Information science

John D Paull Anaesthestist, Launceston General Hospital, PO Box 200, Exeter, TAS 7275. jdpaullATintas.net.au To the Editor: A black day for the MJA, I thought, on seeing the title of the article by Crotty, “More students and less patients: the squeeze on medical teaching resources”.1 I hesitate, but only briefly, to wave the Fowler brothers’ classic work at you. The revised 3rd edition, by the brothers’ proxy, R W Burchfield, notes that “Regrettable, but prevalent among some standard as well as many non-standard speakers, is the use of less with an unprotected plural noun”.2 He goes on to give examples, among which your article title could well appear, and concludes, “The incorrect use is very widespread and seems likely to be ineradicable, however regrettable that may be”. The author of the Editorial is not discussing an amorphous pile of patients. He is writing about a countable number of people, of which, regrettably, fewer are willing to participate in the education of those they expect to look after them in later life.

John D Paull

Helen Randall Senior Assistant Editor The Medical Journal of Australia In reply: We plead guilty, but knowingly so. When this article was being proofread, there was much discussion about this “regrettable” use of less, but in this instance a catchy title was preferred to following Burchfield’s prescription.1 We take comfort from The Cambridge Australian English style guide, which notes that “using fewer rather than less is . . . a stylistic matter rather than one of correct grammar”.2

Helen Randall

Biji T Kurien Senior Research Scientist, Arthritis and Immunology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA. biji-kurienATomrf.ouhsc.edu To the Editor: The smiley icon “ :) ” has been widely used to convey amusement, mirth or jollity in casual email communications. However, there seems to be a lack of simple icons for use by health professionals as email shorthand in different scenarios. I therefore submit the symbols shown in the Box for use by doctors and others involved in health care. All are derived by typing a combination of characters of various font sizes and other features (colour, superscript, subscript, italics, and bold), and all are in Times New Roman font except when stated otherwise. Note that it would be highly inadvisable to use a spell check feature in conjunction with these icons.1 Email icons (“emoticons”) for the health profession Symbol Meaning Bearded doctor with stethoscope around neck Curly-haired (red-haired) doctor/scientist with big moustache Nurse (face) [Characters: { in red, ital, f12; space; colon in black, bold, ital, Sp, f12; space; ” in red, bold, f8;) in red, bold, ital, f8.] Nurse (whole body) [Characters: { in red, ital, f12; space; colon in black, bold, ital, Sp, f12; space; ” in red, bold, f8;) in red, bold, ital, f8; = in yellow, f8; { in red bold f12; 3 in red f9; two colons in red, bold, f10; \ in red, ital, f8; = in green, f28; \ in green, bold, Sb, f8; = in dark red, Sb, f16; / in red, bold, Sb, f8.] Bearded doctor/scientist awestruck on having article accepted in MJA Bearded doctor/scientist awestruck on learning of receipt of Nobel Prize Mouth-to-mouth resuscitation [Characters for lips: “ in Sb, f11.] Identical twins Whole body x-ray [Characters: 8 in f9; space; O in f10; hyphen in f12; { in f12; | in f12; | in f11; | in f10; | in f8; () in f8; five colons in f12; full stop in f12; / in Sp, f12; / in f12. All in bold; convert font to white and highlight characters in black.] Acromegaly and gigantism (same as for twins, but use Courier New) Smoking [Characters for cigarette: [ and ] in bold, ital, f10; ~ in f24.] Obesity Healthy laboratory mice (Courier font) Dead laboratory mice Concerned doctors/scientists discussing experimental failure ital = italics. Sp = superscript. Sb = subscript. f = font.

Biji T Kurien

Quotes from MJA contributors in 2005 It is unusual to find mention of beavers’ living arrangements in a physiology journal but, according to Swain, there are similarities between beaver pond levels and blood glucose levels. A beaver must maintain a constant water level in its pond for the proper functioning of its lodge, just as we must maintain our blood glucose levels within a defined range to ensure, among other things, brain function.1 The beaver controls the water bed by changing outflow over the dam and inflow from the stream beds, just as insulin controls glucose leaving the blood and entering tissues, and, among other things, glucagon affects glucose release from the liver. Analogy and metaphor may be figurative rather than scientific forms of communication but they can nevertheless help us, our students and our patients, to integrate new information by drawing on similarities with prior knowledge. Swain’s engaging beaver pond analogy of blood glucose control is a quiet and gentle one. As you will see in the following selections, this year’s MJA contributors have used a variety of analogies and metaphors (sometimes unwittingly) to try to get their point across. As well as creating a bridge to understanding, these devices inject unexpected and welcome humour into the generally dignified world of medical publishing. You asked for it . . .“Attached is my assessment of the manuscript. It’s a bit like panning for gold — you have to go through a lot of sand to find the gold.” “This is a weak study, well executed. Unfortunately, a great coat of paint does not make up for a deficient underlying structure.” “This is a naïve exercise in stamp collecting without any attempt to ascertain the origin and value of the stamps.” The medicalisation of peer review“The whole paragraph is a case of malignant pharmacological speculation syndrome.” Picture this . . .“The commercialisation of medical patents is but a small tile in the mosaic of Australian innovation . . .” “Epidemiological data provide a window through which theories of causality may be viewed.” “Seeding grants don’t sprout, pilots don’t fly.” Accidentally“ . . . patients [are] falling through the cracks in the Northern Territory.” “We give . . . the incidence of this complication according to medical litterature.” “This is a simply aweful paper.” UnderstoodNot infrequently, the MJA receives manuscripts that challenge the existing scientific dogma or confront our social sensibilities. In such circumstances, it is not unusual for the editors to make certain of the rigour of a manuscript with an additional cycle of peer review. As expressed by one expert reviewer . . . “I will state the obvious. You’ve got a hot potato on your hands. The idea of piercing its skin several times with the fork of extended peer-review will ensure that the thing is less likely to explode when placed in the microwave of public scrutiny.”

Ann T Gregory MB BS, GradCertPopHealth

We can put issues on the agenda, but perhaps not achieve reform For Thomas Wakley, the founder of The Lancet, an important function of his journal was to reform medicine, which he saw as full of incompetence, quackery, corruption, and nepotism. He wanted to reform as well as inform. But can journals reform? Can they lead? Are medical journals important for leadership in medicine? Or is this grandiosity on the part of editors? Aren’t journals there to follow, reflect, and comment rather than to lead? Most editors think that journals can lead Drummond Rennie leading us to the promised land of open peer review. Some years ago, I asked various editors if they could provide me with examples of where journals had shown leadership. All the editors — except one — came up with examples. JAMA had led on promoting a tobacco-free society, preventing nuclear war, drawing attention to the plight of the uninsured in America, promoting the control of violence, and encouraging research into peer review. The New England Journal of Medicine had led by describing and deploring the industrialisation of medicine, encouraging health reform, and drawing attention to the importance of conflict of interest. The BMJ had led on fighting tobacco and improving the standard of statistics in medical journals. The Lancet had led with reducing the risk of nuclear war and encouraging the internationalisation of medicine. The Medical Journal of Australia had led with campaigns on smoking, promoting reform of the World Medical Association, AIDS awareness, Aboriginal health, and traffic safety. The Canadian Medical Association Journal had shown leadership by publishing a highly influential series of articles on critical appraisal of scientific papers. One editor disagreed violentlyThe most interesting response came from Stephen Lock, my mentor and predecessor as Editor of the BMJ. He wrote: Stephen Lock, Editor of the BMJ, 1976–1991. There are no examples of where medical journals have led. Nor is it the journal’s role — which is to provide a forum for debate and to publish checked data. In fact, despite what editors say, I doubt whether any publication has done much leading — for instance, the Socialist landslide in [the British general election in] 1945 was probably due to the WEA [Worker’s Education Association] influence in the forces during the war rather than the Daily Mirror, while Ernest Hart’s [great editor of the BMJ in the 19th century, see below] successes owed more to the BMA parliamentary Bills Committee, and his numerous social contacts, than to the BMJ — and even Robbie Fox’s [great Lancet editor of the 20th century] often cited role in the introduction of the NHS was secondary to Moran’s [Lord Moran, Churchill’s doctor] leadership at the RCP [Royal College of Physicians] and in the Lord’s [House of Lords] debate. Think of the contemporary issues — AIDS, health reform in the USA, and the current NHS debate — and you’ll realise how little influence the journals are having, can have, or should have. What does follow-up tell us?One advantage of having asked editors for examples of leadership several years ago is that it is possible to take a longer term look at whether they were examples of leadership. I deliberately did not define leadership for those editors, but my working definition of leadership by a journal is that it achieves a change that would not otherwise have happened. Ironically, the best two examples of leadership from the list involve Stephen himself. Stephen, together with Drummond Rennie from JAMA and John Bailar, statistical adviser to The New England Journal of Medicine, played a central part in prompting the study of peer review. This process, which is fundamental to all of science not only in deciding which papers to publish but also in the giving of research grants, was largely unstudied until these three urged that it should be. There have now been five international congresses on peer review, and a body of research has been created. This has happened almost entirely within biomedicine, but its results are beginning to percolate into other areas of science. I cannot see that this would have happened without the leadership of Lock, Rennie, Bailar, and their journals. Similarly, the work to improve the quality of statistical reporting was led by Lock and the BMJ, together with other journals. The Lancet published an important series on statistics by Austen Bradford Hill, the BMJ published a series called “Statistics at Square One” (which later as a book sold more than 100 000 copies), and Lock and other editors involved statisticians in the peer review process. Many studies showed that the standard of statistics in medical journals was woeful — it is now better (although still far from perfect). This has an importance way beyond journals themselves. Bad statistics means false conclusions. Doctors and patients were thus being misled. Ernest Hart, Editor of the BMJ, 1867–1898, made use of his extensive social contacts to promote the issue of child protection. Can history furnish examples of journals leading? History can help us with trying to answer the question on whether journals can lead, and I want to examine a campaign of Ernest Hart, Editor of the BMJ from 1867 to 1898.1 Hart was a major public figure in a way that no BMJ editor has been before or since. He was highly controversial, believing that, “An editor needs, and must have, enemies; he can’t do without them. Woe be unto the journalist of whom all men say good things.” Hart tried to lead on many issues, but his most prominent campaign was against “baby farming” — giving infants (often bastards) to carers for money, knowing that the carers neglected and even murdered them. In Hart’s first year as editor, the journal carried a story on the inquest of four children who had all died under the care of the same “nurse”. The journal also published several leading articles on the subject. In 1868, Hart advertised in a newspaper as a father-to-be, offering money for adoption. He received 333 replies and identified Mrs X, who had seven malnourished infants living in her care in dreadful squalor. In the previous 2 years she had registered seven deaths of infants younger than 1 year. Articles in the journal led to questions in parliament. More cases were reported in 1870, and Hart formed with others the Infant Life Protection Society. He was also appointed chairman of the BMA’s Parliamentary Bills Committee in 1872. A bill was drafted and enacted in 1872. It proved to be a weak bill, and a much stronger bill was passed in 1877. The problem was not solved. In 1896, Mrs Dyer of Reading was executed for strangling her charges and throwing them into the Thames. The BMJ published a six-part series on “baby farming and its evils”. The child protection movement grew enormously at this time, and the National Society for the Prevention of Cruelty to Children was founded in 1889. Baby farming: infants (often bastards) were given to ”carers“ who neglected and even murdered them. Peter Bartrip in his history of the BMJ concludes: “The Journal did not singlehandedly cause the Infant Life Protection Act to be passed, but it undoubtedly exerted a powerful influence.”1 We can probably never separate out the role of the journal from broader influences, but journals seem to be good at putting issues onto the professional and public agenda. Evidence from media studies Hugh Clegg, Editor of the BMJ from 1947 to 1965 believed that: “A subject that needs reform should be kept before the public until it demands reform.” The question of whether journals lead or follow is similar to the question of whether the mass media lead or follow, and some in the new discipline of “media studies” have addressed exactly this question. The story of Watergate is often cited as a classic case of the media leading people on what to think. It was in June 1972 that five men broke into the campaign headquarters of the Democratic Party. The incident received extensive publicity from The Washington Post, but initially there was little public interest. Yet the press kept on, and by April 1973, 90% of the American population knew the word “Watergate”. In 1974, President Nixon was forced from office. Did the media depose the president? Clearly they did not do so alone, but they played a crucial role. Maxwell McCombs and Donald Shaw have developed the theory of “agenda setting”.2,3 This means that “We judge as important what the media judge as important.” Bernard Cohen, a political scientist from the University of Wisconsin, puts it this way: “The press may not be successful much of the time in telling people what to think, but it is stunningly successful in telling its readers what to think about.” This chimes with a saying of Hugh Clegg, Editor of the BMJ from 1947 to 1965: “A subject that needs reform should be kept before the public until it demands reform.” McCombs and Shaw analysed the 1968 presidential race between Richard Nixon and Hubert Humphrey to see if they could work out whether the media were leading or reflecting public opinion.2 They looked at nine print and broadcast media used by Chapel Hill residents and ranked stories by position and length. They considered five major issues: foreign policy, law and order, fiscal policy, public welfare, and civil rights. They then looked at how undecided voters ranked these issues, and found that they ranked them exactly the same as the media. The 1968 US Presidential election: Richard Nixon v Hubert Humphrey. But which came first: the media agenda or the voters’ agenda? There have been subsequent studies, and the general finding is that the media interest comes first.3 Later work suggests that agenda setting works best when people are interested in a subject but uncertain about what to think.3 For example, I own a dog and hence am interested in animal experimentation, but I am very uncertain about what the risks and benefits might be. Nobody, as far as I know, has conducted any studies like this with medical journals, but it might be that the findings can be generalised from the mass media to general medical journals. If so, journals can put issues on the agenda and do have some influence on how people think about them — a limited form of leadership. Evidence from campaigningJournals do sometimes consciously set out to lead, to make change happen. At the BMJ I was involved with campaigns to encourage explicit rather than implicit rationing of health care, promote an ethical code that could be used by everybody in health care, and revitalise academic medicine. All produced many fine words but none led to change. This may not be because journals cannot produce change, but because we did not conduct the programs well. The Institute for Healthcare Improvement in the US is running a campaign to reduce unnecessary deaths in hospital, many the result of medical error. The campaign is called the “100 000 lives Campaign”, and its slogan is “Some is not a number. Soon is not a time.” (Box 1). Before launching the campaign, the institute studied political campaigns, and identified six essential features: platform, measurement, communication, field, funds, and values. The start is a clear, scientifically sound, highly developed platform or message. Measurement is essential to know if the campaign is succeeding, and communication must be constant, two-way, and involve many different media. Impact will depend on signing up many people and institutions (creating a field force), and the 100 000 lives Campaign has signed up some 2000 hospitals. Funds are essential, but so are explicit values; the values of the 100 000 lives Campaign include “all in” but “staying on message”. I do not know of a medical journal that has campaigned so carefully, and perhaps a more important question than “Can journals lead?” is “What must they do to make change happen?” ConclusionMy cautious conclusion is that journals can lead, in limited ways (Box 2). They might follow the example of the Institute for Healthcare Improvement and more effectively campaign, but their main contribution may be less to try and achieve precise reform and more to put issues firmly on the agenda. In my years at the BMJ, we tried to lead by promoting evidence-based medicine, encouraging doctors and patients to work in partnership, reminding the rich world constantly of its obligations to the poor world, battling against research misconduct, hastening the flow of information to the developing world, securing the independence of medicine from the pharmaceutical industry, and promoting patient safety. History will judge if we have had any success. 1 The 100 000 lives Campaign A: The campaign poster B: Locations of hospitals in the “100 000 lives Campaign”. 2 A hypothesis on factors that might influence the ability of medical journals to lead One hypothesis, no more, is that journals will be most successful in leading when it is on a topic that is of direct concern to them and where they work together. The successful example shown is the registering of clinical trials. In contrast, the work of the rationing agenda group was not directly concerned with journals and involved only one journal: it failed.

Richard Smith MB ChB, MSc, FRCP

Anyone who regularly writes or reviews for the MJA will know that, halfway through this year, we launched ourselves into the world of electronic submission and peer review. If the editors were catapulted kicking and screaming into the orbit of our new system, we can only imagine how our contributors feel. However, as we all adjust to the thin atmosphere and weightless state up here, we have to admit that it is a fine thing to have all the manuscripts “virtually” at our fingertips. Like astronauts viewing the world from afar, we can see the overall shape of things and can zoom down on the detail at the stroke of a key. Hopefully, this small step for the editors will be a giant step for the speed and efficiency of the MJA. Perhaps because of this innovation, there were slightly fewer submissions for this year’s Christmas Competition than in previous years. However, the quality was very high (undoubtedly both tenacity and a sense of humour are assets in the new submission process). Encouragingly, the contributors came from a range of medical specialties — surgeons, psychiatrists, anaesthetists, physicians, emergency physicians, a corgi and even a geriatrician among them — proving that you can teach both the old and a dog new tricks. For judging this year, the entries were posted on the outside south-western wall of “The pod” (see picture), an oval corrugated structure which functions as the MJA’s boardroom and space probe. Such public placement, under the joint scrutiny of our communications manager and librarian, precluded the usual tricks such as vote tampering, multiple voting and ghost voting. As usual, every entry received at least one nomination, reflecting the eclectic tastes and diverse interests of the MJA staff. In the image category, there was much support for the symbolism of Velakoulis et al’s iconic MRI “findings”, and the sheer freakishness of James and colleagues’ account of an elderly couple’s matching flank haematomas. However, the prize (two bottles of premium Australian wine) goes to Riley and Sallie, for “Finding inner peace”, an important colonoscopic image that should be sent without delay to all world leaders. Entries in the written category, which also carries a prize of two bottles of wine, were, on the whole, disturbing. Among the offerings were studies on the health benefits of ambulance diversion (Fatovich) and the impact of the weather on emergency department attendances (Ou et al), and dissertations on the disease states of popular characters in children’s fiction (McCallum and Smith) and the contents of Nair’s inbox. Ultimately, we were most moved by Cobcroft and Pembroke-Corgi’s earthy account of the medicinal and other uses of dog poo in history, not the least because of the co-author’s excellent nose for a good story. We sincerely thank those who forged boldly into the inner worlds of their imaginations, then into the unknown territory of online submission to enter the competition. As for the rest of you, we like to think that there are other images, ideas, observations and stories hovering out there in cyberspace or languishing in a hitherto undiscovered folder in our new system. Log on and send them in for next Christmas. To infinity and beyond!

Ruth Armstrong BMed

The doctor in literature: satisfaction or resentment? Solomon Posen. Oxford: Radcliffe Publishing, 2005 (ix + 298 pp). ISBN 1 85775 609 6. The Doctor in Literature is physician–author Solomon Posen’s take on how the doctor, as received by patient and society, is represented in Western literature. It is the first of four volumes in the same vein, the others examining the doctor’s personal life, medical career choices, and selected issues such as physician–nurse interactions, abortion, male and female doctors, and sexual fantasies and encounters. Described as a reference guide highlighting 1500 passages from over 600 texts (virtually all available in English), this volume is compiled from Posen’s lifetime of reading with an eye toward literary portraits of physicians. He has identified eleven facets of the physician–patient–society encounter and organised the book around these, with chapters addressing, for example, physician fees, the doctor’s time, bedside manner, emotional distance between doctor and patient, and litigation, as played out by medical characters in literature across the ages. This is not an anthology, for excerpts from literature frequently run but a sentence or two and serve Posen’s points rather than those of cited texts’ authors. Nor is it an annotated bibliography of literature depicting doctors, or even the index that the author suggests medical scholars need, for references are embedded in Posen’s assertions and one must go to endnotes for full information. While documenting “astonishing” constancy in physician–patient relations over two and a half millennia (eg, patients like doctors who are willing to help, society resents doctors’ fees), Posen’s conclusions may be over-engineered. Having excluded texts that employ allegory or symbolism or that portray doctors who traffic in metaphor (psychiatrists, he says) or dark arts or who misbehave as criminals or clowns, he chiefly cites works in which doctors exhibit what he terms “recognizable medical behavior.” His readings of fictional doctors who meet his criteria are straightforward but sometimes sufficiently colored by his own lenses as to miss authors’ satire or social criticism. As a result, Posen’s composite view of medical practice is inherently conservative, and his typical doctor — even more than society’s — is white, male, paternalistic and active rather than contemplative, irreligious, devoted more to profession than family, socially powerful, and resentful of political or institutional control. More historically and culturally nuanced aspects and ethical tensions of the doctor–patient–society triad tend to go unaddressed here, even though many of the cited literary works do take them on. Marcia D ChildressDirector, Program of Humanities in Medicine University of Virginia School of Medicine Charlottesville, VA, USA

Marcia D Childress

Reporting medical news entails a special responsibility The fundamental question in medical journalism is how best to identify, process and report legitimate medical information to the general public . . . The process . . . is far more haphazard and idiosyncratic than outsiders might ever imagine.1 — Timothy Johnson: Chief Medical Correspondent, American Broadcasting Corporation Media coverage provides an essential link between the providers and users of health care. For health care industries, favourable reports on new drugs, procedures and treatments may translate into improved revenue streams from increased sales and rising share values. For medical researchers, media reporting of research findings enhances citation rates and boosts the public profile of their research institutions.2 For an increasingly educated and attuned public, access to developments in medicine affects individual health decisions. Integral to this whole process are journalists, as they largely determine what information is reported. Equally crucial is the responsibility that their reportage be accurate, adequately researched and conveyed in a clear and unambiguous manner. Indeed, the 2001 Australian Press Council guidelines on reporting medical matters stress the need for a conservative and careful approach to this task.3 The Association of Health Care Journalists (AHCJ) in the United States is even more explicit. Its principles for health reporting note that “ journalists have a special responsibility in covering health and medical news”.4 This includes the “professional standards of truth, accuracy and context in every report”, free from any personal, financial or other conflicts of interest. The AHCJ principles provide pragmatic advice on such matters as being vigilant in selecting sources; understanding the medical research process; avoiding vague and sensational language; explaining research outcomes clearly; and outlining the risks and benefits of any treatment.4 With such an abundance of good advice, a high quality of media reporting of health and medical matters would be expected, but this confidence may well be misplaced. In this issue of the Journal (page 190), Smith and colleagues report on the quality of medical news stories published in three high profile Australian newspapers — The Age (Melbourne), The Australian and The Sydney Morning Herald — and two online outlets — “ABC news online” and “ninemsn”.5 Assessments of individual news stories are posted on the media doctor website (http://www.mediadoctor.org.au) and scored using a three-star rating system based on satisfying 10 criteria, such as evidence of disease-mongering, too much reliance on press releases, appropriate reporting of benefits, harms and costs, and the independence of information sources. Twenty of the 104 articles surveyed scored no stars (overall score < 25% of criteria satisfactory), and 11 scored three stars (score > 75% of criteria satisfactory). Overall, both online and print media outlets scored poorly, with an average score of 56.1% for the print media, and 40.1 % for the online media. Criteria that scored poorly across both print and electronic media news reports included quantification of benefits, and harms and costs of treatment.5 Similar findings have been reported for media outlets in North America.6,7 Given that most people know little about the workings of the media, we invited media insiders — three high level journalists — to give their comments on the findings of Smith et al. Herman and Morgan of the Australian Press Council (page 195) welcomed the findings, but cautioned against expectations that initiatives such as media doctor will lead to any spectacular improvement in the quality of health or medical reporting. They suggest that the somewhat better performance of print compared with electronic media may reflect the promulgation in the print media of the Press Council’s 2001 reporting guidelines. Indeed, such guidelines are conspicuously absent in the current Commercial Television Industry Code of Practice.8 Swan (page 194) and Sweet (page 194), both veteran health commentators, stress the need for better cooperation between researchers and journalists, and Sweet is sceptical that exercises such as media doctor will enhance the quality of medical or health reporting. There is an impression that, in the time-poor and chaotic world of journalism, quality is sometimes overwhelmed by the urgent need for copy, and that outside scrutiny of quality is not particularly welcomed or productive.9 There is, however, a more pertinent issue. At the core of the media, as in medicine, is the principle of self-regulation. In such circumstances, it is the attitudes of journalists, their editors and program executives that drive standards, and in this quest for medical reportage, Schwartz and Woloshin have recently advanced a number of simple principles:10 Don’t report preliminary findings: This recommendation applies particularly to Phase 1 trials, studies using animals, and preliminary reports presented at scientific meetings. More than a quarter of meeting presentations are never published.11 Communicate the absolute magnitude of differences: Convey not only the relative risks, but, more importantly, what these mean in absolute terms. Include study limitations: These should be highlighted along with potential conflicts of interest and funding sources. To make health and medical reports as accurate and accessible as possible, there should be greater cooperation between researchers and reporters. To achieve this objective, the “single overriding communication objectives” (SOCOs) of the press release should be pursued. This strategy, developed by the US Centers for Disease Control and Prevention,12 ensures visibility of the main points that the researcher or health expert believes are important. Press releases should also include relevant caveats on the limitations of the research, industry funding and other financial matters. Essentially, the public places a great deal of trust in the health care system and in medical news, particularly if it is based on peer-reviewed data published by medical experts. It would be a pity to destroy such trust through substandard reporting.

Martin B Van Der Weyden MD FRACP FRCPA · Ruth M Armstrong BMed

Objective: To analyse the reviews of medical news articles posted on media doctor, a medical news-story monitoring website.Design and setting: A descriptive summary of operating the media doctor website between 1 February and 1 September 2004.Main outcome measures: Consensus scores for 10 assessment criteria for the medical intervention described in the article (novelty, availability in Australia, alternative treatment options given, evidence of “disease mongering”, objective supportive evidence given, quantification of benefits, coverage of harms, coverage of costs, independent sources of information, and excessive reliance on a press release); cumulative article rating scores for major media outlets.Results: 104 news articles were featured on media doctor in the study period. Both online and print media scored poorly, although the print media were superior: mean total scores 56.1% satisfactory for print and 40.1% for online; percentage points difference 15.9 (95% CI, 8.3–23.6). The greatest differences were seen for the use of independent information sources, quantification of benefits and coverage of potential harms.Conclusions: Australian lay news reporting of medical advances, particularly by the online news services, is poor. This might improve if journals and researchers became more active in communicating with the press and the public.

on behalf of the media doctor study group*

Taking on two global Goliaths Cheers and groans. Those were my conflicting reactions during a recent perusal of the media doctor website. I cheered in admiration at a good idea and at the temerity of the project’s instigators in taking on two global Goliaths — the media and the medical industries. It is an ambitious task for a project run largely by volunteers on a limited budget. I cheered to see media coverage recognised as a public health issue meriting attention and intervention. It was also pleasing to see a systematic attempt to counter the effective public relations campaigns of commercial, professional and other vested interests in the health sector. Clearly the media and its audiences could do with some help in developing better critical appraisal skills when it comes to health and medical claims. And it is a point well made that responsibility for media coverage must also be borne by medical journals, health professionals, researchers and others who provide information to journalists. But I also groaned as I looked at the website, wondering how it would appear to a busy journalist or media manager with no particular background in epidemiology, who did not know, and cared even less, about such things as randomised controlled trials. Would a quick, casual glance at this website convince them to change their ways? I doubt it, especially considering that many health stories are not covered by specialist health journalists. If the project is to succeed in its goal of changing media reporting, it must first do a better job of explaining why this is necessary. And it must do this in a way which is relevant to journalists and the media. Any attempt to influence behaviour — whether of a patient, a doctor or a journalist — needs to be based in an understanding of what is important to the target and what will motivate them to change. This is yet another initiative targeting individual journalists, who are only one component of the media industry. Other powerful forces, notably the commercial prerogative, also shape how health is covered. An analogy can be drawn with efforts to improve the safety and quality of health care, another chaotic industry. Measures aimed at individual clinicians may be helpful, but it is also important to look at the broader culture, system and industry in which they work. The pharmaceutical industry has been so successful at winning positive media coverage because its goals align neatly with the media’s — stories boldly promising medical breakthroughs sell product for both industries. Those who would like better reporting of the uncertainties and complexities surrounding medical developments will have to work much harder to influence media coverage than those promising miracle cures. Another question arising from this project is whether its good intentions may unintentionally reinforce one of the great deficiencies in media coverage of health. It is far easier to report on the latest research finding or new drug than to investigate other issues which may be of far more significance for the community’s health. Whenever a new drug attracts headlines, scarce newsroom resources are diverted from stories investigating social, structural and policy issues affecting health and health service delivery. Encouraging the media to focus even more on its coverage of medicines may have an opportunity cost. So, how to weigh up the cheers and groans? This website is a great idea. But it needs more work and broader thought. There is a report of its early experience in this issue of the Journal (page 190),1 and I hope there will be a follow-up study, detailing the feedback of journalists, news producers, media managers, and editors. And it raises another question: if the website does lead to more balanced, detailed reporting, what impact might this have on the media’s audiences? They may still hope for miracle cures.

Melissa A Sweet

Media outlets have as much responsibility as ever to maintain standards One of the roughest stories about medical coverage I’ve heard was from a bacteriologist who told me about the effort he’d made with a local journalist over a particular research story. But to his horror, when the article was published in the newspaper, every time the word “bacterium” should have been used, “virus” appeared instead. Outraged, he rang the journalist who gave him the standard response — that it was the subeditor’s fault. Not giving up, our intrepid researcher rang the subbie who told him “It wasn’t me, it was the editor”. So he called the editor whose response was, “I used journalistic licence. I reckoned our readers knew the word virus better. It doesn’t matter does it?” This, of course, is every researcher’s worst nightmare. But it is only a relative risk. It’s true that you don’t advance your academic career by the number of citations on the evening television news. On the other hand, a report of your findings in one TV news slot will reach an audience equivalent to a lifetime’s presentations at learned gatherings, or even, dare I say it, readers of the MJA? So, if the work was worth doing and has been accepted by your peers, it is surely worth telling the community. However, that doesn’t absolve us in the media from getting it right and resisting the influence commercial interests have in pushing products, attitudes and diseases, real or invented.1 The article by Smith et al describing the experience of media doctor in this issue of the Journal (page 190)2 shows the extent to which some of our major media outlets, including the ABC, in their reporting of medical news, fall below the sorts of standards that might allow the community to make rational decisions about their health and medical care. The situation may actually be worse, as media doctor does not monitor talkback radio where public relations companies pushing their clients’ wares can access large numbers of listeners. In addition, there are important problems, such as the way the media can increase stigmatisation of people with major mental illnesses,3,4 that are not necessarily monitored by media doctor’s approach. Before we become too overwrought though, we are not as badly off in Australia as in other countries, particularly the United States and the United Kingdom, where newspaper tabloids can be breathtakingly odious, flaunting science, objectivity, social responsibility and a host of other values in the fight for sales. The solution is not necessarily to have more doctor–journalists. There are several excellent health reporters with no technical background. Their success comes from staying on the job and being determined to learn the analytical skills required rather than moving on to other more prestigious rounds like economics or politics. A growing number of journalism schools teach some of the essentials of science reporting, but cadets and trainees don’t always come with communication degrees. That means media outlets themselves have as much responsibility as ever to maintain standards. However, there is only so much that public embarrassment from media doctor or from the ABC’s weekly TV program Media Watch5 can do. Researchers should complain when they see things done badly, which can make a difference because the line of least resistance should be to do things well. For example, Professor David Pennington, who chaired the “AIDS Task Force” in the early days of the AIDS epidemic, made a significant impact on coverage by intervening actively in the interests of accuracy and defusing prejudice. My gripe with media doctor is that they don’t monitor The Health Report (http://www.abc.net.au/rn/talks/8.30/helthrpt/default.htm). As we in the Fourth Estate like to say, any coverage is good coverage.

Norman Swan FRCP, DCH

Each side needs to appreciate the other’s agenda Media doctor, an attempt by a group of medically well informed people to monitor and rate medical news reports, is a welcome initiative. It aims to improve the standard of health and medical reporting in Australia’s press and the media in general. Whether it can do that, even if expanded to Australia-wide coverage, is a moot point, but well worth considering. No matter how good the website’s intentions, for the project to meet its goals, it is essential to gain the confidence and cooperation of newspaper editors and journalists, as well as their counterparts in radio, TV and the expanding online medium. The media doctor group has made a good start, and a report of their early experience is published in this issue of the Journal (page 190).1 The report is reasonable, reasoned and, clearly, deliberately non-adversarial. Less welcome is the marking and star rating system used for evaluating medical news articles, although the recent move to a five-star, rather than three-star, rating may improve this element, making the rating more sensitive to differences in article quality. We believe, however, that the 10-criteria marking system is subjective and that the criteria themselves may need examining. For example, not all the criteria are of equal weight and some elements, while relevant to refereed papers within the medical profession, may not be as important when assessing lay press reports of medical breakthroughs. The better handling of medical news reporting was one of the motivations that led the Australian Press Council to issue Reporting guidelines in April 2001.2 It is perhaps relevant, and noted in the report by Smith et al,1 that the print media (guided we hope by the Council’s advice) scored significantly higher in terms of the group’s criteria than the electronic/online media, for which a similar guideline has not been issued. A canvassing of opinions on the publishing side is vital to establish the goodwill and cooperation needed to achieve the improved standards media doctor seeks. The Press Council and the bodies dealing with electronic media could undoubtedly help by ensuring that ethical reporting guidelines similar to those of the Press Council are widely disseminated to all segments of the media. The media doctor group is right in not expecting any spectacular improvement in the standards of medical reporting, but is justified in hoping that a judicious and informed examination of medical news reports will improve reporting standards. Again, it needs to be stressed that reports in the general media are not meant to meet the same rigorous standards as those in the medical literature. Moreover, general media reports can be supplemented by well written and accessible commentary from the medical profession to ensure that accurate information is promulgated. Editors cannot guarantee that journalists assigned to cover a medical breakthrough will have the requisite technical knowledge (The New York Times once sent its golfing correspondent to interview Einstein), and this places more responsibility on researchers to ensure that they are clear in what they say to journalists — perhaps, compromising a little to achieve some lay understanding — and are not themselves the cause of the misunderstanding. One weakness in the article by Smith et al is that the authors could not trace many of the press releases from which the stories were derived to see if the “errors” arose from the source rather than the reporter.2 Co-author John Morgan provides one illustrative anecdote: Once I was sent to interview Macfarlane Burnet on immunology. At one stage he talked for about 20 minutes on one aspect. When he finished, I wrote 150 or so words and read them back to him. I asked if what I’d written was right? He told me off for smoking, thought for a while and said: “It’s not entirely right, but it would take 1000 words to make it any better.” Now that’s the sort of help a struggling reporter needs. Good journalists don’t mind being asked to read back what they are writing, but the interviewee must be prepared to take a reasonable approach, to explain any objection and not to renege on some earlier quote. The need for each side to appreciate the other’s agenda should be widely discussed. Doctors should understand that reporters and editors are often better judges of what constitutes news for their readers and that they are subject to (self-) regulation when they commit egregious errors. Most publications are happy to clarify or correct material when errors are made known to them. Journalists are aware of the problems faced by professionals in explaining highly technical matters. Journalists should be aware of their ethical responsibilities, and doctors should be aware of the need to reveal their links to commercial operations or their funding sources. Perhaps the media doctor initiative will help to foster an atmosphere of trust on both sides.

Jack R Herman · John A T Morgan

How to submit a manuscript using Editorial Manager Prepare your submission To submit your manuscript online, you will need: 1. An electronic manuscript file that contains no identifying information (no author names or addresses, no acknowledgements). 2. An abstract of your manuscript. All articles except Letters to the Editor, Obituaries and Book Reviews require an abstract of some kind (see <www.mja.com.au/public/information/instruc.html>). Even an editorial requires a one- or two- sentence descriptive abstract. 3. Details of your co-authors: name, qualifications, position, institution, email address. 4. A disclosure statement completed for all authors. Our disclosure form is available at <www.mja.com.au/ public/information/disclosure.doc>. 5. High-resolution copies of any figures or photographs in separate files (if your manuscript is illustrated). 6. A covering letter in support of your submission (not required for Letters to the Editor, Book Reviews or Obituaries) saved in a separate electronic file. Register with Editorial Manager Everybody needs a username and password to log in to the MJA’s Editorial Manager site. If you haven’t used Editorial Manager with the MJA before, you will need to register first. Go to <www.editorialmanager.com/mja/>, click on “Register”, and follow the steps. We have registered all MJA reviewers already. If you are a reviewer, you should have received your username and password in an email. Submit your article Go to <www.editorialmanager.com/mja/> and click on “Submit a manuscript”. There are several steps to making a submission. Each time you complete a step, the system saves your work. If your session is interrupted for any reason, you can come back and complete your submission at a later time. Problems? Call Kerrie Harding or Christine Hooper in the editorial office: +61 2 9562 6666. No internet access? Send your submission by post. We would appreciate receiving the manuscript on a disk as well as on paper, if that is possible. On 1 July 2005, the MJA began using an online manuscript submission and peer review system called Editorial Manager. Provided by Aries Systems in the US, Editorial Manager is used by many journals throughout the world (including Australian Health Review, American Heart Journal, Annals of Emergency Medicine, and Cell). Indeed, many MJA authors and reviewers have already used Editorial Manager or a similar system. Editorial Manager records manuscript submission and peer review in a database accessible via the world wide web. This administrative technique is very efficient. Authors enter their submissions directly into the database, receiving instant confirmation that their work has been received. Using Editorial Manager, authors are less likely to omit required information from their submission, and this reduces delays. Editorial Manager streamlines the communication between editors and potential reviewers, and makes it easy and quick for reviewers to receive a copy of the manuscript. The same streamlined method of communication is used to submit reviews, request manuscript revisions, and receive a final article. Journals using Editorial Manager commonly report that the administrative work and time taken to reach a decision on manuscripts are greatly reduced, and the number of manuscripts submitted rises. Editors, authors and reviewers can log in at any time to check the status of their manuscripts. Because Editorial Manager is a web-based system, it is available wherever and whenever there is an internet connection, not just in the office. This accessibility also makes it easier for authors and reviewers overseas to contribute to the MJA. So, we are expecting Editorial Manager to bring many benefits — benefits that should ultimately be expressed in better articles published more quickly in the MJA. We are also nervously prepared for the potential downside. New computer systems never appeal to everybody. The website provides plenty of written instructions, but we are also ready to spend time on the phone with new users answering their questions. We encourage all users of the system to give us feedback to guide future development of the system. And, although we are encouraging all authors to use Editorial Manager, no author will be discriminated against for not using the system. You can still post us a handwritten essay, if that is your modus operandi, and the editors (some with a thrill of nostalgic pleasure) will respond in like style. We do feel, however, that most authors will be much better served by the new system, and strongly urge them to take it up.

Craig M Bingham BA · Christine Hooper · Kerrie Harding

Not so long ago, the International Committee of Medical Journal Editors (ICMJE) — represented by 11 general medical journals including The Medical Journal of Australia — took a fairly passive and advisory role in medical publishing. The major outcome of its efforts was the Uniform requirements for manuscripts submitted to biomedical journals, which is an internationally accepted reference for biomedical publishing. It gives recommendations for preparing manuscripts for submission, and includes statements on editorial roles and responsibilities, authorship, and ethical issues governing biomedical publication.1 Recently, the ICMJE has adopted a more aggressive, interventional role. This new function first surfaced with the ICMJE’s 2001 statement Sponsorship, authorship and accountability, which conveyed the requirements for publishing clinical trials conducted with corporate sponsorship.2 The statement’s bottom line was that publication of such trials depended on compliance with transparent processes regarding responsibility for the trial, access to and control of data, and control of publication by researchers. In short, transparency and independence were stressed. The next ICMJE foray came with its 2004 statement on Clinical trial registration,3 which, despite being cautiously welcomed by research and media commentators,4,5 has reverberated in the research community, and in particular in the pharmaceutical industry, ever since.6 This statement was a response to the pharmaceutical industry’s longstanding unethical practice of “silent” clinical trials. It decreed that ICMJE journals would only consider publishing reports of trials that had been registered before enrolling the first participant. This policy came into operation on or after 1 July 2005 for new trials, and any ongoing trials are to be registered before 13 September 2005. The need for prospective registration of clinical trials is not a new idea.7,8 Almost a decade ago, for example, the Australian Health Ethics Committee first acknowledged the need to establish a clinical trials register in Australia.9 Now, in one swoop, the ICMJE has provided the impetus to move trial registration from the realm of theoretical nicety to its rightful place on various ethical and political agendas. In a follow-up statement in May this year, Is this clinical trial fully registered?,10 the ICMJE reaffirmed its clinical trial registration policy and endorsed the World Health Organization’s minimal registration data set of 20 fields. It also reaffirmed its requirements for an acceptable clinical trial registry: it must be electronically searchable, with free access; it must be open to all registrants; the trial data must be validated; and it must be a not-for-profit concern. The clinical trial registry site currently endorsed by the ICMJE is sponsored by the United States National Library of Medicine (http://www.clinicaltrials.gov), but the committee acknowledges that further registries will come on stream. These are under development in Japan, India and South Africa.11 In May this year, the Australian Government announced a grant of $1.5 million for the establishment of The Australian Clinical Trial Registry at the National Health and Medical Research Council Clinical Trials Centre at Sydney University.12 The Australian Registry (http://www.actr.org.au) complies with ICMJE and WHO requirements and became available for registrations in late June 2005. It is highly likely that more national trial registries will emerge. The WHO is currently developing an approval process to assess compliance of registers with ICMJE and WHO requirements.11 The WHO also plans to provide a web-based portal to all registries. These developments make sense: a cluster of national and regional clinical trial registries linked by an international agency. The WHO is ideally suited to assume this role and it will free the ICMJE to do what it does best — formulate publication policy.

Martin B Van Der Weyden MD, FRACP, FRCPA · Davina Ghersi BAppSc, MPH

In September 2004, the members of the International Committee of Medical Journal Editors (ICMJE) published a joint editorial aimed at promoting registration of all clinical trials.1 We stated that we will consider a trial for publication only if it has been registered before the enrolment of the first patient. This policy applies to trials that start recruiting on or after 1 July 2005. Because many ongoing trials were not registered at inception, we will consider for publication ongoing trials that are registered before 13 September 2005. Our goal then and now is to foster a comprehensive, publicly available database of clinical trials. A complete registry of trials would be a fitting way to thank the thousands of participants who have placed themselves at risk by volunteering for clinical trials. They deserve to know that the information that accrues from their altruism is part of the public record, where it is available to guide decisions about patient care, and deserve to know that decisions about their care rest on all of the evidence, not just the trials that authors decided to report and that journal editors decided to publish. We are not alone in pursuing this goal. The World Health Organization (WHO), through meetings in New York, Mexico City, and Geneva, has brought us close to the goal of a single worldwide standard for the information that trial authors must disclose. Around the world, governments are beginning to legislate mandatory disclosure of all trials. For example, among the bodies considering new legislation is the US Congress, where the proposed Fair Access to Clinical Trials (FACT) Act would expand the current mandate for registration of clinical trials. Many other journals have adopted our policy of requiring trial registration. These initiatives show that trial registration has become a public issue. But, as our deadline for registration approaches, trial authors and sponsors want to be sure that they understand our requirements, so that reports of their research will be eligible for editorial review. The purpose of this joint and simultaneously published editorial is to answer questions about the ICMJE initiative and to bring our position into harmony with that of others who are working toward the same end. Our definition of a clinical trial remains essentially the same as in our September 2004 editorial: “Any research project that prospectively assigns human subjects to intervention and comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome.” By “medical intervention” we mean any intervention used to modify a health outcome. This definition includes drugs, surgical procedures, devices, behavioural treatments, process-of-care changes, and the like. We update our 2004 editorial to state that a trial must have at least one prospectively assigned concurrent control or comparison group in order to trigger the requirement for registration. Among the trials that meet this definition, which need to be registered? The ICMJE wants to ensure public access to all “clinically directive” trials — trials that test a clinical hypothesis about health outcomes (eg, “Is drug X as effective as drug Y in treating heart failure?”). We have excluded trials from our registration requirement if their primary goal is to assess major unknown toxicity or determine pharmacokinetics (phase 1 trials). In contrast, we think the public deserves to know about trials that could shape the body of evidence about clinical effectiveness or adverse effects. Therefore, we require registration of all trials whose primary purpose is to affect clinical practice (phase 3 trials). Between these two extremes are some clinical trials whose prespecified goal is to investigate the biology of disease or to provide preliminary data that may lead to larger, clinically directive trials. We recognise that requiring public registration of trials whose prespecified goal is to investigate the biology of disease or to direct further research might slow the forces that drive innovation. Therefore, each journal editor will decide on a case-by-case basis about reviewing unregistered trials in this category. Authors whose trial is unregistered will have to convince the editor that they had a sound rationale when they decided not to register their trial. The ICMJE will maintain this policy for the next two years. We will then review our experience. Our September 2004 editorial specified the information that we would require for trial registration. Attendees at a recent meeting of the WHO registration advisory group identified a minimal registration dataset of 20 items (Box). The WHO-mandated items collectively address every key requirement that we established in our September 2004 editorial. The ICMJE supports the WHO minimal dataset and has adopted it as the ICMJE’s requirement: we will consider a trial for publication if the authors register it at inception by completing all 20 fields in the WHO minimal dataset. As individual editors, we will review the data in the registration fields when we decide whether to consider the trial for publication. We will consider a registration dataset inadequate if it has missing fields or fields that contain uninformative terminology. If an investigator has already registered a clinical trial in a publicly owned, publicly accessible registry using the data fields that we specified in our 2004 editorial, we will consider that registration to be complete as long as each field contains useful information. Acceptable completion of data fields is an important concern. It shouldn’t be, but it is. Many entries in the publicly accessible clinicaltrials.gov database do not provide meaningful information in some key data fields. A search conducted on May 4, 2005 (Deborah Zarin, MD, personal communication) indicates that certain pharmaceutical-company entries list a meaningless phrase (eg, “investigational drug”) in place of the actual name of the drug, even though a US law requires trial registrants to provide “intervention name” (http://www.fda.gov/cder/guidance/4856fnl.htm). Many companies and other entities are completing the data fields in a meaningful fashion. Data entries must include information that will be of value to patients and health professionals; the intervention name is needed if one is to search on that intervention. We recognise that clinical trial registries have many uses, but whatever the use, a worldwide uniform standard for a minimal database is necessary. We have participated in the WHO effort to establish a clinically meaningful trial registration process. The ICMJE supports this ongoing project. When it is complete we will evaluate the process, and if it meets our primary objectives, we will adopt it. We stated our requirements for an acceptable trial registry in the September 2004 editorial, and they remain the same. The registry must be electronically searchable and accessible to the public at no charge. It must be open to all registrants and not for profit. It must have a mechanism to ensure the validity of the registration data. The purpose of a clinical trials registry is to promote the public good by ensuring that everyone can find key information about every clinical trial whose principal aim is to shape medical decision-making. We will do what we can to help reach this goal. We urge all parties to register new and ongoing clinical trials. If in doubt about whether a trial is “clinically directive,” register it. Don’t use meaningless phrases to describe key information. Every trial participant and every investigator should be asking, “Is this clinical trial fully registered?” Minimal registration dataset* Item Comment 1. Unique trial number The unique trial number will be established by the primary registering entity (the registry). 2. Trial registration date The date of registration will be established by the primary registering entity. 3. Secondary IDs May be assigned by sponsors or other interested parties (there may be none). 4. Funding source(s) Name of the organisation(s) that provided funding for the study. 5. Primary sponsor The main entity responsible for performing the research. 6. Secondary sponsor(s) The secondary entities, if any, responsible for performing the research. 7. Responsible contact person Public contact person for the trial, for patients interested in participating. 8. Research contact person Person to contact for scientific inquiries about the trial. 9. Title of the study Brief title chosen by the research group (can be omitted if the researchers wish). 10. Official scientific title of the study This title must include the name of the intervention, the condition being studied, and the outcome (eg, The International Study of Digoxin and Death from Congestive Heart Failure). 11. Research ethics review Has the study at the time of registration received appropriate ethics committee approval (yes/no)? (It is assumed that all registered trials will be approved by an ethics board before commencing.) 12. Condition The medical condition being studied (eg, asthma, myocardial infarction, depression). 13. Intervention(s) A description of the study and comparison/control intervention(s) (For a drug or other product registered for public sale anywhere in the world, this is the generic name; for an unregistered drug the generic name or company serial number is acceptable). The duration of the intervention(s) must be specified. 14. Key inclusion and exclusion criteria Key patient characteristics that determine eligibility for participation in the study. 15. Study type Database should provide drop-down lists for selection. This would include choices for randomised vs. non-randomised, type of masking (eg, double-blind, single-blind), type of controls (eg, placebo, active), and group assignment, (eg, parallel, crossover, factorial). 16. Anticipated trial start date Estimated enrolment date of the first participant. 17. Target sample size The total number of subjects the investigators plan to enrol before closing the trial to new participants. 18. Recruitment status Is this information available (yes/no) (If yes, link to information). 19. Primary outcome The primary outcome that the study was designed to evaluate. Description should include the time at which the outcome is measured (eg, blood pressure at 12 months). 20. Key secondary outcomes The secondary outcomes specified in the protocol. Description should include time of measurement (eg, creatinine clearance at 6 months). * The data fields were specified at a meeting convened by the World Health Organization in April 2004; the explanatory comments are largely from the International Commitee of Medical Journal Editors.

Catherine D De Angelis · Jeffrey M Drazen · Frank A Frizelle · Charlotte Haug · John Hoey · Richard C Horton · Sheldon Kotzin · Christine Laine · Ana Marusic · A John P M Overbeke · Torben V Schroeder · Harold C Sox · Martin B Van Der Weyden

Mention the name Alistair Cooke, and his legendary Letter from America immediately springs to mind.1 For 58 years his weekly commentaries on happenings in the United States were beamed by the BBC to many countries around the world, including Australia. Indeed, Cooke’s Letter from America was the catalyst for commissioning a regular short piece on the “goings-on” in health care, the medical profession and academia in the United Kingdom. The opportunity to view these through antipodean eyes was entirely fortuitous. Three prominent Australian academics left our shores some 3 years ago to take up prestigious positions in the “old country”: David Weller moved from Flinders University to Edinburgh, Konrad Jamrozik from the University of Western Australia to London, and Richard Heller from Newcastle University to Manchester. With little ado, our expatriate trio agreed to provide regular comments on medicine in the UK. The commentaries were to be journalistic rather than academic, with a humorous or quirky edge, but were also to reflect the profession’s sensitivities and conservatism. And so the Postcard from the UK was born. But now, almost 2 years on, the Postcard will cease to be delivered, and this issue carries the last one. This unfortunate turn of events is due to the break-up of the Postcard’s triumvirate, with the return of one of its members to Australia. Thus, all parties concerned agreed to “pull the plug” on the Postcards. Since December 2003, various Postcards have amused, amazed and even affronted some of our readers, both in Australia and in the UK. The more memorable Postcards have covered such issues as: UK health inequalities, which still reflect the British class divide;2 the political crusades imploding the National Health Service;3 the dependence of the NHS on “the energy of slaves” — through recruitment of doctors and other health professionals from the former British Empire’s colonies;4 and the Sir Humphrey Appleby approach to the bureaucratic Research Assessment Exercise, which gives the lie to the commitment of UK universities “to profess”.5,6 The final Postcard in this issue of the Journal (page 556) explores the difficulties confronting the NHS in bringing IT systems on stream.7 What, then, is the lasting message of the postcards? The issues involving the UK health system, its medical profession and academia are mirrored in our system, and the solutions seem to come from the same cookbook. Both countries’ bureaucracies are incredibly insular and spawn ill-conceived ideas, reflecting their isolation. But, overall, we are left with an impression of the political impotence of the UK medical profession and its institutions compared with those in Australia, a situation to be expected if most doctors are, in reality, public servants. In the meantime, sincere thanks to the Postcard’s trio and vale to our Postcard from the UK.

Martin B Van Der Weyden MD FRACP FRCPA

QuestionCan a regimen of chewing sucrose-free gum after meals reduce the incidence of caries and remineralise white spot lesions (demineralised and non-cavitated incipient caries) in a population with a moderate incidence of caries? Trial details Design: A cluster-randomised controlled trial with two arms. Setting: Elementary schools in Budapest, Hungary, where water was not fluoridated at the time of the study. Participants: 583 schoolchildren aged 8–13 years (mean age, 9.6 years). Participants and their parents or guardians were required to sign an informed consent form. Non-participation rates and profiles were not reported, and inclusion and exclusion criteria were not specified. Interventions: The intervention group chewed sucrose-free gum (65% polyols [sorbitol and mannitol], 30% gum base and 5% sweeteners and flavours) for 20 minutes after meals, three times a day; the control group did not chew gum. Two meals a day were available at the schools, facilitating supervision of gum chewing. Other chewing sessions were unsupervised. After baseline clinical examination, classes within grade levels were randomly assigned to either arm, provided that each grade level had more than one class with sufficient participants available. No significant differences in baseline caries scores were detected between the intervention and control groups. No modifications were made to the oral hygiene and dietary practices of participants. Main outcome measures: Participants were examined at 1 and 2 years by a single blinded examiner, using a mouth mirror, explorer and transillumination to aid diagnosis of interproximal caries. Drying of teeth and radiographs were not used. Clinical examination results were expressed as World Health Organization (WHO) DMFS (decayed, missing and filled surfaces) scores or Radicke scores. WHO DMFS scores include a category for incipient carious lesions, and are commonly used caries experience indices, quantifying decayed, missing and filled surfaces. Main results: 1-year and 2-year scores for DMFS increment were adjusted for by baseline DMFS scores. Using the Radicke DMFS scores, reductions in caries increment for the intervention group were in the order of 43.6% (P = 0.008) and 38.7% (P = 0.018) at 1 and 2 years, respectively. Using the WHO DMFS scores (inclusive of incipient lesions), reductions in caries increment for the intervention group were in the order of 41.7% (P = 0.028) and 33.1% (P = 0.008) at 1 and 2 years, respectively. Conclusions: The authors concluded that chewing sucrose-free gum after meals provided a positive anti-caries effect. CommentaryRationale for the trialTo confirm previous trials reporting positive anti-caries effects of sucrose-free gum chewing.1-5 Whereas most previous trials were conducted in populations with a high incidence of caries, the authors sought to investigate within an industrialised population with moderate caries incidence. Trial methodsAs no intervention was elected for the control group, participant blinding was not feasible. Thus, the authors did not offer alternative explanations for the positive result. The intervention may have initiated different preventive oral hygiene and dietary practices between groups. Also, the intervention group may have been less likely to seek confectionery, and hence a less cariogenic diet, compared with the control group. Participant flow was poorly reported, obscuring potential sources of bias. Follow-up was excellent, with 93.8% presenting for 2-year clinical examination. However, this follow-up rate was not broken down between intervention and control groups. It is feasible that this rate may have been lower in the more procedurally demanding intervention group, and those not presenting for follow-up may represent participants with less concern for their oral health. Reporting of withdrawal after randomisation (of particular interest to the intervention group) was also poor. Mechanisms for capturing adverse events were not described. No adverse events were reported, except for one that was not related to the chewing gum, but resulted in withdrawal. There is concern that adverse events not related to the chewing gum were not adequately monitored. Compliance, especially for out-of-school chewing, is a challenge in a trial such as this. School chewing compliance was reported as unproblematic, but the method of monitoring was not described. Out-of-school chewing compliance was assessed by gum wrapper return (93% of students returned more than 90% of wrappers). This does not accurately reflect if gum was chewed and by whom. The authors recognised that gum chewing could not be accurately assessed in the control group. However, prohibition of gum chewing in schools was described. New informationThis study suggests a positive anti-caries effect of chewing sucrose-free chewing gum after meals within an industrialised population with moderate caries incidence. To confirm such an effect, the role of bias would require greater attention. Implications for clinical practiceThe authors advise that sucrose-free gum-chewing be considered on an individual and organisational level. From the perspective of a cost–benefit analysis, this is premature. The gum-chewing regimen described is expensive and needs to be considered against other preventive measures, such as fluoride gels and mouth rinses, before the authors’ recommendations can be embraced. The evidence for the superior efficacy of chewing gum sweetened with xylitol over that sweetened with sorbitol is not unanimous.3-5 Budapest may benefit more from fluoridation of its water supply.

Claudine E Tsao BDSc · Michael V Morgan BDSc, MDSc, PhD

Good study design involves minimising all possible sources of bias. Two important sources of bias arise through failure to mask (ie, conceal), first, the randomisation process and, second, the treatments after randomisation. Allocation concealment is the term used to describe the procedure for protecting the randomisation process so that the treatment to be allocated is not known before the patient is entered into the study. Blinding relates to the masking of the treatments after randomisation — from the patient, the investigator or the outcomes assessor. Without exception, allocation concealment is achievable in all randomised clinical trials. In contrast, it is not always possible to blind people to study treatments received. The CONSORT statement strongly encourages detailed reporting of the allocation concealment process and the measures taken to preserve blinding (Box 1).1 Allocation concealmentFailure to conceal the process of random allocation will potentially result in a non-randomised trial, while successful allocation concealment will reduce selection bias. No matter what method is chosen to randomly allocate patients (eg, by simple random numbers, permuted blocks or minimisation), if the investigator or clinician (or the patient) is able to identify the impending treatment allocation and is able to influence the enrolment (or selection) of participating patients, the value of randomisation is compromised. Selection bias may have been introduced, whereby the treatment assignment is no longer truly random and an imbalance in prognostic factors between treatment groups occurs. If this arises, assessment of the treatment comparison is compromised. Failed concealment from the investigator or clinicianSingle-centre trials in which randomisation is conducted on site and the randomisation method is known to the participating investigators are at high risk of this problem. If an investigator has influence over the number of patients enrolling in a trial, or the order in which they are randomised, he or she has the potential to introduce selection bias into the study by directing particular patients into preferred treatment groups while excluding others. However, even if the investigator knows the allocation sequence, the problem will not arise if all consecutive eligible patients are being enrolled in order of presentation, as is often the case in trials in emergency departments, intensive care units or any acute care setting. Ideally, a successful allocation concealment process is ensured when all investigators are ignorant of future treatment allocations and have no control over the order of patients randomised into the trial. Failed concealment from the patientPatients may change their willingness to participate in a trial if they know or suspect which treatment they will receive. If patients are aware of their allocation before randomisation, they may be influenced to withdraw before randomisation or wait until their preferred treatment is available before entering the study. Baseline imbalances as a direct result of concealment violation may not be evident across the whole trial, although patients from particular sites or patients from particular investigators may show consistent differences between treatment groups in various baseline prognostic factors. In practice, the method of allocation concealment is often not reported or is poorly described.2-7 Any trial report should provide enough detail to describe the quality of both allocation concealment and blinding strategies. The use of sequentially numbered, opaque, sealed envelopes, pharmacy-controlled allocations, coded identical containers or kits, and central randomisation systems (telephone or web based) are considered adequate concealment methods and are often implemented to protect the randomisation.8 Allocation lists that can be prepared in advance or may be guessed because of a known pattern (eg, permuted blocks of fixed size) are more susceptible to deciphering. No strategy is entirely tamper-proof, although remote systems are generally more secure.9 Blinding (masking)Blinding describes the status of the patient and/or the clinician-investigator after randomisation: Single blind: Either the patient or clinician (usually the patient) remains unaware of the treatment assignment. Double blind: Both the patient and investigator are unaware of the allocated treatment. Open label: All parties are aware of treatment being received after randomisation. Triple blind: The patient, the investigator and either those who adjudicate the study outcomes (the outcomes assessment committee) or those who monitor the study safety (the safety and data monitoring committee) are unaware of the allocated treatment. A blinded safety committee will see the data from the treatment groups in coded form (ie, labelled as X and Y), and so are also blinded to treatment allocation. Unblinding: The disclosure, planned or unintended, of the allocation of one, a group, or all of the participants. Failure or inability to blind people to the treatment assignment in a trial potentially introduces important biases. These include reporting bias (by either the patient or investigator), assessment bias (where assessment is part of an investigator’s role), and concomitant treatment bias by either the patient or investigator; all such biases contribute to differences between groups other than those resulting from the allocated study treatment. In open-label trials, all of these biases might occur. It is recommended that the study’s blinding be explicitly detailed when trial design and results are reported.1,10 In particular, authors should report how blinding was maintained for patients, investigators or clinicians and outcomes assessment committees. Consequences of treatment knowledge after randomisationIf patients are not blinded to their allocated treatment, then knowledge of treatment may influence their responses to the intervention and their reporting. Commonly, patients assume that the new intervention will be more beneficial than the control or standard treatment. Compared with clinical event outcomes, patient-rated outcomes (for example, quality of life, pain and discomfort) are particularly sensitive to patients’ knowledge of the intervention to which they have been allocated. Similarly, if investigators are aware of the patients’ study treatment, their knowledge may influence, first, their management of the patient and, second, their classification of responses and events. For example, in the Aspirin Myocardial Infarction Study,11 men and women who experienced a myocardial infarction were randomised to receive 1 g aspirin a day or matching placebo. If they or their doctors had been aware that they were taking aspirin, they might have ascribed all their gastrointestinal symptoms to aspirin. Symptoms suggesting peptic ulcer, gastritis or erosion of gastric mucosa occurred in 23.7% of the aspirin group but also 14.9% of the placebo group. Because the study was well blinded, it was possible to attribute only 8.8% of the symptoms to the aspirin treatment. Generally, drug trials involving oral, topical or intravenous administration can be set up as a double-blind study by the use of a matching placebo. Many surgical trials comparing intraoperative techniques with an identical external incision can be designed as single-blind trials, but comparisons between medical and surgical interventions are inevitably unblinded — that is, open-label trials. When a treatment has a distinctive side effect which is likely to be expressed in most patients (such as toxic effects from chemotherapy), the use of a placebo may be futile. To blind or not to blind?A double-blind design is desirable for any trial. When there is an active comparator in a drug evaluation trial, blinding can be ensured by the use of a so-called double-dummy design. This involves giving all patients two formulations: one group receives the active treatment plus a placebo of the alternative treatment, and the other group receives the opposite combination (see Box 2). To successfully mask the treatment, a placebo treatment should be identical in appearance (size, colour, weight, feel, odour, etc) and route of administration, and should be tested to make certain that its benign nature cannot be detected. Patients’ or investigators’ preconceptions about the value of the treatment may affect a trial’s results. For example, in a trial of the effect of vitamin C on symptoms of colds, volunteers took vitamin C or a placebo for 9 months, with an increase in the dose at the onset of a cold.12 Because of the differences in taste between the vitamin and the placebo, some of the participants became aware of their treatment. In this group, the vitamin C had a reported benefit, but vitamin treatment did not appear to help those who remained blinded. The breakdown of the blinding led to inconclusive results, illustrating the importance of ensuring that blinding is done with care. Masking data and intermediate outcomes during the studyWhen routine collection of clinical data during a trial (eg, blood tests) may potentially unblind investigators, providing investigators with summary information should be considered. For example, in a long-term cardiovascular trial assessing the effect of cholesterol-lowering treatment on the incidence of cardiovascular events, knowing individual lipid profiles during follow-up may unblind the clinician and patient. If the blood tests are performed by a central laboratory, it may be possible to provide a summary report simply stating that a patient’s values do or do not fall within a prespecified range, without compromising the patient’s safety, masking the individual data and preserving the blinded status of the investigator. Blinded outcome assessmentBlinded assessment of outcomes is possible in most trials, regardless of whether the clinician or the patient is aware of the treatment allocation. Clinical outcomes should be assessed by people who are not aware of the patient’s treatment allocation (and preferably not involved in the patient’s clinical management) so that all patients are assessed identically. In this way, outcomes will not be influenced by beliefs about the study treatments being compared. In general, blinding becomes less important for reducing observer or information bias as the outcomes become less subjective and more objective (that is, bias is more prevalent with a subjective outcome such as degree of pain or extent of depression, but is eliminated with an outcome such as death from any cause). For outcomes such as biochemical or pathology result markers, assessment by calibrated, accurate instruments is often sufficient to ensure no bias is present. If patients are required to provide their own assessment of an outcome, it is recommended that more than one item of the same type be reported to allow reliability to be measured. Effect of allocation concealment and blinding on the interpretation of trial resultsAn open-label trial with successful allocation concealment and blinded assessment may provide more reliable and more valid results than a double-blind trial with unsuccessful allocation concealment or compromised outcome assessment. Blinding does not guarantee an absence of bias, although empirical evidence does endorse a reduction of bias when adequate blinding strategies have been implemented. Allocation concealment (before randomisation) is thought to have a stronger influence on the reduction of bias than blinding (after randomisation).3,5 A checklist for successful allocation concealment and blinding is provided in Box 3. When and how to unblind participants and investigators during the trialProcedures should be established at the start of any randomised controlled trial for possible unblinding of the investigator and patient to an individual patient’s data during the trial. In most cases, unblinding would be carried out when the patient’s safety is at risk and this knowledge is required for emergency treatment. Often, however, if simply ceasing study treatment is a viable option for the patient’s care, it should not be necessary for unblinding to occur. Whenever possible, the chief investigator’s agreement should be sought before requests for individual unblinding are made. The process of unblinding should be such that only the data for one patient should be disclosed at any one time, and an audit trail maintained of all requests and their justifications. 1 CONSORT checklist of items to report when reporting a randomised trial1 Section and topic Item no. Descriptor Allocation concealment 9 Method used to implement the random allocation sequence (eg, numbered containers or central telephone), clarifying whether the sequence was concealed until interventions were assigned. Implementation 10 Who generated the allocation sequence, who enrolled participants and who assigned participants to their groups? Blinding (masking) 11 Whether or not participants, those administering the interventions and those assessing the outcomes were blinded to group assignment. If done, how the success of blinding was evaluated. 2 Double-blind double-dummy trial design Randomised allocation Patient receives Active treatment 1: Tablet Active treatment 2: Capsule 3 Checklist for successful allocation concealment and blinding Allocation concealment Investigator-clinicians are unaware of exact details of how the chosen randomisation method is being implemented (eg, ignorant of block sizes used in a permuted block randomisation scheme). All staff responsible for providing allocations have adequate training. An audit trail is maintained to ensure the integrity of the allocation process.13 If possible, a centralised or remote randomisation service is used (either by telephone, fax, email, the internet, a coordinating centre or site pharmacy). Remote randomisation can mean telephoning or faxing another person or clinic department to receive the next allocation. Blinding Appropriateness of blinding of patients and investigators (double-blind or single-blind) is ascertained. The implementation process for blinding is planned, including deciding whether a placebo treatment is to be used, and ensuring the process maintains the relevant parties’ ignorance of the treatment after randomisation. Evaluation of outcomes ensures objective assessment of all patients. Unblinding Ceasing study medication, if this is an option, is preferable to unblinding. A method of unblinding is available quickly in a genuine emergency. Specific methods If envelopes are used, there is an audit trail recording each envelope opened (date and time) and envelopes are numbered, tamper-proof and opaque so that the contents remain concealed unless the envelope is destroyed or damaged.13 If kits or containers are used, they are identical (weight, size, appearance), numbered and tamper-proof. The allocation process is reproducible.

Peta M Forder BSc, MPH · Val J Gebski BA, MStat · Anthony C Keech FRACP, MScEpid

Medical researchers have a moral responsibility to communicate their findings to the public There is no greater commitment than a government’s investment in the healthcare of its citizens. If we, as medical researchers and practitioners, are to preserve public trust and support for our scientific enterprise, we need to pay more attention to translating the benefits and grandeur of science into the common language of the general community.1 Although educators and journalists also communicate the achievements of medical science, doctors and scientists have a greater responsibility to increase the availability and salience of science to the public. I believe we can move further towards realising this goal by keeping several key questions in our minds. How have and how can biomedical breakthroughs benefit humanity? The development of vaccines and immunotherapies is at the top of my list of major medical advances that have changed humanity’s lot for the better. During the past year, the medical crises created by epidemics of Ebola virus and SARS have demanded the creation of new vaccines, which are now poised for clinical trials.2 Other developments in medicine include antibiotics to combat infection, organ transplantation to extend life, high resolution imaging that has reduced the number of invasive surgical procedures and, most recently, the global Human Genome Project, which is revealing secrets about the basis of life. In April 2003, the world simultaneously celebrated the 50th anniversary of Watson and Crick’s description of the DNA double helix and the International Human Genome Sequencing Consortium’s completion of the human genome sequence. However, the completion of the human genome sequence represented only the beginning in genomics research; it has led to the unveiling of a bold new vision for its future.3 Translating genome-based knowledge into health benefits will be a major focus of future genomics research. Virtually all diseases, with the exception of trauma, have a genetic component and an environmental component. One of the projected outcomes of the Human Genome Project is the development of personalised medicine. All patients who share the same diagnosis for a certain disease do not respond the same way to treatment. In some cases, we are already able to determine, based on genetic profiles, which patients will be responsive to specific drugs, and then to specifically deliver the most appropriate to eradicate the disease.4 We have entered a new era of multigeneration, population-based research. This will facilitate innovative genetic studies to identify the paediatric precursors of specific adult diseases, based on the comparative analyses of genetic profiles of children, their parents, and grandparents. Imagine the possibility of identifying genes in newborns responsible for cardiac disease, or diabetes, or arthritis, or specific cancers — and then managing and/or preventing the onset of these diseases. The overall improvement in quality of life would be extraordinary, and we are closer than you might think to achieving this goal. Many scientists have suggested the concept of newborn genetic “passports” in which the complete genetic profiles of newborns will be documented in medical files at birth. On the one hand, this sounds quite exciting, but the social implications are profound. As doctors and scientists, we must act now and we must act together to establish rigorous guidelines and boundaries for the use of genetic informatics with respect to: health insurance; genetic information and the workplace; genetic privacy and confidentiality; and, the forensic use of genetic information. Accordingly, the US National Human Genome Research Institute in Bethesda, Maryland, has developed the Ethical, Legal and Social Implications Research Program to ensure that genetic research is conducted in an ethically sound manner; that genetic technologies are integrated appropriately into clinical and non-clinical settings; that genetic information is correctly interpreted and appropriately used; and that health professionals and the public become more genetically literate.3 How important is advocacy in supporting the mission of research and addressing critical social issues? John Porter, former Illinois Congressman and Chairman of the US Subcommittee on Labor, Health and Human Services, and Education, stated: Since most members of Congress are not scientists, citizen scientists must individually inform, educate, inspire, and direct their representatives regarding public policy decisions affecting science.4 When Americans were polled by Research!America about who they believe should have the most influence on how government medical research funds are spent, they indicated that patients (first) and scientists (second) should have the most influence.4 (Research!America is a not-for-profit, membership-supported public education and advocacy alliance for medical and health research.) Scientists must continue to remember that it is a privilege to be engaged in research, and that the relationship between science and society is growing ever more intimate. The spirit of enquiry behind science is not self-sustaining — it is increasingly dependent on societal support. Thus, we have a moral responsibility to be good stewards of this support and to communicate our findings to the public in order to build on that trust and seek broad input. It is critical for greater success that advocacy groups work together for better healthcare and biomedical research. Typically, in the US, joint advocacy on many issues will involve the Association of American Medical Colleges (AAMC), research institutes, academic institutions, hospitals, state and local organisations, voluntary health associations, philanthropic foundations, individuals, and business and industry, as well as biomedical professional societies. As a representative of American scientists, I have valued opportunities to work closely with the US Congress. From 2000–2002, I was privileged to serve as President and Immediate Past-President of the Federation of American Societies for Experimental Biology (FASEB) — over 70 000 scientists speaking with one voice. Through directed advocacy effects of “acting now and acting together” we were successful in: doubling the NIH budget (1999–2003), from $13.6 billion to $27.2 billion; securing federal funding for human embryonic stem cell research; supporting genetic non-discrimination legislation to protect the use of private, genetic information (a work in progress); and developing debt-relief programs for physician–scientists to encourage this endangered species into the pipeline. What are the economic benefits of investing in research? Simply put by the Lasker/Funding First Foundation, “Investment in research saves lives and money”. Increases in life expectancy have contributed to national budgets. For example, in Australia between 1960 and 1999, longevity improved from 73.9 years to 81.8 years for females and from 67.9 to 76.2 years for males, at an estimated worth of $5.4 trillion.5 With respect to government support of biomedical research, the statistics when comparing the US with Australia were astonishing to me. I have recently learnt that in the 2000–2001 budget year, whereas the budget for the NIH was $17.8 billion, the Australian Commonwealth budget for health and medical research was a more modest $665 million.5 This represents a fourfold difference per citizen, with the US government spending about $130 per person and the Australian government about $33. I felt humbled, acquiring a more profound respect for my world-class Australian medical research colleagues, who, with truly limited resources, have made significant contributions to the field. Among these contributions are the discovery of lithium in treating bipolar disorder, as well as major advances in childhood diseases of spina bifida and sudden infant death syndrome. Australian researchers have also discovered a powerful secret to success — working collaboratively in interdisciplinary teams towards a common goal. Researchers around the world could all learn a lesson from Australian scientists; as the US budget for research begins to shrink, American scientists will have to adopt the Aussie philosophy in order to survive in the “business”. With competing demands on government resources, who will pay for tomorrow’s discoveries? I believe that projects leading to future discoveries will be paid for by creative partnerships between academic, philanthropic, corporate and government agencies. I also believe such projects should be guided by advocacy, led by scientists, to advance treatments and cures. We should always remember the wise words of Paul Rogers, Chair of Research!America: “Without research, there is no hope.”

Mary JC Hendrix PhD

Quotes from MJA contributors in 2004 Much that is written for the Medical Journal of Australia is never intended for print. Volumes of correspondence, for the editors’ eyes only, flow into our in-trays — notably reviewers’ forthright opinions and authors’ robust rebuttals. Paradoxically, at times these missives seem better written and more suited to publication than the related manuscript! Straightforward, simple and clear, concise and precise, they are an editor’s delight. This Christmas, as always, we want to wish our contributors “Happy reading and all the best for your writing in the New Year!”. In this vein, we share with you some of the most memorable manuscript-related remarks received this past year. They reinforce general words of advice often given to aspiring writers. Respecting the various authors (and protecting ourselves), these quotes — now in print — have been de-identified. Make your point“The act of writing down guidelines always promotes debate and criticism, but it is important to ensure that the debate moves forward rather than in circles.” “On reading this paper, I wondered whether I was losing my mind. This is for you to judge. I cannot see a coherent argument.” Time matters“The feeling obtained on reading this paper is that a lot of time and effort has been expended and many trees felled for no particular reason.” “I’m sorry that I’ve been slow with this opinion. I don’t think, however, that either science or medicine will be damaged by the delay.” “I happened to have some spare time this afternoon, so I have undertaken the review already (if there is a prize for most rapid review for the Journal, then I want to be considered).” Declare conflict of interest“It is tempting to give it [this manuscript] a glowing review, which it indisputably deserves, but some degree of bias might be alleged since, unless the paper’s authorship has changed since the last draft I worked on, I am one of its authors!” Aim high . . . . . . but temper hyperboleReviewer: “The final section of this article is somewhat evangelical...” Author: “The article’s ‘somewhat evangelical’ tone is part of a desire to make people notice the enormity of the task, to stimulate debate and, possibly, more effective action.” Be scientific“I do not think a show of hands at a conference is scientific evidence to support an argument.” “The statement that a result can be clinically important but not statistically significant is nothing other than wishful thinking.” Be fearless“I look forward to drawing swords against your referees.” Be yourselfWe like Letters to the Editor to be short — no more than 400 words in length. Sometimes reviewers’ well-intentioned suggestions can seem impossible to accommodate. One author responded with individual flair. Reviewer: “... Point 8. It would be useful to summarise the current . . . constraints . . . in a box so that non-Australian authors will understand what is being discussed.” Author: “In 400 words, mate? Your sense of humour is even better than the editor’s.”

Ann T Gregory MB BS, GradDipPopHealth

Randomised controlled trials should be the basis for developing clinical guidelines and for decisions about individual patient management. They should also inform public health policy. However, their capacity to fulfil these roles will depend on how closely a trial’s participants reflect the general population of patients with the disorder that has been investigated. The extent to which a trial’s findings are relevant to the broader population of patients with the disorder is referred to as the trial’s generalisability, or external validity. The CONSORT statement refers to generalisability under Item 21 (Box 1).1 Well-written reports should discuss the various factors that influence the generalisability of the trial’s findings. Julian and Pocock have proposed a checklist of questions to assist with this assessment (see Box 2).2 To determine the generalisability of a trial’s findings, several aspects require scrutiny. Is the patient population representative of the broad target group?To make this assessment, it is firstly necessary to examine the inclusion and exclusion criteria for the trial. These criteria determine the characteristics of the potential participants. They are particularly important for trials assessing new drugs, because patients with any significant degree of renal or hepatic impairment, or any significant comorbidity, are often excluded. Excluding such participants may result in a trial population that represents only a subsection of the broader population with the disorder for which the drug may be indicated. Secondly, the baseline data should describe the population that participated in the trial. Demographic variables, age range, as well as clinical data such as blood pressure, staging of disease and any listed comorbidities, will help readers decide whether the trial population closely resembles the patient population (or individual patient) for which a decision about management is required. In some trials, the entry criteria are considerably broader than the population actually recruited. This discrepancy will only be evident if adequate baseline data are presented. For example, in a study of combination chemotherapy in malignant breast cancer, no radiotherapy was allowed in the protocol.3 Results were reported on the basis of the extent of lymph node involvement — 0–3 nodes or 4 or more — and readers might assume that the findings of the trial would apply to participants with many (more than 10) involved nodes. However, less than 8% of patients with more than 10 involved nodes were included in the study, as clinicians referred these higher-risk patients for radiotherapy rather than enrolling them in the trial.4 The original trial report did not tell readers that the group with more than 4 involved nodes actually comprised patients with primarily 4 to 10 involved nodes.5 Participant flow diagramThese diagrams are useful for assessing generalisability of trials. If properly completed, flow diagrams will indicate the number of participants: screened for participation; with the condition of interest; classed as ineligible (on the basis of exclusion criteria); and who did not elect to participate. If the population randomly allocated to groups within the trial represents only a small proportion of those with the condition of interest and assessed for eligibility, it is probable that the generalisability of the findings of the study will be limited. Large trials assessing warfarin therapy for atrial fibrillation have enrolled only about 15% of those who were potentially eligible, and this substantially limits the generalisability of their results.6,7 Where eligible patients who entered randomised trials have been compared with those who were eligible but did not participate, differences have emerged. In a study of therapy for temporomandibular disorders, 18 eligible patients did not consent and 60 were randomly allocated to trial arms.8 The 18 patients who did not consent reported more pain than those who participated, perhaps restricting the findings of the trial to those with milder pain. Differences were also evident between enrolled and unenrolled patients in the Thrombolysis in Myocardial Infarction (TIMI 9) trial.9 The TIMI 9 registry prospectively evaluated patients with ST-segment-elevation myocardial infarction. There were no exclusion criteria for the registry, but there were exclusion criteria for the randomised trial. Patients in the registry, but not enrolled in the trial, had higher baseline risk for adverse outcomes. Screening logsScreening logs list the numbers of individuals screened, eligible and enrolled, as well as reasons for not enrolling eligible patients. They thus allow readers to judge whether there are differences between patients who were and were not enrolled in the trial. If the two populations are similar, the generalisability of the trial is increased. A template of the typical information collected in the screening log is presented in Box 3. This information should be limited to the most important characteristics of the relevant population to minimise the burden on trial staff collecting the data. Screening logs also describe the range of participants with the disease being seen at each investigation site, and the patterns of care of these people. For those deemed ineligible, the criteria excluding them from the study are documented, providing further information as to the generalisability of the intervention to this cohort.10 The results of the study will apply more to subjects excluded because they were not available for follow-up or were just outside the age range than to those with concomitant disease. ComorbiditiesIn some trials, during random allocation, patients may be stratified by comorbidities regarded as potential confounders. In others, particularly in clinical trials of new drugs, comorbidities may be exclusion criteria. If these comorbidities are relatively common, the exclusion criteria will significantly limit the generalisability of the trial outcomes. This is an important issue in drug trials, as comorbidities are often exclusion criteria. When the drug is registered for use, the listed indication is often relatively broad, so it is necessary to scrutinise the clinical trials section of the product information to obtain a clearer picture of the patient population which was studied. If a patient for whom the drug is being considered has one of the comorbidities which was an exclusion criterion, whether the drug will be efficacious or safe is unknown. Such a dilemma exists with the “statin” lipid-lowering drugs. Over 160 000 patients have participated in trials of statins, but almost all of these trials have excluded patients with significant renal or hepatic disease.11-13 If some patients have characteristics which were not reported in the trial’s population, it is conceivable that the trial’s results are not relevant to these patients. Subgroup analysesAs adolescents and pregnant women are not usually included in trials, most clinical trials are of limited relevance to these groups. If there are a priori reasons to expect differences between subgroups, the trial may have stratified participants by these potential confounders. The findings of the trial will be most generalisable if the benefits are evident in each subgroup of the trial, as well as across the entire study population.14 In clinical trials with large numbers of patients or events, it is possible to have reliable subgroup analyses which may help prescribers to relate the trial’s findings more closely to patients for whom they are trying to select appropriate therapies. ConclusionsThe main purpose of conducting randomised clinical trials is to identify improvements in clinical care. Ideally, the findings of trials should apply to a wider population than those included in the trial. It is therefore vital that every effort is made to have a broad selection of patients from the population of interest to minimise selection bias. Numerous exclusion criteria will restrict the patient population and progressively diminish the generalisability of the findings of the intervention under evaluation. It is the responsibility of those reporting trials to include aspects of generalisability when discussing their findings. It is the task of those responsible for treating patients, producing clinical guidelines and formulating public health policy to carefully assess the generalisability of clinical trials before applying their findings.15 1 CONSORT checklist of items to report when reporting a randomised trial.1 Section and topic Item no. Descriptor Discussion Generalisability 21 Generalisability (external validity) of the trial findings. 2 Concepts covered in Julian and Pocock’s criteria for assessing generalisability2 Representativeness of patients for the condition in practice. Proportion of eligible patients participating. Conformity of the treatments and background care (doses, durations, follow-up period, etc) to standard practice patterns. Consistency of measured outcomes with conclusions drawn. Appropriate balance of surrogate and clinical outcomes. Reliability of evidence on efficacy and safety findings. Coverage of all relevant outcomes (adverse events and side-effects). Consideration of the study findings in the context of other available evidence. 3 Screening log template Site identification/name: ______________________________________ Date of visit: __________________________________________ Subject initials: ____________ Clinician initials: ____________ Age: ____________ Sex: ____________ Is the subject recruited into the study? yes / no If no: then: a) Main reason for exclusion: ______________________________ _____________________________________________________ _____________________________________________________ Reasons for exclusion: 1. Subject refusal 2. Clinician refusal (with possible reasons) 3. Ineligible (specify which inclusion criteria are not met and which exclusion criteria exist) 4. Language difficulties 5. Other b) Treatment actually given: _______________________________ _____________________________________________________ _____________________________________________________

J Paul Seale PhD, FRACP, FRCP · Val J Gebski MStat · Anthony C Keech FRACP, MClinEpi

Clinical trials typically require the collection of many data to describe the participants and for measuring their response to an intervention. In addition to the primary analysis of treatment effect, investigators can use these data to perform multiple analyses, but there are important pitfalls with their use.1,2 Here, we discuss three common types of secondary analyses: analyses of multiple outcome variables; analyses of trial outcomes that account for prognostic factors (adjusted analyses); and using trial data to answer secondary research questions (see definitions in Box 1). The use of trial data for population subgroup analyses has been discussed earlier in this series.3,4 What are the problems?The two main problems introduced by multiple analyses are, firstly, the increased probability of detecting intervention effects where none exist (“false positives” owing to multiple comparisons — type I errors), and secondly, the limited capability (“power”) of trials to detect a true treatment effect in secondary outcomes if not enough participants are enrolled to show a statistically significant difference in these outcomes (“false negatives” — type II errors). One study compared trial protocols with their subsequent publications, and provided empirical evidence of the selective reporting of positive trial results.5 The use of multiple analyses is therefore of particular concern when these are conducted post-hoc as a “fishing expedition”, and undue emphasis is given to positive findings. Item 18 of the CONSORT checklist (Box 2) recommends that investigators report on all multiple analyses and declare which were prespecified and which were conducted as exploratory activities after investigators were unblinded to the treatment allocation of participants.6 Analyses of multiple outcomesAdvantagesInvestigators may choose multiple outcomes to measure the effect of treatment. This is an advantage when different parameters provide information about different aspects of the treatment response.1 Secondary analyses may also assist the interpretation of the primary analysis. For example, in a recently reported trial comparing chemotherapy regimens in the treatment of patients with metastatic breast cancer, investigators selected two primary outcomes as the most important measures of treatment effect: the overall tumour response rate (measured as complete and partial response) and time to treatment failure. Secondary outcomes, including overall survival, toxicity and quality of life, provided additional information about the treatment effect.7 Including a set of supplementary outcomes may also be a practical solution when different investigators value outcomes differently. Multiple-outcomes analysis is particularly useful when a statistically significant benefit of treatment on the primary outcome can be confirmed or strengthened by a consistent effect on other relevant outcomes. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial evaluated the effectiveness of pravastatin for preventing cardiovascular events in patients with diabetes or impaired fasting glucose and a history of coronary heart disease.8 The finding of a statistically significant reduction in the risk of a major coronary event was supported by a similar reduction in the risk of a revascularisation procedure or stroke. Such findings may also advance the understanding of the relationships between outcomes. PitfallsThe type and number of analyses performed should be reported so that readers can assess the probability of detecting a treatment effect by chance alone. This is often poorly documented in trial reports.5 Additionally, major discrepancies have been observed between the primary outcome specified in the trial protocol and that reported in the published article.5 Chan et al reported that of 76 trials that prespecified a primary outcome in the trial protocol, 20 (26%) did not report on this outcome in the published article, and of 63 trials that specified a primary outcome in the published article, in 11 (17%) it was not mentioned in the trial protocol.5 An example of the latter was a study reporting on the percentage of patients with graft occlusion as the primary outcome, even though the study was not originally designed to measure a difference in this outcome.5 Caution is needed when unexpected results from multiple analyses are interpreted. Inconsistent results are more credible if the outcome variables are restricted to those that were prespecified in the trial protocol, are clinically relevant, and are based on plausible biological mechanisms. A variety of statistical corrections can be performed to take into account the increased probability of a chance finding with multiple testing. A statistically significant treatment effect for one outcome and not other clinically related outcomes may also indicate that the sample is too small — that is, the study lacks power. Interpreting the results of analyses that are underpowered is difficult. This is a common problem, for example, in the mandatory reporting of adverse events in drug trials. A trial may report on a large set of adverse events, but it will commonly not have been powered to detect a statistically significant difference in these outcomes between the trial’s study groups.1 Composite endpointsTo overcome the problem of insufficient power, investigators may combine data from clinically related outcomes to form one or more composite endpoints. This approach reduces the number of analyses required while retaining all the potentially valuable information. The TAXUS IV trial was a double-blind randomised controlled trial to determine the safety and effectiveness in coronary artery disease of paclitaxel-eluting stents compared with bare metal stents.9 The primary outcome of the trial was the incidence of revascularisation procedures due to reocclusion of the target vessel at 9 months. A composite endpoint, “major adverse cardiac events” (defined as death from cardiac causes, myocardial infarction, or revascularisation procedures), was a secondary outcome. At one year after the procedure, the rates of cardiac death and myocardial infarction were similar between the study groups, while the rate of target-vessel revascularisation was 62% lower (P < 0.0001) in the patients receiving paclitaxel-eluting stents than in those receiving bare metal stents.9 The treatment effect on revascularisation rates appeared to drive the results for the composite endpoint, resulting in a reported 49% reduction in major adverse cardiac events (P < 0.0001) at 12 months. Combining disparate events can lead to an overestimate of the clinical importance if a positive finding is largely driven by the less important events. Overall, as a result of the potential to overinterpret or misinterpret the results of analyses of multiple outcomes, readers should seek information in the methods section of the report about the primary purpose and outcomes that the trial was designed to address and interpret any additional findings in this context. Adjusted analysesClinical trials use a concealed randomisation process, with or without stratification by key prognostic factors, such as age and sex, to help to ensure the baseline similarity of the study groups.10 However, even well-conducted random allocation may still result in chance imbalances.11 If an imbalance in an important prognostic factor occurs, statistical methods can control for this imbalance by including the factor as a “covariate”. This is referred to as adjusted analysis, or a multivariate analysis if more than one covariate is included. While adjusted analyses can statistically accommodate imbalances between study groups in non-randomised studies, in randomised studies they should usually be considered supplementary to the unadjusted analysis of the primary outcome. If the adjusted effect estimate differs from the unadjusted estimate, interpretation may be a problem. For example, if some covariate data are missing and these participants are excluded from the adjusted analysis, it will not be clear whether observed differences result from controlling for this factor or another, unknown effect of these exclusions. Adjusted analysis may be indicated when a factor is known to strongly predict the outcome (for example, age and survival), even when the imbalance observed between study groups does not reach statistical significance.12 In general, adjusted analyses frequently improve the precision of the estimate of treatment effect, even when the correlation of the covariates with the study outcome is not strong.13 Another recent review of 50 consecutive published trials showed that the methods and reporting of adjusted analyses vary widely in clinical trials.14 Of the 36 trials with an adjusted analysis of the primary outcome, 42% did not report on the methods used to select the covariates.14 Using inappropriate methods for adjusted analyses may cause inaccurate and misleading results. Ideally, investigators should prespecify any prognostic factors that, if unbalanced, may affect the study outcomes and should plan for adjusted analyses accordingly. However, some strong predictors of the outcome may only become apparent at data analysis on formal testing (so-called exploratory analysis). In this situation, investigators should clearly describe when and how covariates were selected for the adjusted analysis. In any case, the primary emphasis should be on the unadjusted results, because investigators are able to conduct multiple adjusted analyses using different sets of covariates, which may lead to overinterpretation or selective reporting of significant findings. The findings of the primary unadjusted analysis are strengthened if the results of the adjusted analysis are consistent with them. Other ancillary analysesA clinical trial may seek to address ancillary questions unrelated to the primary question so as to optimise the use of resources required for a large clinical trial. Ancillary questions may relate to the treatment effect on other conditions of interest, such as the association between hormone replacement therapy and dementia in women recruited to a large trial investigating hormone replacement therapy and cardiovascular disease.15 Substudies may also use trial data to investigate epidemiological questions about the natural history of disease, the biological mechanisms of the disease16 or the treatment response.17 Ideally, these ancillary studies should be designed before the trial starts. However, important new information or scientific debate may arise during or after the trial to justify the use of trial data to investigate new hypotheses. Their results are more convincing if the decision to conduct the analysis has been made before unblinding. The same potential for overinterpretation and selective reporting of the results of multiple comparisons and reduced power apply to exploratory analysis, and any new findings should be regarded as new hypotheses for validation in future studies. The principles of planning, reporting, analysing and interpreting multiple analyses are shown in Box 3. These are not intended to discourage investigators from conducting potentially important exploratory analyses of plausible new hypotheses. Rather, they encourage the balanced reporting of all analyses to prevent unsound manipulation of data or undue emphasis on particular findings that may misdirect future research or compromise the interpretation of results for clinical practice. 1 Definitions Primary outcome: The health parameter measured in all study participants to detect a response to treatment. Conclusions about the effectiveness of treatment should focus on this measurement. Primary analysis: The statistical test performed to determine whether there is a difference in the primary outcome between participants allocated to receive the treatment and those allocated to the control arm. Secondary outcomes: Other parameters that are measured in all study participants to help describe the effect of treatment. Baseline variables: The characteristics of each participant measured at the time of random allocation. This information is documented to allow the trial results to be generalised to the appropriate population/s. Specific characteristics associated with the patient’s response to treatment (such as age and sex) are known as prognostic factors. Multiple analyses: Comparisons between the study groups for more than one outcome. They increase the likelihood of detecting a difference between the treatment and control group owing to chance alone (false positive). Common examples of multiplicity in trials include the use of: multiple outcomes, including surrogate endpoints; multiple treatment comparisons (in a multiarm trial); subgroup analyses to detect differences in the treatment effect in one or more subsets of trial participants; adjusted analyses to control for imbalances in prognostic factors between the study groups; repeated measures over time of the same outcome; and interim analyses of the treatment effect at different stages in the trial. Exploratory analyses: Analyses that were not specified before the trial or, for blinded studies, analyses planned after the investigators were unblinded to the treatment allocation of participants. These analyses may be driven by the results of the primary analysis. 2 CONSORT checklist of items to include when reporting a trial6 Selection and topic Item no. Descriptor Ancillary analyses 18 Address multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those prespecified and those exploratory. 3 Checklist for multiple analyses Design and methods Were the primary and secondary outcomes for the detection of treatment response prespecified? Was the trial designed to have adequate power for the analyses of all outcomes? Were the covariates for the adjusted analyses and/or the method used to select these covariates prespecified? Were the substudies based on an existing trial or biological data? Were the substudies planned prior to unblinding of data? Analysis Have corrections for multiple-significance testing been performed? Was the combination of data into a composite outcome appropriate? Was the interpretation of the composite endpoint results appropriate? Reporting Are the total number of analyses performed reported? Was the power calculation reported for the primary outcome? Secondary outcomes? Are the rationale and methods of any adjusted analyses reported? Are the number and type of covariates in the adjusted analyses reported? Are the unadjusted and adjusted results reported? Are the prespecified analyses clearly distinguished from the exploratory analyses? Interpretation Is appropriate emphasis given to the primary outcome? Have the relationships between interrelated outcomes been explored with equal interest? Are the findings of the multiple analyses discussed in the context of current biological knowledge and current research?

Sarah J Lord MB BS, MScEpid · Val J Gebski BA, MStat · Anthony C Keech MScEpid, FRACP

Altruism and trust lie at the heart of research on human subjects. Altruistic individuals volunteer for research because they trust that their participation will contribute to improved health for others and that researchers will minimise risks to participants. In return for the altruism and trust that make clinical research possible, the research enterprise has an obligation to conduct research ethically and to report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavourably on a research sponsor’s product. Unfortunately, selective reporting of trials does occur, and it distorts the body of evidence available for clinical decision-making. Researchers (and journal editors) are generally most enthusiastic about the publication of trials that show either a large effect of a new treatment (positive trials) or equivalence of two approaches to treatment (non-inferiority trials). Researchers (and journals) typically are less excited about trials that show that a new treatment is inferior to standard treatment (negative trials) and even less interested in trials that are neither clearly positive nor clearly negative, since inconclusive trials will not in themselves change practice. Irrespective of their scientific interest, trial results that place financial interests at risk are particularly likely to remain unpublished and hidden from public view. The interests of the sponsor or authors notwithstanding, anyone should be able to learn of any trial’s existence and its important characteristics. The case against selective reporting is particularly compelling for research that tests interventions that could enter mainstream clinical practice. Rather than a single trial, it is usually a body of evidence, consisting of many studies, that changes medical practice. When research sponsors or investigators conceal the presence of selected trials, these studies cannot influence the thinking of patients, clinicians, other researchers, and experts who write practice guidelines or decide on insurance-coverage policy. If all trials are registered in a public repository at their inception, every trial’s existence is part of the public record and the many stakeholders in clinical research can explore the full range of clinical evidence. We are far from this ideal at present, since trial registration is largely voluntary, registry data sets and public access to them varies, and registries contain only a small proportion of trials. In this editorial, published simultaneously in all member journals, the International Committee of Medical Journal Editors (ICMJE) proposes comprehensive trials registration as a solution to the problem of selective awareness and announces that all eleven ICMJE member journals will adopt a trials-registration policy to promote this goal. The ICMJE member journals will require, as a condition of consideration for publication, registration in a public trials registry. Trials must register at or before the onset of patient enrolment. This policy applies to any clinical trial starting enrolment after 1 July 2005. For trials that began enrolment before this date, the ICMJE member journals will require registration by 13 September 2005 before considering the trial for publication. We speak only for ourselves, but we encourage editors of other biomedical journals to adopt similar policies. For this purpose, the ICMJE defines a clinical trial as any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (eg, phase I trials), would be exempt. The ICMJE does not advocate one particular registry, but its member journals will require authors to register their trial in a registry that meets several criteria. The registry must be accessible to the public at no charge. It must be open to all prospective registrants and managed by a not-for-profit organisation. There must be a mechanism to ensure the validity of the registration data, and the registry should be electronically searchable. An acceptable registry must include at minimum the following information: a unique identifying number, a statement of the intervention (or interventions) and comparison (or comparisons) studied, a statement of the study hypothesis, definitions of the primary and secondary outcome measures, eligibility criteria, key trial dates (registration date, anticipated or actual start date, anticipated or actual date of last follow-up, planned or actual date of closure to data entry, and date trial data considered complete), target number of subjects, funding source, and contact information for the principal investigator. To our knowledge, at present, only www.clinicaltrials.gov, sponsored by the United States National Library of Medicine, meets these requirements; there may be other registries, now or in the future, that meet all these requirements. Registration is only part of the means to an end; that end is full transparency with respect to performance and reporting of clinical trials. Research sponsors may argue that public registration of clinical trials will result in unnecessary bureaucratic delays and destroy their competitive edge by allowing competitors full access to their research plans. We argue that enhanced public confidence in the research enterprise will compensate for the costs of full disclosure. Patients who volunteer to participate in clinical trials deserve to know that their contribution to improving human health will be available to inform healthcare decisions. The knowledge made possible by their collective altruism must be accessible to everyone. Required trial registration will advance this goal.

Catherine De Angelis MD · Jeffrey M Drazen MD · Frank A Frizelle MB ChB · Charlotte Haug MD · John Hoey MD · Richard Horton · Sheldon Kotzin · Christine Laine MD, MPH · Ana Marusic MD, PhD · A J P M Overbeke MD, PhD · Torben V Schroeder MD, DMSc · Hal C Sox MD · Martin B Van Der Weyden MD, FRACP, FRCPA

QuestionDoes early detection (by prostate-specific antigen [PSA] testing and digital rectal examination) and treatment of prostate cancer reduce the risk of death from prostate cancer among men aged 45–80 years invited to screening? Trial details Design: Randomised controlled trial. Setting: Population-based study in Quebec City, Canada. Participants: 46 193 men aged 45–80 years registered on the electoral roll of Quebec City and metropolitan area. Interventions: Invitation to attend annual PSA testing and digital rectal examination to screen for prostate cancer from November 1988 to December 1996. Main outcome measure: Deaths from prostate cancer. Main results: Death rates from prostate cancer over 8 years were 48.7 per 100 000 man-years for unscreened men and 15 per 100 000 man-years for screened men; the death rate was 69% lower in screened men. Conclusions: The authors concluded that “. . . this approach demonstrates, for the first time, that early diagnosis and treatment permits a dramatic decrease in deaths from prostate cancer.” CommentaryRationale for the trialScreening for prostate cancer could be done by means of PSA testing, but whether this would reduce mortality from the disease was not known. No randomised trials on the question had been undertaken when the study began in 1988. Trial methodsBenefit from cancer screening can only be validly assessed by randomised trials which compare mortality rates over the same time period among people randomly allocated to early detection and treatment or to usual care. This is necessary because studies of cancer screening can show an apparent benefit even if screening is completely ineffective, because: Survival may appear better among screen-detected cases simply because the diagnosis was made earlier (“lead-time bias”) — if the time of death is not altered, cases detected by screening may be getting more “disease time” rather than more life time; Screening preferentially detects slower, less aggressive cancers which have a longer preclinical (but screen-detectable) phase — fast-growing cancers are more likely to be missed by screening because they are more likely to develop and progress in the interval between screenings, giving the appearance of better outcomes among screened people (“length-time bias”); and People who attend for screening are generally healthier and more health conscious, so their risk of death from any cause is lower.1 The major strength of this study is that it was designed as a randomised trial and therefore could potentially validly answer the question. Important methodological features of good randomised trials are: high-quality randomisation with allocation concealment; blinded assessment of outcomes; high follow-up rates; and analysis by intention to treat.2 The major (and fatal) weakness of this study is that the primary analysis was not as a randomised trial (ie, by intention to screen). The authors compared the prostate cancer mortality rate among men who were screened (15 deaths/100 000 man-years) with that among men who were not screened (48.7 deaths/100 000 man-years). However, they included in the screened group men who had not been allocated to screening, but who sought screening anyway. They also included in the non-screened group men who were allocated to screening but did not attend. They thus destroyed their randomisation, reducing the study to an observational one. Their analysis yields a statistically significant, and apparently impressive, 69% relative reduction in prostate cancer mortality. However, this analysis is almost certainly biased (by one or more of the biases listed above). The authors also report what they originally set out to do — an intention-to-screen analysis which preserves the randomisation — as a secondary analysis. They report a 6% relative reduction in prostate cancer mortality (relative risk, 0.94) but provide no significance test or confidence interval. We have estimated these from the article’s data and found the result to be non-significant, with a 95% confidence interval of about 0.71–1.25. This means the true effect could be anywhere between about a 30% reduction to a 25% increase in prostate cancer mortality. The null result may be attributed to the poor participation in screening in the study. In the group invited to screening, only 23.1% actually attended for screening. In the control group, 6.5% of uninvited men attended for screening. While these “drop-out” and “drop-in” rates do not invalidate the study if it is analysed correctly, they inevitably cause a substantial attenuation of the intervention if it is effective. It is possible to adjust for this attenuation (due to poor participation) by methods previously described.3,4 However, in the case of this trial, adjustment will not be useful, as the adjusted estimate will also be non-significant, with a wide confidence interval. New informationNone — this trial contributes no new valid information. Implications for clinical practiceNone — we still have no evidence from good-quality, randomised trials about whether screening for prostate cancer reduces prostate cancer mortality. Two large trials are in progress, but are not expected to report results for some years yet.

Alexandra L Barratt MPH, FAFPHM, PhD · Alan S Coates AM, MD, FRACP, AStat

When decisions about a new intervention are being made, the “net clinical benefit” of the intervention needs to be assessed. This requires balancing all the reported benefits and side effects of the intervention. The adverse events experienced in a trial must be known in sufficient detail for their severity and relationship to treatment allocation to be judged. Reporting of such events is the subject of item 19 of the CONSORT statement (Box 1).1 What is an adverse event?The definition of adverse events (AEs) adopted by the International Conference on Harmonization (ICH) is shown in Box 2; it is designed to document all untoward events occurring in a clinical trial.2,3 AEs are thus both those events for which there is a known or plausible association with treatment and those for which there is none. Adverse drug reactions (ADRs) are those AEs that may reasonably be attributed to the medication (Box 2), distinguishing between medications that are used in accordance with their marketing approval (eg, in the approved dose, patient population and indication) or not.2,3 AEs are also classified as being serious or non-serious (Box 2 and Box 3). Standard schemes used to classify AEs, usually by body system, allow for easier comparison between different trial results and between different treatment options. Examples include the International classification of diseases,4 and the Medical dictionary for regulatory activities.5 Some classifications also grade severity of AEs, such as the Common terminology criteria for adverse events (CTCAE) system of the United States National Cancer Institute,6 which has five grades of severity, ranging from 1 (mild) to 5 (death). Regulatory requirements for reporting adverse eventsTo reliably report on AEs, procedures must be in place from the beginning of a trial for systematically recording and reporting them.2 All investigators participating in a clinical study, and their respective human research ethics committees (HRECs), must have been provided with an investigator’s brochure which includes all relevant information known about the safety, efficacy and pharmacodynamics of the investigational drug, and a description of the possible risks and adverse drug reactions associated with the drug and similar products.2 Good clinical practice guidelines require investigators to report immediately to the trial sponsor any serious AEs that occur during the conduct of a trial.2 In turn, many countries require the study sponsor to then report these to national regulatory authorities. An AE which is considered to be a serious unexpected adverse drug reaction7 must be notified by the sponsor to relevant regulatory authorities as an “expedited” SAE within 7 days of awareness for events that were fatal or life-threatening, and within 15 days for others.3 ICH guidelines for good clinical practice, as adopted internationally, also specify that all serious unexpected adverse drug reactions should be reported to the relevant HRECs.7 It is not possible to assess the significance of AEs from reports in which the treatment allocation remains blinded and the number of participants exposed to the trial medications is unknown. Hence, Data and Safety Monitoring Boards (with the ability to review events and their frequencies unblinded, if preferred) are an important (although insufficiently used8) mechanism for protecting the safety of trial participants9 and for ensuring that studies are stopped as soon as it becomes clear that the trial intervention is beneficial or harmful.10,11 Australian requirements for adverse event reportingIn Australia, the Therapeutic Goods Administration (TGA) only requires reports on serious unexpected adverse drug reactions that occur in Australia, and that it be informed of any significant safety concerns that arise from the sponsor’s monitoring of overseas safety reports and of any action undertaken by overseas regulatory agencies.3 In Australia, the section of the ICH good clinical practice guidelines on reporting to HRECs has been overridden by the National statement on ethical conduct in research involving humans.12 This mandates that investigators inform the TGA and HRECs of “all serious or unexpected AEs that occur during the trial and may affect the conduct of the trial or the safety of the participants or their willingness to continue participation in the trial”. One consequence of this directive is that HRECs in Australia are being inundated with large numbers of essentially uninformative AE reports.8 Presentation of adverse event reportsPatient selection can influence the rates of AEs. It is important that the trial population is described adequately so that clinicians can assess the risk of a particular treatment for an individual patient. It is also important that the mechanisms used to elicit reporting of AEs are documented. Volunteered reports of AEs can give incidences of AE markedly different from those ascertained through checklists or diaries.13,14 Counts of adverse eventsThe numbers of patients who had each type of AE should be clearly detailed in the study report. If some patients experience more than one type of AE, the numbers of each event type should also be documented.1 Both the number of patients experiencing at least one occurrence of the event of interest (for statistical analyses) and the total number of such events observed (for cost–benefit analysis) help interpretation (Box 4). Types of adverse eventsThe types of events chosen for reporting must be prespecified and may be selected on the basis of absolute numbers of events (ie, the most common events), biological relevance to the drug or study question, clinical relevance, or safety (ie, serious or severe events are reported). Adverse events by treatmentPresentation and comparisons of AEs are generally reported by allocated treatment (ie, the intention-to-treat [ITT] principle), but reporting by “treatment actually received” can also be useful in some settings. For example, where non-compliance rates with allocated treatment are substantial, ITT analyses will under-report treatment-related AEs. However, analyses by “treatment actually received” will provide only non-randomised comparisons and therefore contain a varying degree of selection bias.16 Therefore, ITT methods should be routinely reported, and data for treatment actually received should be added, with an explanation as to why, if there are high rates of non-compliance. Treatment withdrawal after adverse eventsAdverse events resulting in withdrawals from treatment should also be adequately described, as they reflect tolerability of treatment, and will be useful for both patients and clinicians to better assess the importance of particular reported AEs. Abstracts and keywordsFinally, when the study is published, the abstract and keywords should mention the term “adverse events”, even if none occurred in the study, to facilitate retrieval of AE data from databases such as MEDLINE.17 Current deficiencies in trial reportsA statement in the results section of a publication that “no adverse events were observed on the trial medication” without details in the methods section of the steps taken to ascertain AEs is difficult to interpret. What is less apparent is how difficult it really is to convey useful information on the types, severity and incidences of the AEs observed. Even large, multicentre studies published in first-rate journals can fail to report the number of patients who withdrew because of side effects of the trial medication. For example, a large study on the efficacy of irbesartan in preventing the development of nephropathy in patients with type 2 diabetes and microalbuminuria has the following description of the AEs observed: “Serious adverse events during treatment and up to two weeks after treatment were recorded in 22.8 percent of the patients in the placebo group and 15.4 percent of those in the combined irbesartan groups (P = 0.02). Nonfatal cardiovascular events were slighty more frequent in the placebo group (8.7 percent, vs. 4.5 percent in the 300 mg group; P = 0.11). The study medication was permanently discontinued in 18.9 percent of the patients in the placebo group, as compared with 14.9 percent of those in the combined irbesartan groups (P = 0.21).”18 In the report, the AEs that led to discontinuation were not described. Furthermore, it was unclear whether they were related to the condition being treated, to the trial medication, or to intercurrent illnesses. Guidelines have been developed to help researchers give useful information about AEs for reporting, both in general1 and for particular classes of trial, such as chemotherapy19 or postoperative analgesia.13 The need for such guidelines is evident from studies of adequacy of AE reporting. In one evaluation of reporting of safety data from clinical trials of HIV treatment, the severity of AEs was regarded as adequately defined in only a third of trials.20 In a subsequent study in other clinical areas, only 39% of trials adequately reported clinical adverse effects and only 29% adequately reported laboratory-determined toxicity.21 Other studies show similar rates of deficiencies in AE reporting in a variety of circumstances.22-25 These deficiencies are serious, as they can prevent clinicians from being able to provide patients with balanced information about the scale and scope of risks associated with different treatment strategies. Even when AEs have been well described, retrieving data about them can be problematic — of a sample of 37 trials indexed on MEDLINE or EMBASE known to present AE data, only 49% could be found by searching for text words such as “adverse event”, “side effect” or “h(a)emorrhage”, while adding indexing terms relevant to AEs only improved retrieval to 78%.17 ConclusionLarge randomised controlled trials and meta-analyses of randomised controlled trials are very effective in distinguishing AEs that are caused by the underlying condition from those that are related to the intervention. They can provide clinicians with unbiased information about the frequency and severity of adverse effects at a time when a drug or procedure is new. While other mechanisms for obtaining safety data are needed to detect AEs that are too rare to be detected by even the largest studies (Box 5), or that occur in groups of patients who would normally be excluded from trials (eg, because of illness severity, comorbid conditions or the need for potentially confounding therapies), these do not allow clinicians to quantify the risk of a treatment26 and can give markedly different impressions of the incidence of adverse drug reactions compared with those obtained from randomised clinical trials.27 Only proper reporting of AEs from randomised controlled trials allows adequate assessment of the potential net clinical benefits of interventions. 1 CONSORT checklist of items to report when reporting a randomised trial1 Section and topic Item no. Descriptor Results Adverse events 19 All important adverse events or side effects in each intervention group. 2 Definitions adopted by the International Conference on Harmonization, and adopted by Australia’s Therapeutic Goods Administration2 Adverse event An adverse event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medical (investigational) product. Adverse drug reaction Before marketing approval: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase “responses to a medicinal product” means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility. After marketing approval: a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function. Unexpected drug reaction An adverse drug reaction, the nature or severity of which is not consistent with the applicable product information (eg, investigators’ brochure for an unapproved investigational medication). Serious adverse event or reaction Any untoward medical occurrence that at any dose: Results in death Is life-threatening Requires inpatient hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Causes a congenital anomaly or birth defect 3 Severity and causality of adverse events (AEs) * Or more severe than previously known. NSAE = non-serious adverse event; SAE = serious adverse event; SADR = serious adverse drug reaction. 4 Checklist for presenting adverse event (AE) reports Describe methods used to ascertain AEs (eg, reported by physician or patient) Show events which are unexpected in the context of the treatment given Categorise the seriousness of events where relevant Report AEs by the number of patients affected and by the number of events Report AEs by intention-to-treat methods (may additionally be shown by treatment actually received) Highlight AEs whose severity causes withdrawal or modification of treatment Highlight substantial differences in the risk of an AE for different subgroups of participants Use time-to-event (Kaplan–Meier survival) methods to avoid inflated estimates, where discontinuation rates have been high in long-term trials15 Mention key AE findings in the abstract and keywords of the report 5 Numbers of patients that need to be exposed to a medication to ensure that an adverse drug reaction has a 95% probability of being observed at least once Frequency of adverse drug reaction Minimum no. of patients required* Very common (≥ 10%) 29 Common (1%– < 10%) 299 Uncommon (0.1%– < 1%) 2 994 Rare (0.01%–< 0.1%) 29 956 * Number is based on the lower boundary of each category of frequency.

Anthony C Keech FRACP, MClinEpi · Susan M Wonders BDS · Val J Gebski BA, MStat · David I Cook FAA, FRACP