by the Therapeutic Goods Administration; only then can PI be disseminated by MIMS. MIMS believes that PI, while a valuable resource, is not a stand-alone resource. This is supported by the fact that the entire range of MIMS electronic decision-support modules, such as MIMS DrugAlert (drug–drug interactions) and MIMS AllergyAlert (drug–allergy warnings), are, in fact, derived from reviews of the primary international literature. MIMS welcomes the opportunity to discuss this perspective.

Elizabeth A Donohoo

In reply: It is encouraging that Donohoo, on behalf of MIMS, supports initiatives to more regularly update product information (PI). My review1 demonstrates that necessity. The material published by MIMS is apparently not under their direct editorial control; it depends on PI from the pharmaceutical industry, vetted by the Therapeutic Goods Administration. Revision of PI by drug sponsors has major inertia.2 While the problems in the thyroid area can be serious for a fraction, perhaps 1%–2% per year, of the 200 000 people who take thyroid medications, I made no assertion that the deficiencies identified for thyroid-related medications reflect other PI-based information; that question remains open. Donohoo emphasises that the PI-based information in MIMS is not a stand-alone resource for health professionals, who are able to choose between sources of drug information. By contrast, consumers are offered PI-based consumer medicine information (CMI) as a definitive resource, without choice. The obligatory link between PI and CMI3 is a compelling reason for revision of PI. In my view, the National Prescribing Service, an organisation that publishes the journal Australian Prescriber and fosters quality use of medicines, is the national resource best placed to show initiative to improve the current deplorable state of thyroid-related PI which is, in my view, an impediment to safe, well informed health care for some thousands of Australians. Together with Donohoo, I support debate and initiative.

Jim R Stockigt

In reply: The publications reviewed in Stockigt’s article1 are compendia of product information (PI). Their currency therefore relies on manufacturers keeping the PI up to date. A short scan quickly shows that the PI of some brands has apparently not needed amending for more than 5 years. Examples include certain brands of digoxin (last updated in 2000), roxithromycin (2000), levamisole (1999), levocabastine (1998), pindolol (1993) and ergometrine (1991). Many monthly changes to PI may be made, but, as stated in my editorial,2 it is not always clear whether these changes are substantial amendments or minor variations. To assess whether PI reflects current practice would require Stockigt’s research to be replicated with other drug classes. As PI is brand-specific, the amount of comparative information it contains is limited. This is where information sources independent of the pharmaceutical industry, such as the Australian medicines handbook (http://www.amh.net.au/), Therapeutic guidelines (http://www.tg.com.au/), and the National Prescribing Service (http://www.nps.org.au/) can assist.

John S Dowden

To the Editor: In his review of drug information for thyroid-related medications, Stockigt noted the “outdated advice that antithyroid drugs are not compatible with breastfeeding.”1 However, outdated product information is not unique to antithyroid drugs. Product information rarely states that the drug is safe or advisable for breastfeeding women. Many women receive medicines in the postpartum period: a UK study found that 54% of women were given a drug in hospital and 55% were given a prescription by their general practitioner.2 Yet many breastfeeding women who need medicines are being given incorrect advice, as illustrated by the experience of my podiatrist, Janet. Breastfeeding was going well when, at 4 months postpartum, Janet fell down a flight of stairs. Neither the ambulance officers nor the metropolitan emergency department registrar were willing to administer any pain relief except paracetamol (“unless you are prepared to wean”) — although Janet was in excruciating pain with a fractured 12th rib. At 7 months postpartum, Janet was hypertensive despite treatment. Regardless of her strong desire to continue breastfeeding, her GP and specialist informed her that she needed to change medication and therefore would have to stop breastfeeding. Janet’s case illustrates two issues: firstly, a breastfeeding woman was denied necessary medication because she was breastfeeding, and secondly, her infant was denied continued breastfeeding because of maternal medication. Apparently none of the health professionals sought expert help with decision making surrounding medicines and breastfeeding. Janet encouraged me to use her story to educate other health professionals. For the vast majority of maternal medications, the amount of medication an infant would receive through breastfeeding is less than 1% of an infant dose. In general, if the medication is safe to use in infants, it will be safe for the breastfeeding mother. Only a small number of medications are contraindicated during breastfeeding: these include antineoplastic agents, ergotamine, methotrexate, cyclosporin, and radiopharmaceuticals.3 Information is available about safe use of medicines while breastfeeding (Box). The sources listed in the Box have reviewed the available evidence on individual drugs and given recommendations on whether they are safe to use during lactation. In general terms, they have followed the recommendations for evaluating appropriateness of off-label medicines as suggested by a recent New South Wales working party.4 Medicines used during pregnancy are given safety ratings and the information is available online.5 Australian clinicians need to access such guidance in relation to safe prescribing for breastfeeding women. Sources of information on medicines for breastfeeding women Reference books Pharmacy Department, Royal Women’s Hospital, Melbourne. Drugs and breastfeeding. Melbourne: RWH, 2004 (available for sale: tel: 03 9344 2484) Hale TW. Medications and mothers’ milk. 12th ed. Amarillo, Tex: Pharmasoft Medical Publishing, 2006 (available for sale at: http://neonatal.ttuhsc.edu/lact) Websites Drugs and lactation database (LactMed), a new searchable website set up by the US National Library of Medicine (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT) World Health Organization. Breastfeeding and maternal medication (http://www.who.int/ child-adolescent-health/New_Publications/NUTRITION/BF_Maternal_Medication.pdf) Telephone advice Pharmacy departments of tertiary maternity hospitals Drug Information Centre, Pharmacy Department, Royal Women’s Hospital, Melbourne (tel: 03 9344 2277)

Lisa H Amir

Variation between laboratories and reference sources in the units used for reporting pathology results raises the possibility of medical error. Data submitted to the RCPA Quality Assurance Programs demonstrate wide variation in the units used for reporting therapeutic drug concentrations. This potential source of medical error needs to be addressed by all parties involved in communicating drug concentrations and providing support information.

Graham R D Jones MB BS, DPhil

To the Editor: We write in response to recently published consensus recommendations for the off-label use of pharmaceuticals, which provide a common-sense, evidence-based approach to a commonly encountered clinical problem.1 The recommendations indicate that, other than for exceptional or research indications, off-label use of a medicine is generally not recommended unless there is high-quality evidence supporting such use. However, for some older pharmaceuticals, there is little incentive to perform additional trials to generate good evidence to support off-label use. An example is rifampicin, which is commonly used in combination with fusidic acid to treat methicillin-resistant Staphylococcus aureus (MRSA) infection, but is not licensed or subsidised by the Pharmaceutical Benefits Scheme (PBS) for this indication. Rifampicin has a well defined toxicity profile, with a long history of use in treating tuberculosis and preventing meningococcal disease. Rifampicin-based combinations for staphylococcal infection are recommended by Australian and international guidelines,2,3 and supported by small clinical trials.4 For rifampicin, a generic drug, there is no financial incentive for the manufacturers to apply for an additional indication for treating MRSA infection. Since 1998, an orphan drugs policy has encouraged sponsors of patented pharmaceuticals to apply for indications that may only involve small numbers of patients and has waived Therapeutic Goods Administration (TGA) fees for such marketing applications. A “rule of rescue” has also operated, lowering the regulatory bar for serious diseases that are otherwise untreatable. Despite these initiatives, no application to add the treatment of MRSA infection as an indication for rifampicin (in combination with another active agent) has been received by the TGA.5 A solution would be for the National Health and Medical Research Council (NHMRC) to commission clinical trials where further evidence is required. This proposal could see an expanded role for the National Institute of Clinical Studies (NICS), which will soon be incorporated into the NHMRC. The NICS/NHMRC could also make applications to the TGA for the approval of pharmaceuticals for particular indications, particularly for orphan diseases and generic drugs. Reviews of evidence could be generated from within the NHMRC or from external bodies such as professional Colleges and societies, or groups of experts such as those appointed by the Board of Therapeutic Guidelines Limited. Clinical trials could be performed in conjunction with overseas research agencies and draw from within the existing budget of the NHMRC. This initiative would improve prescribing through the generation of appropriate evidence and may also redefine the utility of some established off-label indications. It could reduce out-of-pocket expenses for patients by facilitating PBS listing. As this initiative would focus on relatively low-cost generic drugs and/or uncommon orphan indications, it would be unlikely to have a significant impact on the cost of the PBS. It would also help focus the clinical research agenda on clinical practice and encourage the use of appropriate generic pharmaceuticals.

Allen C Cheng · Priscilla M Robinson · Ken Harvey

Is it unethical to avoid using all available information to monitor drug safety? Adverse effects of health care have recently been in the news, from the worrying unexpected cardiovascular risks associated with use of the cyclooxygenase-2 inhibitor rofecoxib (Vioxx) to reports of high percentages of complications following routine surgery.1,2 As medical care becomes more complex, sophisticated and expensive in Australia, it is paramount that we have the best systems in place to monitor its impact and evaluate its safety and efficacy. In this issue of the Journal, Kelman and colleagues acknowledge the limitations of randomised controlled trials (RCTs) in detecting all harmful effects of medicines and make a plea for modernising Australia’s system of pharmacovigilance by building upon the latest technological and data capabilities that we have. They recommend shifting from the existing archaic system of postmarketing surveillance, which relies on piecemeal reporting of adverse events, to a more systematic approach that would include using existing centrally collected, administrative health care databases. Kelman et al claim that by merging information from prescriptions and the Pharmaceutical Benefits Scheme with readily available data on major health outcomes (eg, deaths, hospital admissions, registers of cancer and other diseases), Australia would have a powerful capacity to evaluate the effects of drugs in real-world situations. What are the advantages and disadvantages of such a proposal, and what is happening internationally? The system proposed by Kelman et al has several advantages: The data already exist, and it may even be irresponsible to not use them for important evaluations of health care outcomes; Such data linkage would provide more comprehensive information on both drug use and outcomes and hence would be less likely to be biased than RCTs, which use selected samples with variable participation; The data would cover a large patient population, increasing the likelihood that any adverse effects would be rapidly identified; and It is an inexpensive system compared with very large RCTs or other epidemiological studies, and it would allow greater capacity for pharmacoepidemiology to evaluate the appropriate use of drugs across the whole population. However, there are also potential disadvantages associated with such a data linkage system: There are privacy concerns surrounding the use of individual patients’ data; The analysis and interpretation of linked datasets pose considerable challenges; for example, with common adverse events such as heart attacks or stroke, any associations found must be analysed in relation to other known risk factors, details of which may not be available or may not be accurately reported in the linked data; and There will be costs involved in establishing a national capacity for data linkage. In some jurisdictions, such as Western Australia (through the WA Data Linkage Unit), such data linkages have been carried out for many years, both to evaluate medical care and to conduct epidemiological studies on heart disease, cancer, birth defects, and other health problems.3-5 As a result, the WA Data Linkage Unit and the researchers it serves have considerable experience in linking, analysing and interpreting the complexities of such data, and have developed best practice in relation to privacy concerns. These analyses have had a major impact on improving health services in the state (see Brook et al5 for examples). If all Australian health care data were linked to drug exposure data (from the Pharmaceutical Benefits Scheme), this linkage could provide very precise estimates of the risks and benefits of drugs for the whole population, as well as for subgroups that are often excluded from RCTs, such as children, pregnant women, and people with multiple diseases or other risk behaviours, such as smokers. If linked data are routinely evaluated for outcomes associated with new drugs, adverse events could be detected before considerable harm is done to patients. We must be able to demonstrate to the community that linking data for the sake of the public good does not invade their privacy. Both the National Health and Medical Research Council and the Australian Law Reform Commission are preparing reviews that will help to clarify and, we hope, support these activities. The WA Data Linkage Unit has developed a protocol for linkage that aims to protect privacy.6 This “win–win” approach means that researchers who require linked data on drug exposures and patient outcomes never see any patient-identifiable information. Since the WA Data Linkage Unit’s protocol has been in place, requests for access to identifiable data have reduced markedly.7 When people in the general community were asked if they approved of their information being used in this way, they were found to be not only supportive of it, but they questioned why it was not already being done (C Kelman, Associate Professor in Population Health, Australian National University, personal communication, 2005). Most international developments in pharmacoepidemiology are taking place in the United States, Canada and the United Kingdom, with relevant authorities in these jurisdictions concerned about the safety and cost of drugs, and ensuring efficacy and appropriate prescribing.8 Their recommendations generally support those of Kelman and colleagues. While health care data linkage systems similar to that in WA exist in England, Scotland, the US and Canada, none of these systems are nationwide or have the routine ability to link health care records with drug prescription data; Australia could perhaps lead the world in this regard. We strongly believe that Australia has an opportunity to establish a cutting-edge capacity to monitor its health care system. We also believe that if society has the capability to better monitor the safety of new drugs, it may be unethical not to do so — avoiding the use of information that would help reduce risk to individuals suggests a willingness to allow people to be harmed. At the very least, this conflicts with the physician’s duty to patients to “first, do no harm”. We think the time has come to expect more — not simply to avoid harm and reduce risk to individual patients, but to actively seek to maximise the wellbeing of all citizens. Improved pharmacovigilance is one important step towards this goal.

Fiona J Stanley FAFPHM, MFCCH, FRACP · Eric M Meslin PhD

The current drug regulatory system is outdated and relies primarily on a process of premarketing evaluation, followed by periodic reviews of reported adverse events. While long-term medicine use for chronic conditions is now commonplace, current drug evaluation systems do not incorporate the comprehensive evidence accruing over time in clinical practice. Good quality, routinely collected data on medicines use are now available in some countries. Consistent with international opinion, we propose an expanded and integrated system of medicines regulation for Australia, based on a surveillance system that improves safety monitoring by complementing existing systems, making best use of routinely collected data, and leveraging the power of information technology. Australia is well placed to pilot such a model system.

Chris W Kelman MB BS, PhD · Sallie-Anne Pearson PhD · Richard O Day MB BS, MD · C D'Arcy J Holman MB BS, PhD · Erich V Kliewer PhD · David A Henry MB ChB, FRCP

To the Editor: St John’s wort (SJW) (Hypericum perforatum) is a natural medicine commonly used for treating depression. We recently encountered a case of an overdose of SJW leading to serious manifestations in the patient. A 16-year-old girl presented to the emergency department with seizures and confusion. She was intubated and admitted to the intensive care unit. The only relevant history was of febrile convulsions at the age of 4 years. There had been no head trauma. Results of a computed tomography brain scan and cerebrospinal fluid examination were unremarkable. Electrolyte levels were normal, and standard drug toxicological screens were negative. An electroencephalogram (EEG) confirmed diffuse spike wave activity consistent with generalised epileptic activity. On further questioning, it was found that she had taken large quantities of SJW — up to fifteen 300 μg tablets a day in the 2 weeks leading up to admission and an additional 50 tablets just before presentation — for a recent “depressive episode”. Depression had not been formally diagnosed, and the tablets had been obtained “over the counter” from a local pharmacy. A provisional diagnosis of seizures due to an overdose of SJW was made. High performance liquid chromatography was not performed to quantify hypericum extract in serum and urine, as these tests are not available in our hospital. A repeat EEG at discharge on Day 6 was normal, and there were no further seizures in the following 6 months. Psychiatric assessment during the patient’s hospital stay revealed a likely suicide attempt following recent social stresses. There is some evidence for the efficacy of SJW in treating depression.1 In the United States and Australia it is available without prescription, but in Germany, where it is prescribed more frequently than fluoxetine for depression, it is available by prescription only. The reported incidence of adverse drug reactions to SJW is 0–5.7%.2 Although these are usually minor and transient, more serious adverse reactions (such as serotonin syndrome) have been reported.3 SJW was implicated as a likely, but unproven, cause of seizure-related events in a recent review,4 but our case appears to be the most severe reported so far. Adverse reactions are thought to be more common if SJW is taken in conjunction with selective serotonin reuptake inhibitors, but have also been described when SJW is taken alone.5

Dharshi C Karalapillai · Rinaldo Bellomo

To the Editor: Sanderson et al provide an interesting viewpoint about how the community, including medical practitioners, have embraced complementary and alternative medicine (CAM).1 However, if we were reviewing this article for publication, we would ask the authors to: make a valid distinction between those complementary and alternative therapies promoted as curative versus those considered palliative; define how they decided which therapies belong to one or other side of the arbitrary CAM boundary; review and justify the boundaries for the “therapeutic footprint” in a more evidence-based and rigorous way; locate specific therapies inside the footprint; locate where chemotherapy lies within the footprint, in light of the recent review showing, for the vast majority of adult malignancies, its marginal survival benefits considering its high costs, both monetary and healthwise;2 emphasise that there are relatively few recorded adverse events for CAM compared with conventional cancer care (Therapeutic Goods Administration Medicine Summary reports 2003, 2004, 2005 — Dr K Mackay, Acting Director, Adverse Drug Reactions Unit, TGA, personal communication); and vigorously question the marketing of conventional medicines, such as trastuzumab (Herceptin, Roche), to vulnerable patients and an uncritical public when the evidence suggests huge expense and little, if any, survival benefit.3 Perhaps a distinction also needs to be made between CAM therapies, many of which provide proven symptomatic relief, and those lifestyle interventions, such as exercise,4 dietary change,5 and social support, which provide symptomatic relief and may also confer a survival benefit. It does not serve the profession well when many cancer patients and their carers have to go outside the medical system to access information, advice and therapies which they should have easy access to within the system. In fact, we might even question how helpful these arbitrary boundaries are when all that patients and doctors want is to use what works and what is safe.

Craig S Hassed · Vicki Kotsirilos · Marie Pirotta · Avni Sali

In reply: We would like to thank Hassed and colleagues for their comments on the “therapeutic footprint” and their questions about locating specific therapies within the model. While it was outside the scope of our article to critically analyse different treatments using the model (as benefits and risks will vary from patient to patient), we would like to direct Hassed et al to a more detailed consideration of the risks and benefits of chemotherapy.1 We do not see our model as a tool to categorise or economically appraise specific treatments, but rather as one to help conceptualise the key issues to be considered when proposing treatment — the evidence for benefits and risks, contextualised according to treatment goals. The model provides a basis for comparison, taking us beyond arbitrary and unhelpful arguments about the distinctions between complementary and alternative therapies and their boundaries. We hope that the model will encourage evaluation of evidence for all therapies and support critical evaluation not only of drugs, but also lifestyle interventions that may benefit patients. The primary or essential purpose of the model is to encourage the posing of questions like those articulated by Hassed and colleagues to any therapist — whether they identify as medical, complementary or alternative.

Christine R Sanderson · Bogda Koczwara · David C Currow

Objective: To identify whether the rate and average daily dose of stimulant prescribed for attention deficit hyperactivity disorder (ADHD) in Western Australia differed according to the geographical remoteness and socioeconomic status of the patient.Design and data sources: Secondary analysis of population-based administrative pharmacy data from 2004, stratified by the Accessibility/Remoteness Index of Australia (ARIA+) categories and the Index of Relative Socio-Economic Disadvantage (IRSD) quintiles for WA (2001 Census).Outcome measures: Rate ratios of stimulant prescription and mean average daily dose (in dex-equivalents) stratified by age (2–17, 18+ years), sex, ARIA+ category and IRSD quintile.Results: The rate of stimulant prescription was 2.3 to 5.3 times greater in major cities in WA compared with remote and very remote parts of the state. The association between socioeconomic disadvantage and the rate of stimulant prescription was highly variable. Adults with the least socioeconomic disadvantage were significantly more likely to receive stimulants compared with their most disadvantaged counterparts; however, the reverse association was seen with children. The average daily dose of stimulant prescribed did not vary greatly across remoteness or socioeconomic categories.Conclusion: Remoteness and socioeconomic disadvantage are significantly associated with rate of stimulant prescription for ADHD in WA, but not associated with average daily dose of stimulant prescribed. Further research is needed to understand why considerable variation exists in the use of prescribed stimulants for ADHD.

Janine Calver PhD · David Preen PhD · Max Bulsara MSc · Frank Sanfilippo PhD

Over the past 10 years, the management of HIV infection has been transformed by an increased number of effective antiretrovirals (ARVs), with more convenient dosing and improved tolerability. Optimal management of HIV infection includes at least three effective ARVs; from at least two different drug classes. Current strategies and drugs can effectively control HIV and significantly reduce morbidity and mortality. However, no cure is yet possible. Appropriate use of ARVs leads to suppression of virological replication (to below the limit of detection using commercial assays to measure HIV in plasma) and an increase in CD4+ T cells with few adverse effects. Greater than 95% adherence to drug therapy is required for effective viral suppression and immunological improvement. Monotherapy, two-drug combinations, sequential ARVs, drug “cycling”, and treatment interruptions are ineffective management strategies and lead to earlier disease progression and emergence of drug resistance. Drug–drug interactions are common and caution is required when prescribing ARVs that inhibit or induce the cytochrome P450 pathway.

Luke F Chen MB BS(Hons) · Jennifer Hoy MB BS, FRACP · Sharon R Lewin MB BS(Hons), PhD, FRACP

To the Editor: We read with interest the “Diagnostic Dilemma” by Peter et al.1 The case raises interesting management issues. The first is initiation of antibiotics. Despite 1 week of fever, rigors, haematuria and loin pain, we are informed that the patient was in no distress at initial assessment. In this situation there is, despite the anxieties of resident staff, no urgent need to administer antibiotics; hospitals are controlled, monitored environments in which observation, review and investigation can be undertaken, within reason, if a diagnosis is not immediately made. The second issue is antibiotic selection. The provisional diagnosis was a urinary tract infection, and ceftriaxone and gentamicin were administered. The justification for the use of two agents with a similar spectrum of antimicrobial activity is not given.2 Likewise, no justification is given for the use of a potent nephrotoxin in the presence of moderately severe acute renal failure. Flucloxacillin was added “to broaden the gram-positive antibiotic cover”. It is not apparent why staphylococcal cover was sought at this stage. All cultures (blood, urine and pleural fluid) remained negative. At Day 14, ceftriaxone and gentamicin were changed to ticarcillin/clavulanic acid and ciprofloxacin “because of persistent fever and rising [white cell count]”; this decision in the absence of positive cultures is not explained. The patient’s renal function deteriorated further and he became profoundly acidotic. In fact, the patient’s renal function had performed heroically, given administration of gentamicin for 2 weeks in the presence of acute renal failure at admission. In the intensive care unit, flucloxacillin was replaced with vancomycin; the rationale is not explained. This case illustrates important points regarding antibiotic use. Despite significant renal impairment at admission, the patient was administered a 2-week course of a nephrotoxic antibiotic, which contributed to renal collapse. This situation would have been terminal if not for supportive intensive care. The treating team appears to have managed the patient as if sepsis were a given, and yet all cultures remained negative. This illustrates a basic but crucial teaching point — fevers, chills, rigors, raised inflammatory markers and neutrophilia do not necessarily equate with sepsis. If this experience reflects routine practice elsewhere (and it is our experience that it does), is it any wonder that we have reached an era in which we now encounter organisms so resistant that they are essentially untreatable?3

Mark A Boyd · Stephen Hedger

In reply: Boyd and Hedger have raised concerns regarding the initiation and choice of antibiotics in our recent case report.1 Several aspects of this correspondence need to be addressed. The primary focus of the article was to highlight an important and probably underrecognised cause of unexplained metabolic acidosis, and discussion regarding antibiotic choice was not within the scope of the article. Further, the patient’s management before admission to the intensive care unit was by a different treating team. Subsequent case-note review did not reveal reasons for initiation or choice of antibiotics other than described in our article, although it was evident that gentamicin doses were adjusted based on drug levels. We agree that a less nephrotoxic agent could have been chosen and that the profligate use of antibiotics in the absence of strong evidence of infection could have been avoided. The excessive use of antibiotics in the current medical milieu may stem from a physician’s lack of confidence, or even legal ramifications of “watching and waiting” in the setting of “fevers, chills, rigors, raised inflammatory markers and neutrophilia”, as encountered in our patient.

John V Peter · Natasha Rogers · Sandra L Peake

Does drug product information need a use-by date? Do not rely on the Australian approved product information for up-to-date advice about drug therapy. This seems to be the main message of Stockigt’s review of entries for thyroid disease in prescribing references, which are based on the product information supplied for each drug. In some cases the information was so out of date, its recommendations were potentially harmful.1 While these findings will not surprise everyone,2 many health professionals will be disturbed to know that they cannot completely trust the product information approved by the Therapeutic Goods Administration (TGA). It is often the source that people turn to when seeking detailed drug information. As the product information also underpins consumer medicines information and sets the boundaries for advertising, flaws could have far-reaching consequences. The Therapeutic Goods Act 1989 (Cwlth) has little to say about product information other than it relates to “the safe and effective use of the goods, including information regarding the usefulness and limitations of the goods”. Details about what should be in the document are contained in the Australian regulatory guidelines for prescription medicines.3 These guidelines do not state that the product information should be kept up to date. When a sponsor company applies to have a new drug registered in Australia, it supplies a draft of the product information. This is scrutinised by the TGA and the Australian Drug Evaluation Committee to check that the information reflects the evidence supporting the drug’s safety and efficacy. Although the sponsor can make safety-related notifications, the product information cannot be changed after registration without the TGA’s approval. At the time of registration, the accuracy of the product information is at its zenith; however, it may soon be outdated. With the pressure to approve drugs quickly, new information is likely to emerge after the product is marketed. Some drugs seem to be approved mainly on the results of phase II trials. Their product information will therefore need updating when the results of phase III trials become available. Adverse effects may only emerge after marketing. A review in the United States of 548 new drugs found that more than 10% later acquired a “black-box” warning about serious adverse effects or were withdrawn.4 While major safety concerns are likely to trigger an update of the product information, less prominent problems may be overlooked. In Australia, the sponsor is responsible for keeping the information up to date. How seriously this responsibility is taken is unclear. Updating product information, particularly about old and possibly less profitable products, and disseminating the changes may not be a top corporate priority. The TGA also has to set priorities. It has limited resources but many areas of regulatory responsibility, including complementary medicines. While the TGA was once government-funded, it now has to recover all its costs in fees and charges. Having the regulator funded by fees from the industry it regulates may have disadvantages. Industry probably prefers to pay the TGA to register new drugs, than to dust off the product information of old drugs. To manage within its resources the TGA has adopted a “risk management approach” to regulation.5 Activities with a low risk of adverse outcomes receive less scrutiny. This is why complementary medicines are not evaluated before they are listed in the Australian Register of Therapeutic Goods. Similarly, the TGA’s risk analysis may not identify the product information of old drugs as a high risk. Many old drugs only have brief product information. This may not have been updated for years and it can be difficult to know its currency. The date of approval at the end of the document reflects the most recent change. However, this change may have been a minor variation rather than a rigorous review. Perhaps there is a need for a “use-by date”. Drugs have an expiry date, so why not extend the concept to product information? This would require a date to be set for a comprehensive check of the product information. Such reviews would be more frequent early in the product’s life to ensure emerging data were included. For older products the reviews could be less frequent, but at least there would be a mechanism for checking that the information was not obsolete. This could be an opportunity for specialist societies to assist the TGA with updating. Regularly reviewing product information would require greater resources for the TGA. As the TGA can charge for changes to the product information, the mechanism exists to recover the additional costs. (Changes to the product information involving the evaluation of data currently cost about $4000.) Although an agreement between the TGA and industry to keep product information up to date seems sensible, there are likely to be commercial objections. The TGA’s philosophy is to regulate while “freeing industry from any unnecessary regulatory burden”. Most corporations aim to cut costs, so it is possible that a company may withdraw an old drug rather than be forced to review the product information and then pay to have it approved. In 2005, the TGA circulated a discussion paper on improving access to information about prescription medicines.6 This contained several suggestions for greater use of electronic methods to make up-to-date product information easily available. The outcome of this discussion is currently unknown. Would a recommendation to update the product information regularly be accepted in a business environment focused on new products, cost containment and reduced regulation?

John S Dowden MRCGP, MICGP, FRACGP

Product information (PI) for thyroid-related medications endorsed by the Therapeutic Goods Administration, as reproduced in the commonly used compilation publications June 2006 MIMS (Monthly index of medical specialties) annual, MIMS Online and the Australian prescription products guide 2006, was evaluated to see whether it reflects contemporary therapeutic practice. Compared with current medical literature, these PI-based sources provide inadequate, inaccurate or outdated therapeutic directives. Examples include: Incorrect advice that thyroxine therapy should always begin at very low dosage. Failure to recommend increased thyroxine dosage early in pregnancy (thus placing the offspring of women being treated for hypothyroidism at risk of impaired fetal brain development). Incorrect and potentially unsafe advice to treat thyrotoxicosis with stable iodide in late pregnancy. Failure to advise serial adjustment of antithyroid drug dosage until after a patient becomes euthyroid (this can result in iatrogenic thyroid dysfunction). Outdated advice that antithyroid drugs are not compatible with breastfeeding. Recent initiatives to upgrade consumer medicine information (CMI) appear to accept PI-based sources as a reliable benchmark for CMI. That inference is not warranted for thyroid-related medications. Accountability for the updating of clinical information in PI needs to be defined, and the process for updating PI may need to be modified. Quality drug information, both PI and CMI, depends on fluent, evidence-based collaboration between suppliers, regulators, prescribers, specialist clinicians and consumers.

Jim R Stockigt MD, FRACP, FRCPA

Over a 3-year period, seven patients who were taking HMG-CoA reductase inhibitors (statins) presented to our respiratory service with interstitial pneumonitis. Clinical course varied, with the condition responding to prednisolone treatment and cessation of statins in three patients, and progressing slowly despite this management in another three, while one patient died of associated cardiac disease. While a causative role cannot be confirmed, clinicians should be aware of the possible association. Two patients who presented with interstitial lung disease to our hospital’s respiratory service in 2000 prompted us to research a possible association between this disease and therapy with statins (hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors). A literature review revealed several isolated cases of pneumonitis in the setting of statin therapy.1-3 Thereafter, we prospectively recorded patients referred to our unit who had interstitial lung disease and were undergoing statin therapy, where no other clear cause of the pneumonitis was evident. All cases have been reported to the Adverse Drug Reactions Advisory Committee. Clinical recordsBetween January 2000 and December 2003, our service saw 58 new presentations of interstitial lung disease, including the two patients discussed above. Data on these patients were retrieved from an ambulatory care database of newly presenting patients kept prospectively by our service. Their diagnoses are shown in Box 1. Eight cases were thought to be drug-associated: five of these were potentially linked to statin therapy, two to nitrofurantoin and one to amiodarone. Another two patients were referred to our service during hospital admissions in other specialties not included in our database. Details of these patients were retained from consultation records. Clinical details of the seven patients taking statin therapy are shown in Box 2. Most patients presented with dyspnoea and non-specific examination findings consistent with interstitial lung disease, such as bilateral crepitations on chest auscultation. None had clubbing. Some patients had a background of smoking and mild chronic obstructive airways disease, while others had no specific risk factors. Statins potentially implicated were atorva-statin (10–40 mg daily), pravastatin (40 mg daily) and simvastatin (10–40 mg daily). No patients were taking other medications known to be implicated in interstitial lung disease. Pneumonitis was diagnosed based on clinical assessment, along with demonstration of interstitial infiltrates on high-resolution computed tomography and reduced transfer factor for carbon monoxide diffusion on lung function testing (Box 3). Management comprised prednisolone or other immune-modifying treatment and/or withdrawal of the statin. In three patients treated with both prednisolone and statin withdrawal, pneumonitis decreased (Patients 3, 5 and 7). In another three, the condition progressed slowly: one of these (Patient 1) did not take prednisolone, and another (Patient 2) initially continued statin therapy and experienced respiratory failure necessitating home oxygen therapy before it was ceased. He died 18 months later of respiratory failure. The third (Patient 4) experienced slow progression despite statin withdrawal and treatment with prednisolone and azathioprine. The remaining patient (Patient 6) was treated with prednisolone but continued statin therapy, and died from coexisting cardiac disease, probably exacerbated by interstitial lung disease. DiscussionStatins are the most often prescribed class of medication for treating hypercholesterolaemia. They act primarily by inhibiting HMG-CoA reductase, thereby inhibiting cholesterol biosynthesis and improving lipid profiles. However, recent research has revealed multiple immunomodulatory, vascular endothelial, antioxidant and other effects of statins.4 These so-called “pleiotrophic” effects have led to statins being studied in a host of unrelated clinical settings, including osteoporosis, multiple sclerosis and Alzheimer’s disease. While research is ongoing, it appears that statins have profound multisystem effects that extend well beyond lipid metabolism. Statins are, on the whole, well tolerated, with the most commonly reported adverse effects being gastrointestinal upset, headache, rash and a dose-dependent elevation in serum levels of liver transaminases. The best characterised rare, but potentially serious, adverse effects are myopathy and polyneuropathy. These adverse effects are probably dose-related and may occur more often in patients taking medications known to inhibit statin metabolism.5 There are also a few reports of lupus-like syndromes, polymyositis/dermatomyositis with lung involvement, and hypersensitivity pneumonitis associated with statin therapy.1-3,6-9 The timing of onset appears unpredictable, with many patients having been taking statin therapy for many months or years before symptoms develop. Clinical features varied in severity from mild dry cough and rash through to severe and progressive respiratory failure. Low-titre antinuclear antibody (ANA) positivity and a raised erythrocyte sedimentation rate were also described in some patients. There are only four reports of open lung biopsy in these cases, two showing hypersensitivity pneumonitis with granuloma formation, one showing diffuse alveolar damage and the other showing non-specific interstitial pneumonitis. Most — but not all — patients responded to drug cessation and therapy with prednisolone or other potent immunosuppressive agents.2,8,9 Our patients shared many features with these patients. However, we did not observe rash of a dermatomyositic, lupoid or urticarial type, or lupus or polymyositis-like syndromes in our patients. Instead, all presented with respiratory symptoms — shortness of breath with or without dry cough — generally of insidious onset. Two out of six patients tested were positive for ANA with no other clinical features of connective tissue disease. The findings on transbronchial biopsy, when performed, were non-specific. Radiological appearances varied between alveolitis and fibrosis, but none showed the characteristic subpleural basal honeycombing that is common in usual interstitial pneumonia. The occurrence of alveolar eosinophilia in two out of the four patients who underwent bronchoalveolar lavage, which has previously been described in drug-hypersensitivity pneumonitis, and the response in several patients to drug cessation and/or corticosteroid therapy also point to a potential drug-induced pneumonitis. One previous case of pneumonitis has been reported in the setting of statin therapy, which was confirmed by open lung biopsy, and where the findings closely resembled those in amphiphilic drug toxicity, such as that reported with amiodarone. The authors hypothesised that a toxic mechanism, possibly mediated by statin effects on lipid metabolism, led to the observed intralysosomal lamellar inclusions in pneumocytes and interstitial cells.9 Thus, while not fully characterised, there is a putative mechanism through which statins may cause interstitial pneumonitis. Detecting rare side effects of commonly prescribed medications has always been a challenging task for the clinician. It is even more difficult when symptoms present insidiously, months or years after medication has been commenced, and the disease process has multiple potential aetiologies, which are not fully characterised. Similarly, interstitial lung disease remains a challenging diagnostic area even for experts in the field. Failure to recognise an under-lying cause of the pneumonitis often leads to the diagnosis of usual interstitial pneumonia being accepted. With continuation of the causative agent, the expected clinical pattern is progressive deterioration leading to respiratory failure and death, which also closely resembles the expected course of usual interstitial pneumonia. We hope that our description of our patients and review of the possible role of statins in interstitial lung disease will raise awareness of the potential association between statin therapy and this uncommon and often fatal condition. The effects of withdrawal of statin therapy on development of interstitial lung disease in patients taking this class of medication require further study. 1 New presentations of interstitial lung disease, 2000–2003 Diagnosis Number of patients Sarcoidosis 26 Usual interstitial pneumonitis 10 Non-specific interstitial pneumonitis 9 Drug-associated 8 Hypersensitivity pneumonitis 2 Asbestosis 2 Connective tissue disease-associated 1 2 Clinical details of seven patients with interstitial lung disease receiving statin (HMG-CoA reductase inhibitor) therapy Patient Sex, age Presentation Comorbidities Medications at presentation Investigations* Treatment Outcome 1 F, 78 Progressive dyspnoea, dry cough Hypertension, type 2 diabetes, hyperlipidaemia, non-smoker Atorvastatin (10 mg, 1 year), fosinopril, sertraline HRCT: extensive bilateral fibrosis TLCO: 46% No lavage or biopsy ANA-positive (1/40) Colchicine, atorvastatin withdrawn Slow progression: lung function deteriorated but clinical condition stable, little dyspnoea on 3-year follow-up 2 M, 78 Progressive dyspnoea (3 weeks), no cough or fever Chronic obstructive airways disease, IHD, atrial fibrillation, stroke, hyperlipidaemia, depression, ex-smoker Pravastatin (40 mg, 10 years), aspirin, frusemide, isosorbide mononitrate, perindopril, sertraline HRCT: extensive mid and upper zone emphysema, coarse bilateral basal fibrosis TLCO: 14%, mildly obstructed flow volume loop No lavage No biopsy (as poor respiratory reserve) ANA-positive (1/640) Prednisolone (50 mg), pravastatin withdrawn Progression, discharged with home oxygen, died 18 months later (respiratory failure) 3 F, 74 Cough and fever (3 days) (consistent with pneumonia) on background of worsening exertional dyspnoea Chronic obstructive airways disease, IHD, congestive cardiac failure, hyperlipidaemia, ex-smoker Simvastatin (10 mg for 2 years, then 20 mg for 1 year), aspirin, thyroxine, frusemide, diltiazem, nicorandil, long-acting nitrates HRCT: diffuse ground glass left upper lobe and bilateral lower zone No TLCO Lavage: 78% macrophages, 12% neutrophils, 9% lymphocytes Biopsy: non-specific interstitial pneumonitis No ANA test Prednisolone (50 mg), simvastatin withdrawn Gradual reduction in infiltrative change on imaging, lung function stable at 9-month follow-up 4 M, 83 Progressive dyspnoea (6 months) IHD, CABG and aortic valve replacement, atrial flutter, hyperlipidaemia, ex-smoker Pravastatin (40 mg, 1 year), aspirin, digoxin, frusemide, ramipril, ranitidine HRCT: scattered bilateral fibrosis TLCO: 33% Lavage: 68% neutrophils, 26% macrophages, 3% lymphocytes, 1% eosinophils Biopsy: non-diagnostic ANA-negative Prednisolone (40 mg), azathioprine, pravastatin withdrawn Slow progression 5 F, 67 Chronic mild dyspnoea (9 months), dry cough (6 months) Hyperlipidaemia, atypical chest pain, non-smoker Simvastatin (40 mg, 5 years), aspirin HRCT: patchy bilateral upper and lower zone ground glass TLCO: 22% No lavage or biopsy Negative for ANA, ANCA, normal ACE Prednisolone (25 mg, reduced to 10 mg after 3 months), simvastatin withdrawn Marked improvement (TLCO: 51% after 1 month, then 65% after 1 year) 6 M, 68 Progressive dyspnoea and hypoxia IHD, CABG and aortic valve replacement (10 years before), gastro-oesophageal reflux disease, hyperlipidaemia, ex-smoker Simvastatin (10 mg, 2 years), atenolol, candesartan, esomeprazole, frusemide, warfarin HRCT: bilateral fibrosis TLCO: 46%, mild restrictive defectLavage: 19% eosinophils, 19% neutrophils Biopsy: mixed inflammatory and fibrotic change ANA-negative Prednisolone (37.5 mg), azathioprine, simvastatin continued Progressive cardiac failure, died 9 months after presentation 7 M, 64 Progressive dyspnoea, dry cough IHD, CABG and aortic valve replacement (11 years before), peptic ulcer disease, hyperlipidaemia, ex-smoker Atorvastatin (20 mg for 3 years, then 40 mg for 2 years), fosinopril HRCT: bilateral ground glass infiltrates, fibrosis, some traction bronchiectasis TLCO: 44%, mildly obstructed flow volume loop Lavage: 38% eosinophils, 15% lymphocytes, 5% neutrophils Biopsy: thickened alveolar walls with interstitial fibrosis, minimal inflammation ANA-negative Prednisolone (initially 50 mg, then 10 mg maintenance), atorvastatin withdrawn Slight initial improvement (TLCO: 52% at 2-month follow-up), then stable disease HMG-CoA = hydroxymethylglutaryl-coenzyme A. IHD = ischaemic heart disease. CABG = coronary artery bypass graft surgery. HRCT = high-resolution computed tomography. TLCO = transfer factor for carbon monoxide diffusion. ANA = antinuclear antibody. ANCA = antineutrophil cytoplasmic antibody. ACE = angiotensin-converting enzyme. * All patients underwent HRCT and TLCO measurement, while most underwent bronchoscopy with broncho-alveolar lavage and transbronchial biopsy. 3 Investigations in two patients with interstitial lung disease High-resolution computed tomography in Patient 7 at presentation showed bilateral interstitial infiltrates with an area of honeycombing. Transbronchial biopsy specimen from Patient 7 showed a lymphocytic interstitial infiltrate and intra-alveolar macrophages (haematoxylin and eosin stain; original magnification, × 100). Transbronchial biopsy specimen from Patient 6 showed thickened alveolar walls with a low grade inflammatory infiltrate (haematoxylin and eosin stain; original magnification, × 400).

Tim Walker MB BS(Hons) · Joe McCaffery MB BS · Chris Steinfort FRACP

To the Editor: In a recent observational study, Krum et al concluded that the treatment of heart failure after myocardial infarction in Australian teaching hospitals is suboptimal because angiotensin-converting enzyme (ACE) inhibitors, β-blockers and aldosterone antagonists are underutilised.1 We believe that another explanation, mentioned by the study’s authors, is worth exploring further — for valid clinical reasons, it was not appropriate for certain patients to start or continue taking some of these medications. An understanding of the enrolment criteria of relevant clinical trials is informative. The large, long-term ACE inhibitor trials quoted by Krum et al — SAVE,2 TRACE and AIRE4 — between them screened 34 037 patients with myocardial infarction and left ventricular dysfunction. Only 5986 patients (18%) met the inclusion/exclusion criteria to be enrolled in one of the trials. Unfortunately, the CAPRICORN5 (β-blocker) and EPHESUS (aldosterone antagonist) trials did not publish the number of patients screened versus the number randomised, but a glance at their exclusion criteria explains why, for some patients, it may not have been appropriate to start these medications during their hospital stay. Some of the exclusion criteria for CAPRICORN were: unstable angina, ongoing therapy with antiarrhythmics (except amiodarone), secondary or tertiary heart block or sick sinus syndrome unless paced, uncontrolled hypertension (> 160/95 mmHg), bradycardia (heart rate, < 60 beats/min), hypotension (systolic blood pressure, < 80 mmHg), requirement for intravenous diuretics or inotropes, chronic obstructive pulmonary disease with ongoing inhaled β2-agonist or steroid therapy, and unstable insulin-dependent diabetes. Is there any harm in prescribing outside the inclusion/exclusion criteria for clinical trials? A population-based, time-series analysis linking prescription-claims data and hospital admission records of 1.3 million adults in Canada6 showed that hyperkalaemia-related deaths in hospital doubled after the RALES trial (spironolactone) was published in 1999. There was no reduction in re-hospitalisation for heart failure or all-cause mortality. The authors speculated that part of the reason for this was prescription of spironolactone to patients who would have been excluded from the RALES trial. While we would not advocate prescribing strictly within the boundaries of the inclusion/exclusion criteria of clinical trials, it is important to understand these criteria, so that prescribing in “real world” patients is done with care. We are reassured that Krum et al’s study suggests there is discretion in the prescribing of drug therapy. Presumably, during ongoing medical assessment, it will be appropriate for some patients to commence some of these medications (potential benefit outweighs potential harm), while others may need to have their medications reviewed because of adverse events.

Lauren J Bailey · Vasi Naganathan

In reply: We thank Bailey and Naganathan for their thoughtful viewpoint regarding prescribing according to clinical trial criteria. We agree that prescribing in the real world often involves complex decision making, taking into account age, comorbidities, concomitant medications and other factors, whereby guidance regarding individual patients cannot readily be extracted from clinical trial literature. This may certainly contribute to underutilisation of evidence-based drug treatment.1 Nevertheless, several analyses support the contention that physicians who more closely adhere to evidence-based guidelines (which in turn are derived from randomised clinical trials) produce better outcomes for their patients.2,3 Therefore, we would still advocate prescribing as closely as possible to guideline recommendations, while acknowledging that these recommendations may not always be readily applicable to every patient.

Henry Krum

A recent editorial discussed the issue of interactions between doctors and pharmaceutical companies (MJA 2006; 185: 299-300). The reactions ranged from agreement to offence. To the Editor: I would like to congratulate Tattersall and Kerridge on their recent editorial covering the issue of industry influence in medical education.1 Like the authors, I was dismayed on seeing the Australian Medical Association statement to the press regarding the recently revised Australian Competition and Consumer Commission guidelines for disclosure of industry support. Industry supports medical education because it pays, and we would be well advised to remain aware of this basic fact. It amazes me that anyone could subscribe to the view that doctors need industry freebies to remain informed of new therapeutic options in this age of electronic media. We are constantly inundated with information — the issue is to choose reliable, unbiased data. As a rule, industry-sponsored sources of information should be regarded as potentially biased and therefore suspect. In my view, direct industry sponsorship of continuing medical education activities is inappropriate and should not just be regulated, but abolished altogether.

Hans Peter Dietz

To the Editor: Tattersall and Kerridge make the argument that any interaction between industry and clinicians must, of necessity, compromise the decision as to the appropriateness of the particular treatment prescribed.1 The more common situation is that interactions do exist, and this is covered by a process of disclosure of, for example, honoraria or shareholdings. However, this situation is also inadequate, in that the extent of the potential for influence is not disclosed (eg, the size of the honoraria, or the volume of shares held in the company). This is also relevant when it comes to evaluating potential conflicts of interest in medical publications. As the authors note, the health care industry is complex, and interactions do occur between clinicians and industry. In this situation, full and frank disclosure — rather than the mere indication that a relationship exists — is far more appropriate.

Charles M Fisher

To the Editor: I am critical of the article by Tattersall and Kerridge.1 In my opinion, the article comprises a series of pompous announcements from an ivory tower, which hint without actually saying that doctors who attend educational symposia organised by pharmaceutical companies, and who subsequently order the product, are acting improperly. As I see them, the facts are quite otherwise. Medical practitioners have an obligation to do their best for their patients by giving them the most appropriate treatment available, and to keep up to date with their profession. Both these objectives can be achieved by educational symposia organised by the research-based pharmaceutical companies, which introduce new concepts in medicine as well as new products. Research-based pharmaceutical companies play a major role in the development of modern therapeutics through the introduction of new drugs. The development and manufacture in commercial quantities of life-saving compounds in the future, such as, for instance, the new biological agents and the new anticancer drugs that we need so urgently, would not be possible but for the pharmaceutical industry. One cannot imagine this important work being done by other agencies, such as the universities or the government. The Australian Government, in fact, sold its own pharmaceutical company (Commonwealth Serum Laboratories, now CSL Ltd) some years ago. Doctors attend educational symposia run by pharmaceutical companies so as to obtain information that will be useful for their patients, not because they can get a few free drinks and a dinner. The suggestion to this effect is offensive. I note that one of the authors is Director of the Centre for Values, Ethics and the Law in Medicine. I would value his opinion on doctors who advertise directly to the public, such as the eye surgeons who advertise repeatedly on talkback radio, and the promoters of alarming cardiovascular articles that predict catastrophes if one does not apply to the sponsors of the program. To criticise doctors for prescribing products promoted at educational symposia while allowing these other examples to flourish without criticism is, to my mind, hypocritical.

Ian S Collins