Research audit and publication

Best Practice & Research Clinical Anaesthesiology Vol. 20, No. 4, pp. 653e668, 2006 doi:10.1016/j.bpa.2006.09.005 available online at http://www.sciencedirect.com

12 Research audit and publication Brian J. Pollard*

BPharm, MB, ChB, MD, FRCA

Professor of Anaesthesia, The University of Manchester, Honorary Consultant in Anaesthesia and Critical Care, Central Manchester and Manchester Children’s University Hospitals NHS Trust, Editor-in-Chief, European Journal of Anesthesiology University Department of Anaesthesia, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK

The ethics of research, audit and publication have developed mainly within the last fifty years. The Declaration of Helsinki is the universally accepted code of conduct for researchers worldwide. All research has to be approved by an ethics committee, all of which are governed by a centralised structure which is the Central Office for Research Ethics Committees (COREC) in the UK. This standardised system has been developed to oversee all research activity across the whole of Europe and every European county will have an equivalent organisation. The committees concern themselves with research but the differences between audit and research are difficult to discern in many places. If there is any doubt then the advice of the local research ethics committee should be sought. Only the individual him/herself can give consent. This may produce difficulties in cases of certain groups especially unconscious patients and children. The outcome of every study should be published whatever the results and the ongoing development of centralised (national) research trial databases will promote this philosophy. Publication of results thought to be of lesser importance may prove difficult, however, and so there is a temptation to falsify or modify data to make it more attractive. This, together with other activities such as the fabrication of data, plagiarism, dual publication, salami publication, conflicts of interest and irregularities in authorship, have given Editors of journals a number of problems. Many of these issues around publication ethics may prove difficult to detect but the fear of sanctions from employers and professional organisations is a useful deterrent. Key words: scientific misconduct; ethics; ethics committees, research; medical audit; publishing; plagiarism; informed consent.

INTRODUCTION Ethics in the world of research and publishing is not new. It is not a new speciality or a new science. It has been in existence as long as science itself. The ethical principles to * Tel.: þ44 161 276 8650; Fax: þ44 161 273 5685. E-mail address: [email protected] 1521-6896/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.

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which we all presently adhere, however, have only been developed over the last fifty years or so. Interest has also increased markedly in the last five to ten years, driven mainly by a small number of high profile cases where the ethics were called into question. Many believe that it is a minority that has produced a problem for the majority. This may not, however, be an accurate representation of the situation because it is impossible to determine the precise level of unethical behaviour in the world of research and publishing. THE BASIC ETHICS OF RESEARCH Any research that involves patients must be approved by an independent committee specifically established for that purpose. This, in the past, was usually called the Hospital Ethics Committee. From this developed a national system of committees known as the Local Research Ethics Committees (LREC). It then became clear that multicentre studies needed to be considered by many LRECs with a considerable amount of time and resource duplication. The Multi-centre Research Ethics Committees (MREC) were therefore developed. These have all been now taken under the umbrella of a centralised system known as the Central Office for Research Ethics Committees, or COREC. This new organisation came into being following the new ‘‘Medicines for Human Use (Clinical Trials) Regulations, 2004’’, a Government Bill which implemented the wider European Clinical Trials Directive (Directive 2001/20/EC). It came into force on 1st May 2004. Almost a year later, on 1st April 2005, the National Patient Safety Agency (NPSA) in the UK was expanded and COREC came under the umbrella of the NPSA. The effect of COREC has been to standardise the process and requirements of ethical matters concerning patient research across the whole of the UK and bring it into line with other parts of Europe. The information available for patients, public, researchers and members of Ethics committees is extensive and the reader is referred to the COREC website for more information (http://www.corec.org.uk). An ethics committee has a standard membership which includes not only clinicians from several principal specialities but also lay members, patient representatives, statistician, etc. This committee must approve the protocol before the study can begin. The protocol approved must also not be varied without informing the committee. The individual institution (Hospital, University or other) will also have a Research and Development Department which must maintain a database of ongoing research projects and which should have been informed at a relatively early stage of the project proposal. They may require some form of peer review process of the proposal at an early stage. These safeguards are to protect not only the patient but also the researcher. It is very likely that informed consent will have to be taken from every patient recruited. A patient information leaflet will often be needed which can be retained by the patient and has the main elements of the study outlined in terms which a non-medically trained individual can readily understand. The COREC website offers examples of good patient information explanations. It is common to advise that patients are given at least twenty four hours to consider whether or not they wish to be included in a study. This can be extremely difficult in cases which are urgent but then this point would have been considered by the REC at its approval meeting. The issues with respect to animals are no less stringent. The use of animals in research is governed by a local committee in certain countries or by a central agency as in the UK. An individual researcher would be licensed to undertake that particular study in that particular way and be subject to inspection at any time. Detailed records

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have to be taken and retained. National and international guidelines are in place to oversee the local committees work. EU DIRECTIVE The EU Clinical Trials Directive (2001/20/EC) is concerned with ‘the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products for human use’.1 The principal aims seem to have been to harmonise across the EC the administration governing clinical trials. It also attempts to establish transparency, improve the co-ordination of clinical trials across the EC and protect the Human Rights of those subjects who are enrolled in clinical trials. The Medicines for Human Use (Clinical Trials) Regulations 2004 implemented the EC directive in the UK and came into force on 1st May 2004. The reader is referred to the website of the Medicines and Healthcare Products Regulatory Agency (MHRA) for full details of the regulations as they apply to the UK (www.mhra.gov.uk). The following is a summary taken from the website: ‘‘The regulations provide a statutory basis for  Standardisation of procedures for ethical and competent authority consideration and authorisation  Good Clinical Practice (GCP) standards for commencing and conducting trials  Good Manufacturing Practice (GMP) standards for medicines used in clinical trials  Inspections against internationally accepted principles and standards of GCP and GMP supported by enforcement powers.’’ The EU directive and its implementation in the UK was not viewed universally as good news. There was an immediate fear that phase 1 (and possibly phase 2) clinical trials would become virtually extinct in the UK, being transferred to other countries outside the EU. The situation was well summarised by Allen in 2003.2 It is not clear whether this has been a significant change or not. It is likely that some researchers have, however, decided to change their research bases because of the complexities and costs of the new system. In short, the environment could be seen as just too hard with the increased bureaucracy and increased staff. Time will tell whether these concerns are valid or not. Each study or trial involving a medicinal product now must have been authorised by the MHRA as well as an ethics committee, have an identified sponsor, follow specific rules with respect to informed consent and be subject to regulatory inspections. Failure to comply with the regulations may constitute a criminal offence. THE DECLARATION OF HELSINKI The development of ethical issues with respect to research began in earnest some 50e60 years ago. This was in great part fuelled by the issues surrounding the Ethics of using prisoners as unwilling research subjects in the Second World War without any consent and little regard for their welfare. In 1947 in the wake of these scandals, the Nuremberg Code was born. Ten standards were laid down by the war tribunal at Nuremberg to which physicians had to conform when their research involved human subjects.3 These were adopted by locally driven processes in individual institutions and

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from there it was taken up by the World Medical Association who created and adopted the Declaration of Helsinki in 1964.4 There have been a number of amendments of the Declaration of Helsinki over the years the latest being from the World Medical Association General Assembly in Tokyo in 2004. The Declaration of Helsinki is a statement of ethical principles which applies internationally and provides ‘‘guidance for physicians and other participants in medical research involving human subjects’’.4 It has been widened to include human material and human data. The Declaration recognises the need for medical research but places a duty on the researcher to safeguard the life, health, privacy and dignity of the subject. It is essential reading for anybody embarking on a career which involves research on humans and the reader is recommended to visit the website. From the point of view of those planning research paragraph 29 should be carefully noted. This paragraph draws attention to the comparator for testing any new method or treatment. It should be tested against the best currently available and not simply against placebo. The use of a placebo is ethical if there is no already proven treatment or if the condition is so minor that a patient will not be subject to any additional risk. This paragraph must also be continuously borne in mind by the Editor and referees of a scientific journal. Although the ethics committee which approved the study should have picked up on this point, the occasional study can creep through which might potentially breach this part of the code of conduct. Paragraph 30 of the Declaration of Helsinki has provided the stimulus for a great deal of discussion in other forums in recent years. This paragraph puts the onus on the physician to provide, at the end of the study, the best proven method identified by the study. As a past Chair and current member of a Medicines Management (Drugs and Therapeutics) Committee of a major teaching hospital, this chapter author has seen a number of difficult discussions around this issue. For example a physician comes to the end of a study which involves a new, and usually expensive, treatment. The study shows that the new treatment is better for certain patients. Is it ethical to then change the patient back onto an existing (and cheaper) treatment? Probably not as that would go against the advice in paragraph 30. But then who is going to fund this expensive new treatment? The result of these discussions has been to establish closer links with the research ethics committee so that any such issues can, hopefully, be anticipated in advance. In addition to the Declaration of Helsinki, every researcher is governed by his or her own individual professional organisation. The General Medical Council Good Practice in Research guidelines5 set out requirements for every registered medical practitioner who conducts research. Other professions also have their own regulatory bodies, e.g. The Health Professions Council for Clinical Scientists and other professions allied to medicine. CONSENT It is a basic principle of treatment and of Human Rights that the subject consents to the procedures planned and that if any deviation is necessary then that should be checked with the subject first if at all possible. Clearly that is not always possible in the case of, for example, an anaesthetised patient. In the context of routine treatment however, what is going to be done is in the interests of the patient. This is not necessarily the case with research. Informed consent is therefore vitally important and no deviation is possible, unless it is to save the patient’s life, for example.

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The subject in a research study should give free and informed consent. This implies that they have been given sufficient information with which to make their decision. This needs to include details of what is going to be done, the extent of their participation and any risk and benefits to themselves as well as potentially to others. The researcher has responsibility to ensure the well-being of the subject. A researcher must also be aware at all times of any possible consequences and other effects of the study and make every effort to anticipate and prevent any harm from befalling the patients. The very act of participating in a research study may itself cause anxiety and this must be borne in mind if anxiety is one parameter being measured, for example. As mentioned previously, it is common current practice for the Ethics Committee to require a detailed patient information and consent form detailing all of this and which is written in layman’s language. The subject will also need to be given a reasonable period of time (often twenty four hours minimum) to reflect on the information, return with any questions and probably discuss the request with relatives. Such a requirement for a twenty four hour delay can cause problems with research on urgent or emergency admissions. This will have been considered by the Ethics committee however. The situation of research on the Intensive Care Unit or on patients otherwise admitted unconscious has given cause for concern. The only person who can truly give valid consent is the ‘owner’ of the body, i.e. the subject him or herself. That would make such research impossible. The way round is to take ‘consent’ from the nearest relative. Although taking consent from the nearest relative is common practice and the best that we can do, its legal standing must remain in question. Once the patient recovers and can give (or not) their own consent, then the study should be explained to the patient and ‘correct’ informed consent taken from the patient themselves. Clearly the patient is at liberty to decide to refuse to give consent. If the patient does refuse it puts the researcher in a difficult position but provided the ruling of the Ethics committee which approved the study has been followed and the researcher has acted in good faith, then there should be no problems. It is necessary, however, to discard all of the data from that patient. As a part of the consent procedure, each subject must have it carefully explained that they have a complete right to withdraw consent at any time, to refuse to participate, to anonymity and to confidentiality. A competent adult is capable of giving informed consent. But what determines competency? All would probably agree that a ‘normal’ adult can give informed consent and an adult with learning difficulties might not be able to do so. What about the patients who lie between these two extremes? One case in point might be the patient with dementia. Despite apparent confusion or difficulties with understanding, many may still be able to give their own consent and each needs to be treated on an individual basis. A child has traditionally been deemed incapable of giving consent below the age of sixteen years. It is clearly nonsense, however, for a parent to have to give consent one day yet the following day when the child has passed their 16th birthday, they are capable of giving their own consent. Some children much younger may be entirely capable of giving consent. Again each must be considered on its own merits. (See Consent Chapter. Alan Aitkenhead). THE VANCOUVER AGREEMENT In January 1978, the editors of several biomedical journals met together in Vancouver. The agenda was centred around matters of style and preparation of manuscripts for

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publication with the aim of trying to achieve greater uniformity throughout the medical publishing world as a whole.6 This meeting created what was to become known as the International Committee of Medical Journal Editors (ICMJE) [www.icmje.org]. As a part of the agenda, the group also examined some basic principles concerning Ethical matters of publication and much of what followed with respect to our knowledge of the Ethics of publication probably stems from that date. The issues discussed were, in particular, duplicate publication, financial conflicts of interest, rules of authorship and ethical clearance of protocols. This is only the tip of a very complex iceberg, however. THE ETHICS OF PUBLISHING Every journal requires a written statement from the author confirming that the appropriate ethics committee has cleared the study protocol and, by implication, any alterations have also been so approved. We are here taking the word of the author that this has been done. Were it necessary to verify ethical clearance, the only way would be to request proof from the author and that would be extremely difficult. The final paper and the original protocol may have different titles, protocol variations may have occurred and approved, the individual patient consent forms may be filed in the hospital notes, etc. Absolute verification of all aspects of ethical clearance is probably impossible in the majority of cases. It is vital, however, for every researcher to ensure that ethical clearance is correctly obtained and that all records, correspondence, etc are retained for future reference. The regulations with respect to retention of records is unclear in many case but as a general rule, most believe that it is wise to retain all records for a minimum of ten years and in some cases retention for up to twenty five years may be necessary. An analogous situation prevails with research involving animals where a statement will be required confirming that the study has been conducted in accordance with the animal experimentation regulations of the country concerned. Journals all insist on a declaration which may differ slightly between journals in its wording but essentially the manuscript must:  Not have been published before (expect possibly as an abstract or as a part of an academic thesis or lecture)  Not be under consideration by any other journal  Be the work of all of the authors  Have the final draft approved by all of the authors  Not be published again anywhere else  Have been approved by an appropriate ethics/animal use committee Interest in research and ethics seems to have increased in the last five to ten years driven mainly by a small number of high profile cases where the ethics were called into question. Many believe that it is a minority that has produced a problem for the majority. This may not, however, be an accurate representation of the situation because it is impossible to determine the precise level of unethical behaviour in the world of research and publishing. FRAUD IN RESEARCH To determine the prevalence of fraud is probably impossible. Research is prone to accidental mistakes just as any activity would be. Fraud is a deliberate act of omission

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or commission however, aimed at furthering personal gain (e.g. funding, promotion, status) with complete disregard for the consequences. Although we like to think that it is an uncommon and isolated event, evidence exists to suggest that it is actually a widespread activity.7 The results of fraudulent activity may be much more far-reaching than at first realised. The major problem is possible use of the data to guide patient management with potential harm to the patient. Erosion of public trust of course follows on from the various high profile cases which reach the press. DATA FABRICATION It is hard to understand how it may be possible to fabricate a complete data set and this must be extremely rare. Fabrication of part of the data (even just one patient) is probably much more common and in some ways understandable, although that statement is not to condone the practice. Reasons might include the study taking longer than planned, the deadline approaching for writing up, patient recruitment having proved far more difficult than expected. These may be reasons that have lead to data fabrication but they are not excuses to fabricate data. Checking is extremely difficult. The majority of researchers, even though innocent, would be offended by a request from an editor to inspect their data even if the editor had the time to do it. The guilty researcher would probably be even more offended by the request because it might lead to discovery. If a researcher simply provides a set of data collection sheets though it might still be impossible to detect one or two nonexistent patients without going back to the institution and requesting to see every patient‘s notes. Clearly a mammoth e and probably impossible e task. The scientific community relies upon local knowledge to police this aspect8 although it may not be for some years before a fraudulent publication is exposed by another team attempting to repeat the original work. There are statistical tools available which can be used to indicate if data has been fabricated. These rely on the assumption that it is impossible to invent plausible data. It would be risky, however, to try and rely on such tests alone to prove that a data set was fabricated without other evidence. It is clear to see why data fabrication is committed. The academic system in many countries perpetuates it with the ‘publish or perish’ philosophy. In addition, the higher the impact factor of the journal you can reach, the more important you are in the organisation. The income stream to the department may depend upon recruitment if payment is per patient. If the next grant success depends upon a positive finding from this study or promotion to the next grade depends on the outcome of this study and you have told the Head of Department that it will work then there could be a clear stimulus to do something foolish. DATA MANIPULATION AND FALSIFICATION A form of fraud which may be more widespread than data fabrication is data manipulation or falsification. Here the observed result of a scientific experiment is altered to fit in with expectations. Imagine the situation where a study has been completed and the data analysis reveals a difference but p ¼ 0.06. An examination of the data reveals two outliers (there are always outliers in medicine!). If a reanalysis of the data without those two outliers reveals p < 0.05 then all that is necessary is to find an excuse to withdraw those outliers from the analysis. Perhaps there is good reason

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to withdraw them from the analysis (e.g. a minor protocol deviation) but if so, that decision should have been made at an earlier stage and cannot now be made at the data analysis stage. Fraud deceives your peers, the scientific community and you, yourself. If it is a new treatment that is being described there may even be the possibility of harm coming to a future patient because of these actions. How could anyone ever live with that? It is likely to be very difficult for the editor of the scientific journal to discover fraudulent actions. The serious nature of fraud means that it is taken very seriously by the scientific community, and rightly so. If discovered, it may be the end of a promising career and perhaps that is an appropriate action. Every organisation now possesses some system to deal with cases of fraud and it is dealt with at the highest level a common result being the public discredit of the author. PLAGIARISM The simple definition of plagiarism is the use of someone else’s text verbatim. Copying a quantity of text and claiming it as your original words is plagiarism and dishonest. It is not only theft of the written word but also theft of ideas, theft of original thinking and theft of intellectual property. It is a substitute for writing it yourself and taken further, a substitute for original thinking. At what point does plagiarism begin? All would agree that copying large parts of the text of an article is blatant plagiarism and this is well illustrated by the episode which occurred in Anesthesiology in 19989 and in which about 40% of an article was found to be a direct copy from another article. Is duplicating a single sentence or phrase classed as plagiarism? Technically speaking it probably is, but is very much more difficult to prove and very much less likely to be detected, and probably not of any great consequence. In addition, the constraints of language (not just English, but all languages) make it likely that there are only a limited number of ways to express a particular point in one sentence and by chance more than one individual may choose virtually the same combination of words to use. It would also be unusual to be able to detect a single identical phrase or sentence within the body of a large piece of text but this is not giving permission for ‘minor plagiarism’. In order to avoid an accusation of plagiarism, any text taken directly from another source should be clearly marked and the source attributed. A recent development is software which can detect plagiarism and this software is currently being refined. It is in use in some universities in order to catch dishonest students by checking submitted essays. It is likely that it will in time appear as a part of every editorial office. It is not foolproof however. It has been suggested that such software might miss important articles because of their existence behind subscription-only barriers. The current anti-plagiarism software looks for similarities, e.g. a number of identical words in a row. So if I wished to plagiarise a previously published article and I knew that the software simply acted on runs of six words then all I need to do is to ensure that I limit any runs to five words. Also given the expanding ‘industry’ in computer hacking and production of malicious software, it will only be a matter of time before anti-anti-plagiarism detection software is developed.10 Plagiarism may be very difficult to detect. Theoretically, it should be picked up during the refereeing and editorial process. No individual, however knowledgeable, can know all of the text in a subject, and this results in occasional episodes being detected after publication, probably by the plagiarised originator of the text. The embarrassment for

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the journal, author, co-authors, editor, referees, etc., is significant. The end result may be significantly detrimental to the author’s career. So why is plagiarism practised? Clearly it can be a simple, if unfortunate and embarrassing accident. When writing a review article it is possible to lose sight of the origin of some of the material. In these days of word processors with their sophisticated cut and paste abilities it would be very easy to accidentally insert a piece of text from a downloaded reference instead of the piece written by yourself. Plagiarism could, of course, be the simple result of dishonesty, for which there is no excuse e fortunately this seems to be rare. The excuse that it was explained so well by the previous writer is not an excuse to use the same words. Is it possible to plagiarise yourself? Clearly you cannot steal your own written words. As you are the author of the original, you own the intellectual property. That does not, however, provide a valid excuse to repeat the same text in another publication. It is not good practice to duplicate previously published sentences and some refer to this as ‘self plagiarism’. To duplicate a whole article would not be classed as plagiarism but dual publication. An interesting practice has developed over the last few years, which appears at first to border on plagiarism. This is the practice of re-working somebody else’s published data and is becoming more common as the practice of meta-analysis has blossomed. The excuse is that combining the results of several studies and subjecting them to further analysis may produce a more powerful answer than did the individual studies separately. Done carefully and properly, this is not only acceptable but of value to the scientific and medical world. Simply re-working another’s data with the intention of gaining a ‘cheap’ paper is not acceptable, however. Credit must of course be given to the original sources at all times. DUAL PUBLICATION The advantages are obvious e one study, one set of data, one analysis, one literature search, two publications. The title will need to be different of course and the author is credited with two publications on his or her curriculum vitae and double the praise from the Head of Department. The career advantages are quite clear. The view of the scientific community is also quite clear e it is not allowed. In order to try and prevent it, the author must sign a statement confirming that a manuscript is only under consideration by one journal at a time and that the data has not been previously published elsewhere. Dual publication is not just irritating, it wastes valuable space in journals and also may be detrimental to future research and science. If a future meta-analysis is undertaken, the final result may be skewed as one set of data has been counted twice. It may give an erroneous picture of the incidence of a particular disease if the same case is reported more than once. Duplicate publication could over- or under-estimate the efficacy and value of a new drug. There are certain unusual circumstances under which dual publication might be permissible. The same data analysis, reasoning, etc., can be published as a duplicate provided that it is in a completely different language, the readership is completely different, the second readership is very unlikely to encounter the first article and it is of importance to the second group. The original source and the fact that it has been previously published (and possibly translated) must, of course, be stated clearly in the article.

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SALAMI PUBLICATION It is common practice when conducting a research study to measure plenty of variables. When developing the hypothesis around which the study is built, most err on the side of caution and take additional measurements to see if the findings can be better explained in other ways. There is also the generally held opinion that if subjecting a patient to a research study one might as well make a few extra measurements which might be of use later. That is fine, provided it has all been approved by the Ethics committee and is relevant to the hypothesis. What is not fine, however, is taking each different measurement result, analysing it separately and publishing it as a separate paper, although the study population is exactly the same. This practice is fortunately uncommon now and is a practice to be deprecated. All of the data should be analysed together and presented in one paper if possible. If there is too much data then consider two linked papers each of which references the other. Preferably submit them to the same journal so that they can appear together. CONFLICTS OF INTEREST Industry generously supports a great deal of research. Without this support, many departments would be in financial difficulty. The support is usually given to assist in the prosecution of a study to examine a drug or a piece of equipment which is manufactured by the company concerned. There are often comparisons to be drawn with existing drugs or equipment. It is easy to see how bias could accidentally creep in.11 The researchers may be tempted to show one treatment in a more favourable light rather than conduct a completely fair and unbiased experiment. There may also be an effect on the motivation of the researcher.12 For these reasons, financial support and other indirect support must be declared as a part of the publication so that readers are aware of these potential issues. AUTHORSHIP In the 21st century, scientific articles are a very important form of currency. Authorship is therefore an extremely important part of a scientists work. Like any currency, it is subject to abuse. Authorship issues probably have no effect on the actual science itself but are clearly a potential abuse of the ethics. What are the reasons why a scientist needs authorship of articles? These are complex and several and might include personal satisfaction, evidence of intellectual ability and productivity, contribution to the person’s reputation, assistance with promotion and assistance with funding applications. They fuel the ‘publish or perish’ philosophy. There has been an interesting trend of change in the pattern of authorship over the last half a century or so. In the first part of the 20th century, it was common for scientific articles to be written by sole authors or to have very few authors on the article. Individuals were probably marking their authority on individual discoveries. Then from about the 1950s there has been a steady increase in the numbers of authors on a paper. This has been greatest in medicine than in other scientific disciplines.13 The reasons are not completely transparent but probably relate to increases in specialisation and therefore collaboration, together with the need of trainees in many medical fields to undertake research and publish it to aid their advancement.

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The order of the names in a paper has been given great importance over the years. The first author should be the one who did most of the work, the second one the second highest amount, etc. The last author is usually the head of department or senior person. With present day abstracting and referencing systems however, only the first 3 or first 6 names are used. Order then assumes an improper importance. GIFT AUTHORSHIP Gift authorship basically means that a position of a co-author on a paper has been given to an individual who has made no contribution to the content of the paper. The names of the authors of the paper must reflect the team that undertook the study and most journals now require a statement to the effect that every one of the authors has played an active part in the study. In order to qualify for a position on the paper, each individual must have made a substantial contribution including one or all of:       

Conceived the idea Contributed to the study design Written the protocol Been involved in data collection Been involved in data analysis Taken a significant role in writing the manuscript Seen and approved the final version

Just being present when the study took place does not count. Neither does being the head of the department, or a close friend of one of the authors.8 To put it simply, only those who have made a substantial contribution are entitled to be authors. GHOSTWRITING This is a very interesting practice.14 It is quite complex and may be difficult to detect. An individual or possibly a company decides that a review is required. The originator wishes to have a particular message conveyed in the article or a certain bias to be promulgated. A knowledgeable individual, but one who is not widely known, is commissioned to write the article and this person will be paid for the production of the article. A different person, who is held in high esteem by his/her peer group, is then paid a substantial amount of money to allow his/her name to be attached to the article as the ‘author’. The original author will probably not exist on the finished manuscript. The article with the false author is then submitted to a prominent journal and because it is apparently written by an important authority in the subject, stands a much greater chance of being accepted for publication that if it had an unknown name as the author. Many journals now include a statement to the effect that all manuscripts are accepted on the understanding that they have been written by the author who is named on the manuscript. HOW CAN WE BE CERTAIN? The sad fact is that we cannot be one hundred percent certain. Most journals now require statements concerning conflicts of interest, sources of commercial funding, competing interests, reasons for being an author and an assurance that the author so named has written the paper. An expert referee or editor may pick up something

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on suspicion, but this is very difficult. Occasional ones do slip through the net. We rely on all members of the scientific community to help. It is very likely that a proportion of these completely evade detection. The consequences of being discovered remains a powerful disincentive and it is clear that institutions must continue to take this firm stand against unethical publishing practices. But publishing is not an exact science. INVESTIGATING It is likely that the majority of fraud is discovered by chance. A referee undertakes a literature search as a part of the routine review process and uncovers another paper. A colleague in the author’s department becomes suspicious of the output or results. Another team tries to repeat the work with totally different results. Another researcher while undertaking a literature review for their own different studies discovers two papers reporting the same data set. There are many possibilities. But what happens next? A letter is usually sent to the editor of the journal(s) involved drawing it to their attention. The editor then has a duty to act on the information and to initially undertake his/her own investigation to see if there could be some substance in the complaint. The next step would then be to seek advice from an outside and independent source. This could be another editor or trusted individual with appropriate knowledge. The Committee on Publication Ethics (COPE) may also be consulted for advice. If it appears that there is substance in the complaint, then the author’s host institution should be contacted and the onus lies on them to then undertake an independent inquiry. The results could be anything from no action through an internal reprimand to external vilification and being struck off the medical register. It is therefore not a process to be embarked on lightly. It is unwise to indulge in research misconduct! Unfortunately it is very time-consuming to investigate alleged cases of research misconduct. It is also traumatic for the researcher and can also be so for the Editor who can face counter-allegations and aggression from the author of the article under question. COPE states that it is the duty of the Editor-in-Chief to pursue any such allegation whatever happens but it is clear to see that some Editors might not wish to, or be able to devote the time to, a detailed investigation. AUDIT OR RESEARCH? What may concern someone planning a study of any kind is whether it would be classed as research or audit. This is particularly important for a number of small internal studies. It is vital to get this right for a number of reasons which might include governance or insurance matters. Individual workers however, see the main problem as the potential consequences to them e and their patients and colleagues e if they get it wrong. So what are the differences? In many cases it is straightforward, e.g. testing a new drug will be a research project. There are no absolute definitions, however, and individual experience and judgment may at times be required. The following advice is adapted from the COREC website: Research:  is designed with the intention of generating new knowledge  is based on a hypothesis

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may involve a new treatment or technique may involve additional treatments may involve additional investigations allocates subjects to treatment groups using an external process (i.e. not chosen by the doctor/nurse or patient)  involves randomization Audit:  may be designed to provide new knowledge and possibly new or improved care or to define current care systems or processes  seeks to answer a question about a standard of service or care  usually involves comparison against a standard unless it is a study to measure a current service level (i.e. to create a standard)  does not involve a new treatment or technique  uses a simple methodology, e.g. questionnaire, analysis of records, etc.  allocates subjects to groups driven by the ‘normal’ procedures under control of the doctor/nurse or patient and not by any external process  does not involve randomization Despite the advice that is available, there is still confusion. One area of concern is the requirement within undergraduate medical training for students to undertake a project as a part of their education. This has steadily widened as other professions allied to medicine have also required some training in research methods within their curriculum. The result is the need for a huge number of small projects every year across the UK. These projects are primarily for educational purposes and not for the advancement of science and tend to swamp the Local Research Ethics Committee (LREC) at specific times of the year. The situation lead the Government to commission a report chaired by Professor Doyal, Professor of Medical Ethics.15 Amongst the findings were that all existing guidelines, e.g. the Declaration of Helsinki, applied to a student project just as to any other. A recommendation was to set up a student project ethics committees (SPEC) in each University. The logistics behind the implementation of this report are still being considered. In the meantime, uncertainty continues. A recent study presented ten short scenarios to seventy five medical student supervisors, each describing a proposed medical student clinical project, some of which were clearly audit and some clearly research. Only twelve percent agreed with the authors interpretation.16 Of course, the authors may not have been correct in every case. It does serve to illustrate, however, the uncertainty and confusion which abounds. Prideaux and Rogers17 added more fuel to the fire when they pointed out that the publication of a study in a refereed journal meant that it had to have been treated as research and been fully considered by an Ethics Committee. Thus audit could not be published. Ways round this problem are discussed but clarity is far from simple. RESEARCH GOVERNANCE ‘‘The Research Governance Framework outlines principles of good governance that apply to all research within the remit of the Secretary of State for Health.’’18 This first sentence summarises the scope of the document involving as it does, all research of

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whatever kind, which may involve patients and health. It applies to managers, funding organisations, etc., as well as to researchers and to all areas of care e primary, secondary, public health, etc. It is an effort by the Department of Health to put into place a national framework which is able to monitor and regulate research activity in the NHS. The aim is to ensure that all such research is conducted to appropriately high standards. Everybody involved is bound by the principles of research governance as well as the employing organisations and the funding organisations. All are responsible for knowing the law and for ensuring that they remain within the law. They must also be appropriately qualified and it is not appropriate for anyone to work outside their sphere of knowledge. It sets out in detail the responsibilities of all involved people and organisations, including the NHS Trust, University, Funding Body, Sponsor, Investigators and Researchers. It is necessary to ensure that all organisations involved (NHS Trusts, Universities, Pharmaceutical companies, etc.) are signed up to the whole study and all have passed the protocol through their own ethics or regulatory systems. Where a number of hospitals or other agencies are to be involved then it would be classed as a multi-centre study and a slightly different path needs to be followed, the study being considered by a Multicentre Research Ethics Committee (MREC) instead of an LREC. All ethics committees are governed by the Central UK Ethics Committee Authority and now are interchangeable so it is not essential for the ethics committee local to your individual hospital to consider the proposal. At busy times a researcher may find that their proposal is being considered by another ethics committee in a nearby district. A developing part of this policy is the thrust towards a system of central registration of all clinical studies. The proposal is that this database will be in the public domain. Such a database is not yet universal but the driving forces to develop it are building in many countries. One such driving force is ICMJE. They have issued a statement to the effect that all clinical trials must be registered and that unless a trial is registered then it cannot be considered for publication. That currently only applies to the journals centred around ICMJE but is certain to become more universal with time. The argument put forward by ICMJE is that selective reporting of clinical trials is widespread.19 Research workers and journals are less enthusiastic about ‘negative’ results and even less enthusiastic about those with inconclusive end-points. Journals tend to give such results a very low priority and so they may never appear in print. Although financial conflicts of interest are deprecated, a financial sponsor of a trial may also be less than enthusiastic about a publication which places their product at risk. Much of this might be addressed by the development of an open database of ongoing trials. The drive from ICMJE is such that now (as from 1st July 2005 for new studies, September 13th 2005 for ongoing studies) their member journals require every study to be registered in a public access database before a study can be considered for publication. The form of the registration database is also stipulated. It must have the following attributes19:       

Be accessible to the public at no charge Be open to all prospective registrants Be managed by a not-for-profit organisation Have a validation system for all data. Be electronically searchable, Allocate a unique identifying number to each registered trial, Contain a statement of the planned intervention or comparison

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Contain a statement of the study hypothesis, Contain definitions of all outcome measures and end-points List eligibility criteria Give the key trial dates (e.g. start of patient recruitment, planned end date) State the target number of patients State the source of funding Give the Principal Investigator’s name and contact details

Finally the research governance document puts in place a system to allow monitoring visits to any study. Any adverse events must be reported in the way specified at the start of the study; usually to the sponsor, but also to the National Patient Safety Agency. Despite all of the safeguards, something will occasionally go wrong. The highest profile such event in recent times is probably the study of a monoclonal antibody (TGN1412, described as a ‘humanised monoclonal superagonist at the CD28T cell surface receptor’) at Northwick Park Hospital, London in March 2006.20 Within minutes of the administration of this substance the subjects in the active arm began to experience profound side effects described as an acute cytokine storm. This lead to them all being admitted to Intensive Care for, in some cases, a prolonged period of time. They are all still alive but it is unclear whether or not permanent immue damage has been caused to their systems. The study was apparently fully ethically approved and the subjects had given fully informed consent. There is much ongoing debate, however, within a legal framework as well as an ethical framework and we must await the reports of independent investigations. This has shocked the research world and the general public considerably and raised a number of key questions which include motivation of healthy volunteers, financial reward to volunteers and exactly how much information they had been given (and understood and therefore consented to). SAMPLE SIZE Within the guidelines constructed by the various professional organisations it is stated that to be ethically sound a study has to be capable of being published once it is complete. There are many ways of publishing a study varying from the highest impact scientific journal to those which are non-peer reviewed ‘pay-as-you-go’ journals. As a part of the planning of a study, however, thought needs to be given to the meaningfulness of the results. This is closely linked to the number of subjects studied. Thus the ethics of performing a study which cannot produce a result because it is underpowered or flawed in some way raises concerns. Every Ethics Committee now has a statistician as a part of the committee whose task it is to consider this very point. It is therefore essential for every researcher to seek some statistical advice in the preparation of the protocol. Given a situation where there are insufficient statisticians, it is important for a researcher to have some knowledge of study power so that the question of sample size can be addressed early on. Consulting any statistical textbook will help but there are also many good articles in journals which will help the researcher cross this hurdle.21,22 The researcher may be pleasantly surprised at how small a number of subjects they may ‘‘get away with’’. On the other hand, planning to recruit one hundred patients into a study which could never show any meaningful result with less that five thousand patients does not make sense and many would say was also ethically questionable.

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CONCLUSION The responsibility for the maintenance of the current high standards in research and publishing rests with all of us e trainers, heads of departments, supervisors, editors, referees. Serious research misconduct by a physician, e.g. falsification or fabrication of data, may result in GMC disciplinary proceedings and quite likely the person being struck off the medical register. A similar result must be expected with respect to any other professional researcher from their professional organisation and probably their employer. Research, audit and publication are serious matters. Research is not to be undertaken lightly but the rewards e personal and to society e are worth it.

REFERENCES *1. Clinical Trials Directive (2001/20/EC). http://www.mhra.gov.uk/home/idcplg?IdcService¼SS_GET_ PAGE&nodeId¼716 [accessed 21st August 2006]. 2. Allen D. The EU Clinical Trials Directive could spell the end of UK R&D activity. Pharmaceutical Journal 2003; 271: 364. *3. Carlson RV, Boyd KM & Webb DJ. The revision of the declaration of Helsinki: past, present and future. British Journal of Clinical Pharmacology 2004; 57: 695e713. *4. World Medical Association Declaration of Helsinki. http://www/wma.net/e/policy/b3.htm [accessed 21st August 2006]. *5. Good Practice in Research. London, UK: The General Medical Council, February 2002. 6. International Committee for Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. British Medical Journal 1988; 296: 401e405. *7. Jaffer U & Cameron AEP. Deceit and fraud in medical research. International Journal of Surgery 2006; 4: 122e126. 8. Saxen L. Scientific fraud and the editor. European Science Editing 1997; 23: 71e73. 9. Todd MM. Plagiarism. Anesthesiology 1998; 89: 1307e1308. 10. Giles J. Taking on the cheats. Nature 2005; 435: 258e259. 11. Saidman LJ. Unresolved issues relating to peer review, industry support of research and conflict of interest. Anesthesiology 1994; 80: 491e492. 12. Eger II EI. Motivation, bias and scientific integrity. Anesthesiology 1994; 81: 270e271. 13. Onwude JL, Staines A & Lilford RJ. Multiple author trend worst in medicine. British Medical Journal 1993; 306: 1345. 14. Cullen DJ. Ghostwriting in scientific Anesthesia Journals. Anesthesiology 1997; 87: 195e196. *15. The Ethical governance and regulation of student projects. Report of a Working Group on Ethical Review of Student Research in the NHS. http://www.dh.gov.uk/assetRoot/04/12/08/98/04120898.pdf [accessed 21st August 2006]. *16. Alcolado J & Bennett R. Research or Audit? Ethical approval for medical student clinical projects. Medical Education 2006; 40: 491. *17. Prideaux D & Rogers W. Audit or research: the ethics of publication. Medical Education 2006; 40: 497e499. *18. Department of Health, UK, Research Governance Framework for Health and Social Care, Crown Copyright, 2nd edn. April 2005. (Also available at: http://www.dh.gov.uk/PublicationsAndStatistics/ Publications/PublicationsPolicyAndGuidance/PublicationsPolicyAndGuidanceArticle/fs/en?CONTENT_ ID¼4108962&chk¼Wde1Tv). *19. The International Committee of Medical Journal Editors. Clinical Trial Registration: a statement from the International Committee of Medical Journal Editors. Lancet 2004; 364: 911e912. 20. Goodyear M. Learning from the TGN1412 trial. British Medical Journal 2006; 332: 677e678. 21. Batterham AM & Atkinson G. How big does my sample size need to be? A primer on the murky world of sample size estimation. Physical Therapy in Sport 2005; 6: 153e163. 22. Raftery S. Power analysis and errors. Current Anaesthesia and Critical Care 1999; 10: 270e271.