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Mea Culpa: Scientific Misconduct
VOL 26, NO 2
APRIL 2012
EDITORIAL Mea Culpa: Scientific Misconduct
M
UCH HAS BEEN written recently in the anesthesia literature about scientific misconduct, precipitated in large part by revelations and ongoing allegations of misconduct involving Dr Joachim Boldt and that required retraction of more than 60 articles from the medical literature.1-6 The Journal of Cardiothoracic and Vascular Anesthesia has not escaped the fallout from these events.7 Unfortunately, the incidence of scientific misconduct appears to be increasing.8,9 I wrote this opinion from the perspective of the chair of a research ethics board (an institutional review board in the United States). I viewed the ongoing episodes of scientific misconduct as having the potential to undermine the fundamental trust physicians and the public have in the capacity of the scientific process to provide new knowledge and inform medical practice. An article that contains false information, once published and even if retracted, often continues to be cited and included in reviews, lectures, and meta-analyses. These, in turn, could affect medical practice and public policy for considerable periods.10-12 It takes a long time to investigate scientific misconduct,13 and some investigations fail even when fraud has been identified.14 Patients may continue to be (mis)treated by unsuspecting physicians for a considerable period before the misinformation contained in the retracted article becomes common knowledge.15,16 Examples include the use of nonsteroidal agents for the management of perioperative pain17 and, more recently, the misinformation contained in Dr Boldt’s publications regarding the use of starches in the perioperative period.18 In the next few paragraphs, I attempt to provide a brief historic perspective on scientific misconduct and the role of a research ethics board (REB) and investigators in preventing it. This is followed by a brief discussion of what is considered scientific misconduct and how it may be detected. Finally, I try to provide assurance that safeguards are being put in place to try and recognize and prevent scientific misconduct and the role we all must play in detecting it.
HISTORIC PERSPECTIVE, CONSENT FORM REQUIREMENTS, AND THE RISE OF RESEARCH ETHICS BOARDS (INSTITUTIONAL REVIEW BOARDS)
It is not possible to chronicle the entire litany of episodes of scientific misconduct, but I present a few of the more prominent ones for illustrative purposes and the effect they have had on the scientific process.19,20 The birth of research ethics largely has been attributed to the discovery of the atrocities committed in German concentration camps during the Second World War as discovered during the Nuremberg Trials.21 Such experimental questions as “How long can a human survive in cold water approaching the temperatures found in the North Atlantic?”22 and “How can we make seawater drinkable?”21 were performed, needless to say in most cases without informed consent. From this has come the principle that subjects participating in clinical trials should be informed about the risks and benefits of participation in research (an element in every informed consent document today) and enunciated in the Declaration of Helsinki in 1964 and updated periodically since that time (http://www.wma.net/en/30publications/10policies/b3/ index.html). Concurrent to the Nazi experiments, the United States Public Health Agency was conducting an experiment to determine the natural history of syphilis (largely performed on rural poor, uneducated black men).23,24 This experiment continued until 1972 (long after the advent of penicillin, a known effective
The opinions expressed are those of the author and do not necessarily reflect those of the Capital District Health Authority Research Ethics Board for which I work. I currently receive funding for research from AstraZeneca Canada, Alere Canada, GlaxoSmithKline, the Canadian Anesthesiologists’ Society RA Gordon Patient Safety Award, the Nova Scotia Heart and Stroke Foundation, and the Canadian Institutes of Health Research. © 2012 Elsevier Inc. All rights reserved. 1053-0770/2602-0001$36.00/0 doi:10.1053/j.jvca.2011.12.003
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cure) when it was brought to public attention and terminated. Out of the discussion and investigation surrounding this experiment came the requirement, now enshrined in consent forms, that subjects have a right to know about new treatments that may influence their willingness to continue to participate in a clinical trial. In 1966, Henry Beecher (an anesthesiologist) wrote an essay in which he documented examples of scientific misconduct and suggested that, in addition to the requirement for truly informed consent, a research project should be reviewed to determine whether it was ethical to proceed before starting the research rather than after the research was completed. Furthermore, when unethical research was discovered before publication, such research should not be published.25 In 1974, in response to these and other examples of research misconduct, the National Research Act was passed in the United States, which established the role of the US federal government in the oversight of research and gave birth to the formation of institutional review boards charged with the oversight of human research.19 In addition, the National Commission for Protection of Human Subjects of Biomedical and Behavioral Research (commonly known as the National Commission) was established and in 1979 published the Ethical Principles and Guidelines for the Protection of Human Subjects of Research (aka, the Belmont Report). This document outlined the fundamental ethical principles upon which human research should be conducted (http://ohsr.od.nih.gov/guidelines/ belmont.html). In 1999, Jesse Gelsinger died at the age of 18 after his participation in a clinical trial using a viral agent targeted at his disease, ornithine transcarbamylase deficiency.26 A subsequent investigation revealed that the investigator and the institution had a proprietary interest in the experimental agent that was not adequately disclosed to the participant. Out of this case has come informed consent form requirements to disclose possible conflicts of interest. Thus, it can be seen that many of the requirements now present in consent forms have occurred because of previous scientific misconduct, and REBs have arisen out of a need for research oversight in the face of ongoing scientific misconduct. The role of the REB is to protect, to the extent possible, the rights of subjects participating in research, but can REBs detect all scientific misconduct? The answer is no. SCIENTIFIC MISCONDUCT
Table 1 provides a list of elements thought to constitute scientific misconduct. Some are obvious including fabrication of data,11,27 misuse of funds (http://www.cfids.org/advocacy/ cdc-scandal.asp), and failure to disclose a conflict of interest26; whereas others are more difficult to recognize (eg, retaliation, false or misleading statements, and others that are perhaps more an issue of a nondeliberate error). It is the latter group to which I direct my comments because I believe honest mistakes can be made or at least a case can be made that a mistake may have occurred.9,28 It is in this group that I believe efforts can be made to improve (and prevent) scientific misconduct.
Table 1. Practices Considered to Represent Scientific Misconduct Fabrication or falsification of data Plagiarism Plagiarism of ideas Plagiarism of text Self-plagiarism Redundant/duplicate publication Breach of confidentiality Misuse of funds Destruction of records Retaliation Noncompliance with regulatory requirements Violation of REB restrictions Nondisclosure of conflicts of interest False/misleading statements Misleading publication Willful misrepresentation Encouraging/condoning/failure to report misconduct Data from University of Toronto Framework to Address Allegations of Research Misconduct November 27, 2006, and Dalhousie University Policy on Integrity in Scholarly Activity (approved by the Dalhousie Senate December 11, 1995, and amended January 29, 2001).
Confidentiality Breach In this era of sophisticated technology, it is increasingly easy to connect various databases and with this comes the potential for a breach of confidentiality. There are tools available that can link pieces of information previously thought to be nonidentifiable information from disparate sources (eg, postal code and date of birth) and pinpoint a research subject. From there, it is not a large leap of faith to imagine that the identity of an individual with a unique condition could be identified. Because of this, governments and hospital REBs are restricting the amount and type of information that can be transmitted outside the requisite jurisdiction. My suggestion is that requirements from REBs as to how the data will be anonymized and stored and the restrictions imposed on the transmittal of health information should be strictly adhered to to prevent the inadvertent breach of confidentiality that might occur. As another example, it is my understanding that under the Patriot Act, Homeland Security may examine any computer server resident in the United States to collect information it deems necessary without the permission of the database holder (http://en.wikipedia.org/wiki/USA_PATRIOT_Act). This might include hospital databases, including those generated for research purposes. Research tools commonly used, such as Survey Monkey, thus may provide personal data that could be subject to a confidentiality breach through no fault of the investigator. The message here is to collect only the data necessary to answer the research question. Destruction of Records The deliberate destruction of records to prevent scrutiny by regulatory authorities is self-evident as a form of misconduct. However, there are other more subtle situations that require some thought. For example, after the completion of a study, for how long should investigators retain the original data, including REB notifications and approval forms, laboratory data, animal
EDITORIAL
data, patient data, results, and so on? There are certain situations in which this is mandated (eg, any study performed that requires Health Canada approval must retain all records for a period of 25 years [http://www.hc-sc.gc.ca/dhp-mps/compli-conform/ clini-pract-prat/reg/1024-eng.php]). This is the sponsor’s responsibility, but what about data at the local investigator’s site, including REB approval forms? Whose responsibility is it in this case? The answer appears to be quite variable, and many jurisdictions have different time periods and differ on what information will be retained. When questions arise, access to relevant information becomes important. In Dr Boldt’s case, some of the studies in question are more than 10 years old (the period that the German authority requires records to be held29), and the data required to verify the research findings may be destroyed. How does one avoid being caught in such a tangled web? My suggestion is to retain the data for your practice lifetime. It is possible to put all documents in electronic files. This would alleviate some of the difficulties with storage and retrieval although the issues around retaining the technology necessary to read the files might become an issue (remember the 5½-inch disks). Nevertheless, having the information available is much preferred to the alternative of trying to explain findings in the absence of data to support them. Plagiarism The theft of one’s intellectual ideas represents scientific misconduct at its most basic level. The progress of science depends on the presentation of novel concepts that are then explored to determine their utility. When one usurps those ideas for one’s own purposes, one denies the creative genius of the original proponent, and this should not be condoned. How might this occur? As an example, take the case of a grant reviewer who reviews a grant application from a junior investigator involving an area directly related to his/her own research. What is his/her role in this review? Undoubtedly, there is a conflict of interest, which should be disclosed to the granting agency, but it is completely reasonable for him/her to provide commentary as one who is knowledgeable about the methods. What would be completely unacceptable is for the reviewer to deny funding for the application and then take the idea presented and perform the experiments in his/her own laboratory. Detection of this form of plagiarism is difficult to do and relies on the discovery by others in the field for its identification. Theft of Text This form of plagiarism unfortunately is common.4 In essence, one takes the written word (or nowadays copies video, pictures, slides, and so on) and transposes it into his/her own work without proper attribution to the original source. To be charitable, one can envision this may occur because of a certain naivety around the publication process and the ignorance of copyright law. If this is so, it is the obligation of colleagues, senior members of the group, and editorial board members to try to identify the issue when it occurs and correct it. It may be particularly difficult for authors whose native language is not English and who, I believe, in all good conscience, are trying to put together a manuscript in a language with which they are not familiar. Such persons also may not be aware of the implications of copying text without proper attribution. There is soft-
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ware available to identify plagiarism, and many journals are adopting this as a means to identify theft of text prior to acceptance for publication.30 Self-plagiarism For the purposes of this discussion, self-plagiarism is defined as the practice of substantial overlapping of text (and/or data) with another article(s) without full cross-referencing so that they share the same hypothesis, data, discussion points, or conclusions31 (http://publicationethics.org/static/1999/1999pdf 13.pdf [Committee on Publication Ethics]). As described by Cicutto,31 it may take several forms, including the publication of one article that overlaps substantially with another article published elsewhere, typically without acknowledgment (duplicate publication), or the partitioning of a large study, which could have been reported in a single article into smaller published articles/studies (salami publication). It is not difficult to see the attraction for this type of misconduct given the practice among academic institutions to reward productivity based on the numbers of articles published. However, in some cases, I believe it occurs unwittingly out of ignorance of the implications of the practice. Let us examine duplicate publications first. It is common for investigators to present their work, either as preliminary or complete information, at scientific meetings to avoid the inevitable time lag between submission and acceptance for publication (less of a concern now with the introduction of e-prints and publication ahead of press). This often is recorded as published abstracts or proceedings. Failure to disclose this at the time of publication of the main manuscript represents duplicate publication, and investigators should be aware of this. Moreover, for some high-profile journals (eg, The New England Journal of Medicine), such publication would prevent acceptance in that journal. Authors should be aware of journal policies in this regard to prevent disappointment. One solution being adopted is for the simultaneous publication of the manuscript in concordance with its presentation in a public forum. A discussion with the editor-in-chief should clarify the particular journal’s position in this regard. Next, let us examine the concept of salami publication; in short the division of one good manuscript into several manuscripts, each with a slightly different result addressed.31 It can take several forms, including presenting control data that appeared in an earlier publication; using tables or figures published in an earlier article in subsequent publications; publishing similar articles that deal with subgroups of data previously analyzed, discussed, and published as a larger group; publishing the data in two articles with one article written with a clinical focus and the other written with a basic science perspective; and publishing similar articles with different lead authors submitted to journals of the first author’s home country (local-foreign journal).31 Apart from the fact that this dilutes the original message, which may have been of more clinical import had the results all been presented together, such practice has significant implications for copyright law. The publication of previously published copyrighted material, in whatever form, without proper attribution, is an infringement of copyright law and subject to penalty. The message here is clear; if it comes from somewhere else, appropriate attribution should be provided. The previously mentioned software may help identify
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duplicate/salami publication, but readers also may play a role here by bringing the possibility to the editor’s attention. Encouraging/Condoning/Nonreporting Misconduct I believe that many instances of scientific misconduct can be prevented or identified in advance of publication. Many of the examples identified previously could be prevented by appropriate supervision and education of junior investigators32 (and in some cases senior investigators who may be unaware of the shifting ground that is considered scientific misconduct). I would hope that the instances in which deliberate scientific misconduct is being encouraged and/or condoned are few. It is the responsibility of all involved in the scientific enterprise to bring forth suspected instances of scientific misconduct. However, when it is identified before publication, if human research is involved, the respective REB should be notified because it is its role to provide oversight for ongoing human research. This may be extremely difficult in some situations (eg, a graduate student who discovers deliberate fabrication of data by a supervisor), but the consequences of condoning scientific misconduct are not trivial either. They include an overestimation of the magnitude of the effect size of the studied variable (eg, in Boldt’s case, the effectiveness of starch solutions in a variety of clinical scenarios, including use during cardiac surgery33-36; copyright infringement; loss of confidence of the public in the scientific enterprise; loss of reputation for the journals involved and subsequent ability to attract highquality articles (although to their credit many anesthesia journals, including Anesthesia and Analgesia, The British Journal of Anaesthesia, The Canadian Journal of Anesthesia, and The Journal of Cardiothoracic and Vascular Anesthesia have been transparent about the process and diligent in retracting articles identified as falling below the ethical standards required and should be commended for this approach); situations in which public monies have involved a wastage of precious resources that could have been directed to other worthwhile projects; and the wastage of time and money required to investigate such issues, which might have been better spent. Clearly, it is to no one’s advantage to allow scientific misconduct to go unrecognized and unreported. STEPS TO PREVENT SCIENTIFIC MISCONDUCT
The willful and deliberate performance of scientific misconduct likely is going to continue given the drivers for it (ie, publication, money, prestige), and its prevention will require the diligent oversight of all individuals involved in the conduct and reporting of scientific investigations. However, the uninformed and unintended performance of scientific misconduct, some instances such as have been identified earlier, can be prevented.4,9 I previously have outlined some of the ways I believe we can avoid the confusion surrounding some instances of scientific misconduct. In addition, the following are offered as aids to prevent accidental scientific misconduct (quoted from ref. 31): 1. Read the instructions for authors provided by the journal.
2. Acknowledge the contributions of others and the source of ideas and words regardless of whether paraphrased or summarized. 3. Enclose verbatim text/material in quotation marks. 4. Acknowledge sources used in the writing. 5. Understand the material completely and use your own words when paraphrasing. 6. Reference material when in doubt about whether or not the concept or fact is common knowledge. 7. Ensure that references are cited accurately. 8. Do not slice material into multiple separate articles if the results of a single complex study are best presented as a cohesive whole. 9. Alert the editors and readers when submitting a manuscript for publication containing research questions/hypotheses, methods, data, discussion points, or conclusions that have already been published or disseminated in a significant manner (such as previously published as an article in a separate journal or a report posted on the Internet). Editors should be informed in the cover letter, and readers should be alerted by highlighting and citing the earlier published work. 10. Alert the editors when submitting a manuscript for potential publication if there are any doubts or uncertainty about duplication or the redundancy of manuscripts originating from the same study. The authors should alert the editors of the nature of the overlap and enclose the other manuscripts (ie, published, in press/submitted, and unpublished) that might be part of the manuscript under consideration. Augmenting old data that was previously published with new additional data and presenting it as a new study can be an ethical breach and should be fully disclosed to the editors. 11. Write effective cover letters to the editor, especially regarding the potential for overlap in publication. The cover letter should detail the nature of the overlap and previous dissemination and ask for advice on the handling of the matter. 12. Become familiar with the basic elements of copyright law.
To these I would add the following: (1) research institutions should insist that their researchers/graduate students have undertaken formal training in ethical research and publishing; (2) before submission to a journal or granting agency, the article should be examined as part of an internal review process for the presence of plagiarism (this responsibility rests with the department head); and (3) university departments and the faculties of medicine should put in place structures that implement some form of oversight, independent from the investigator(s), for research conducted within their institutions. MEA CULPA
The fact is that some research is unethical, and some researchers are unethical. The role of the REB is to try to prevent unethical research from occurring and to provide oversight of the research as it evolves, with the primary focus on patient safety. However, REBs cannot uncover many aspects of scientific misconduct by unethical researchers. Journal editors, including the Editor-in-Chief and Editorial Board of the Journal of Cardiothoracic and Vascular Anesthesia, will do their part to identify misconduct and prevent publication of articles that are below the ethical standard, recognizing that we are not the “ethical police” and we will miss some of these events. However, I hope I have been able to convey the concept that the identification of scientific misconduct is everybody’s business, including you the reader. If you suspect it, report it; after all, it was the identification of a “too good to be true” figure in an article by a reader of Anesthesia
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and Analgesia that led to the identification of the fraud perpetrated by Dr Boldt. ACKNOWLEDGMENT The author thanks Dr Don Miller and Dr Tom Coonan for thoughtful commentary and review of the article.
Richard I. Hall, MD, FRCPC, FCCP Department of Anesthesia Dalhousie University Queen Elizabeth II Health Sciences Centre and The Capital District Health Authority Halifax, Nova Scotia, Canada
REFERENCES 1. Miller DR: Update to readers and authors on ethical and scientific misconduct: Retraction of the Boldt articles. Can J Anaesth 58:777781, 2011 2. Reilly C: Retraction. Notice of formal retraction of articles by Dr. Joachim Boldt. Br J Anaesth 107:116-117, 2011 3. Shafer SL: Editor’s note: Notices of retraction. Anesth Analg 112:1246-1247, 2011 4. Shafer SL: You will be caught. Anesth Analg 112:491-493, 2011 5. Dyer C: Researcher didn’t get ethical approval for 68 studies, investigators say. BMJ 342:d833, 2011 6. Gibbs NM: Retraction of articles with misleading information. Anaesthesiol Intensive Care 39:344, 2011 7. Retractions. J Cardiothorac Vasc Anesth 25:755-757, 2011 8. Steen RG: Retractions in the scientific literature: Is the incidence of research fraud increasing? J Med Ethics 37:249-253, 2011 9. Wager E, Williams P: Why and how do journals retract articles? An analysis of MEDLINE retractions 1988-2008. J Med Ethics 37:567570, 2011 10. Pfeifer MP, Snodgrass GL: The continued use of retracted, invalid scientific literature. JAMA 263:1420-1423, 1990 11. Shafer SL: Tattered threads. Anesth Analg 108:1361-1363, 2009 12. Miller DR: Publication fraud: Implications to the individual and to the specialty. Curr Opin Anaesthesiol 24:154-159, 2011 13. Sox HC, Rennie D: Research misconduct, retraction, and cleansing the medical literature: Lessons from the Poehlman case. Ann Intern Med 144:609-613, 2006 14. Wager E: Coping with scientific misconduct. BMJ 343:d6586, 2011 15. Trikalinos NA, Evangelou E, Ioannidis JP: Falsified papers in high-impact journals were slow to retract and indistinguishable from nonfraudulent papers. J Clin Epidemiol 61:464-470, 2008 16. Steen RG: Retractions in the medical literature: How many patients are put at risk by flawed research? J Med Ethics 37:688-692, 2011 17. White PF, Kehlet H, Liu S: Perioperative analgesia: What do we still know? Anesth Analg 108:1364-1367, 2009 18. Reinhart K, Takala J: Hydroxyethyl starches: What do we still know? Anesth Analg 112:507-511, 2011 19. Rice TW: The historical, ethical, and legal background of human-subjects research. Respir Care 53:1325-1329, 2008
20. Fischer BA: A summary of important documents in the field of research ethics. Schizophr Bull 32:69-80, 2006 21. Markman JR, Markman M: Running an ethical trial 60 years after the Nuremberg code. Lancet Oncol 8:1139-1146, 2007 22. Berger RL: Nazi science—The Dachau hypothermia experiments. N Engl J Med 322:1435-1440, 1990 23. Curran WJ: The Tuskegee syphilis study. N Engl J Med 289: 730-731, 1973 24. White RM: Unraveling the Tuskegee study of untreated syphilis. Arch Intern Med 160:585-598, 2000 25. Beecher HK: Ethics and clinical research. N Engl J Med 274: 1354-1360, 1966 26. Wilson RF: The death of Jesse Gelsinger: New evidence of the influence of money and prestige in human research. Am J Law Med 36:295-325, 2010 27. Reynolds SM: ORI findings of scientific misconduct in clinical trials and publicly funded research, 1992-2002. Clin Trials 1:509-516, 2004 28. Steen RG: Retractions in the scientific literature: Do authors deliberately commit research fraud? J Med Ethics 37:113-117, 2011 29. Hoffart J, Teichmann A, Wessler I: Biomedical research in Germany: The role of ethics committee and state medical association. Anesth Analg 112:501-503, 2011 30. Butler D: Copycat trap. Nature 448:633, 2007 31. Cicutto L: Plagiarism: Avoiding the peril in scientific writing. Chest 133:579-581, 2008 32. Leading by example. Nature 445:229, 2007 33. Delaney AP, Dan A, McCaffrey J, et al: The role of albumin as a resuscitation fluid for patients with sepsis: A systematic review and meta-analysis. Crit Care Med 39:386-391, 2011 34. Groeneveld AB, Navickis RJ, Wilkes MM: Update on the comparative safety of colloids: A systematic review of clinical studies. Ann Surg 253:470-483, 2011 35. Raja SG, Akhtar S, Shahbaz Y, et al: In cardiac surgery patients does Voluven(R) impair coagulation less than other colloids? Interact Cardiovasc Thorac Surg 12:1022-1027, 2011 36. James MF: Pro: Hydroxyethyl starch is preferable to albumin in the perioperative management of cardiac patients. J Cardiothorac Vasc Anesth 22:482-484, 2008
APRIL 2012
EDITORIAL Mea Culpa: Scientific Misconduct
M
UCH HAS BEEN written recently in the anesthesia literature about scientific misconduct, precipitated in large part by revelations and ongoing allegations of misconduct involving Dr Joachim Boldt and that required retraction of more than 60 articles from the medical literature.1-6 The Journal of Cardiothoracic and Vascular Anesthesia has not escaped the fallout from these events.7 Unfortunately, the incidence of scientific misconduct appears to be increasing.8,9 I wrote this opinion from the perspective of the chair of a research ethics board (an institutional review board in the United States). I viewed the ongoing episodes of scientific misconduct as having the potential to undermine the fundamental trust physicians and the public have in the capacity of the scientific process to provide new knowledge and inform medical practice. An article that contains false information, once published and even if retracted, often continues to be cited and included in reviews, lectures, and meta-analyses. These, in turn, could affect medical practice and public policy for considerable periods.10-12 It takes a long time to investigate scientific misconduct,13 and some investigations fail even when fraud has been identified.14 Patients may continue to be (mis)treated by unsuspecting physicians for a considerable period before the misinformation contained in the retracted article becomes common knowledge.15,16 Examples include the use of nonsteroidal agents for the management of perioperative pain17 and, more recently, the misinformation contained in Dr Boldt’s publications regarding the use of starches in the perioperative period.18 In the next few paragraphs, I attempt to provide a brief historic perspective on scientific misconduct and the role of a research ethics board (REB) and investigators in preventing it. This is followed by a brief discussion of what is considered scientific misconduct and how it may be detected. Finally, I try to provide assurance that safeguards are being put in place to try and recognize and prevent scientific misconduct and the role we all must play in detecting it.
HISTORIC PERSPECTIVE, CONSENT FORM REQUIREMENTS, AND THE RISE OF RESEARCH ETHICS BOARDS (INSTITUTIONAL REVIEW BOARDS)
It is not possible to chronicle the entire litany of episodes of scientific misconduct, but I present a few of the more prominent ones for illustrative purposes and the effect they have had on the scientific process.19,20 The birth of research ethics largely has been attributed to the discovery of the atrocities committed in German concentration camps during the Second World War as discovered during the Nuremberg Trials.21 Such experimental questions as “How long can a human survive in cold water approaching the temperatures found in the North Atlantic?”22 and “How can we make seawater drinkable?”21 were performed, needless to say in most cases without informed consent. From this has come the principle that subjects participating in clinical trials should be informed about the risks and benefits of participation in research (an element in every informed consent document today) and enunciated in the Declaration of Helsinki in 1964 and updated periodically since that time (http://www.wma.net/en/30publications/10policies/b3/ index.html). Concurrent to the Nazi experiments, the United States Public Health Agency was conducting an experiment to determine the natural history of syphilis (largely performed on rural poor, uneducated black men).23,24 This experiment continued until 1972 (long after the advent of penicillin, a known effective
The opinions expressed are those of the author and do not necessarily reflect those of the Capital District Health Authority Research Ethics Board for which I work. I currently receive funding for research from AstraZeneca Canada, Alere Canada, GlaxoSmithKline, the Canadian Anesthesiologists’ Society RA Gordon Patient Safety Award, the Nova Scotia Heart and Stroke Foundation, and the Canadian Institutes of Health Research. © 2012 Elsevier Inc. All rights reserved. 1053-0770/2602-0001$36.00/0 doi:10.1053/j.jvca.2011.12.003
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cure) when it was brought to public attention and terminated. Out of the discussion and investigation surrounding this experiment came the requirement, now enshrined in consent forms, that subjects have a right to know about new treatments that may influence their willingness to continue to participate in a clinical trial. In 1966, Henry Beecher (an anesthesiologist) wrote an essay in which he documented examples of scientific misconduct and suggested that, in addition to the requirement for truly informed consent, a research project should be reviewed to determine whether it was ethical to proceed before starting the research rather than after the research was completed. Furthermore, when unethical research was discovered before publication, such research should not be published.25 In 1974, in response to these and other examples of research misconduct, the National Research Act was passed in the United States, which established the role of the US federal government in the oversight of research and gave birth to the formation of institutional review boards charged with the oversight of human research.19 In addition, the National Commission for Protection of Human Subjects of Biomedical and Behavioral Research (commonly known as the National Commission) was established and in 1979 published the Ethical Principles and Guidelines for the Protection of Human Subjects of Research (aka, the Belmont Report). This document outlined the fundamental ethical principles upon which human research should be conducted (http://ohsr.od.nih.gov/guidelines/ belmont.html). In 1999, Jesse Gelsinger died at the age of 18 after his participation in a clinical trial using a viral agent targeted at his disease, ornithine transcarbamylase deficiency.26 A subsequent investigation revealed that the investigator and the institution had a proprietary interest in the experimental agent that was not adequately disclosed to the participant. Out of this case has come informed consent form requirements to disclose possible conflicts of interest. Thus, it can be seen that many of the requirements now present in consent forms have occurred because of previous scientific misconduct, and REBs have arisen out of a need for research oversight in the face of ongoing scientific misconduct. The role of the REB is to protect, to the extent possible, the rights of subjects participating in research, but can REBs detect all scientific misconduct? The answer is no. SCIENTIFIC MISCONDUCT
Table 1 provides a list of elements thought to constitute scientific misconduct. Some are obvious including fabrication of data,11,27 misuse of funds (http://www.cfids.org/advocacy/ cdc-scandal.asp), and failure to disclose a conflict of interest26; whereas others are more difficult to recognize (eg, retaliation, false or misleading statements, and others that are perhaps more an issue of a nondeliberate error). It is the latter group to which I direct my comments because I believe honest mistakes can be made or at least a case can be made that a mistake may have occurred.9,28 It is in this group that I believe efforts can be made to improve (and prevent) scientific misconduct.
Table 1. Practices Considered to Represent Scientific Misconduct Fabrication or falsification of data Plagiarism Plagiarism of ideas Plagiarism of text Self-plagiarism Redundant/duplicate publication Breach of confidentiality Misuse of funds Destruction of records Retaliation Noncompliance with regulatory requirements Violation of REB restrictions Nondisclosure of conflicts of interest False/misleading statements Misleading publication Willful misrepresentation Encouraging/condoning/failure to report misconduct Data from University of Toronto Framework to Address Allegations of Research Misconduct November 27, 2006, and Dalhousie University Policy on Integrity in Scholarly Activity (approved by the Dalhousie Senate December 11, 1995, and amended January 29, 2001).
Confidentiality Breach In this era of sophisticated technology, it is increasingly easy to connect various databases and with this comes the potential for a breach of confidentiality. There are tools available that can link pieces of information previously thought to be nonidentifiable information from disparate sources (eg, postal code and date of birth) and pinpoint a research subject. From there, it is not a large leap of faith to imagine that the identity of an individual with a unique condition could be identified. Because of this, governments and hospital REBs are restricting the amount and type of information that can be transmitted outside the requisite jurisdiction. My suggestion is that requirements from REBs as to how the data will be anonymized and stored and the restrictions imposed on the transmittal of health information should be strictly adhered to to prevent the inadvertent breach of confidentiality that might occur. As another example, it is my understanding that under the Patriot Act, Homeland Security may examine any computer server resident in the United States to collect information it deems necessary without the permission of the database holder (http://en.wikipedia.org/wiki/USA_PATRIOT_Act). This might include hospital databases, including those generated for research purposes. Research tools commonly used, such as Survey Monkey, thus may provide personal data that could be subject to a confidentiality breach through no fault of the investigator. The message here is to collect only the data necessary to answer the research question. Destruction of Records The deliberate destruction of records to prevent scrutiny by regulatory authorities is self-evident as a form of misconduct. However, there are other more subtle situations that require some thought. For example, after the completion of a study, for how long should investigators retain the original data, including REB notifications and approval forms, laboratory data, animal
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data, patient data, results, and so on? There are certain situations in which this is mandated (eg, any study performed that requires Health Canada approval must retain all records for a period of 25 years [http://www.hc-sc.gc.ca/dhp-mps/compli-conform/ clini-pract-prat/reg/1024-eng.php]). This is the sponsor’s responsibility, but what about data at the local investigator’s site, including REB approval forms? Whose responsibility is it in this case? The answer appears to be quite variable, and many jurisdictions have different time periods and differ on what information will be retained. When questions arise, access to relevant information becomes important. In Dr Boldt’s case, some of the studies in question are more than 10 years old (the period that the German authority requires records to be held29), and the data required to verify the research findings may be destroyed. How does one avoid being caught in such a tangled web? My suggestion is to retain the data for your practice lifetime. It is possible to put all documents in electronic files. This would alleviate some of the difficulties with storage and retrieval although the issues around retaining the technology necessary to read the files might become an issue (remember the 5½-inch disks). Nevertheless, having the information available is much preferred to the alternative of trying to explain findings in the absence of data to support them. Plagiarism The theft of one’s intellectual ideas represents scientific misconduct at its most basic level. The progress of science depends on the presentation of novel concepts that are then explored to determine their utility. When one usurps those ideas for one’s own purposes, one denies the creative genius of the original proponent, and this should not be condoned. How might this occur? As an example, take the case of a grant reviewer who reviews a grant application from a junior investigator involving an area directly related to his/her own research. What is his/her role in this review? Undoubtedly, there is a conflict of interest, which should be disclosed to the granting agency, but it is completely reasonable for him/her to provide commentary as one who is knowledgeable about the methods. What would be completely unacceptable is for the reviewer to deny funding for the application and then take the idea presented and perform the experiments in his/her own laboratory. Detection of this form of plagiarism is difficult to do and relies on the discovery by others in the field for its identification. Theft of Text This form of plagiarism unfortunately is common.4 In essence, one takes the written word (or nowadays copies video, pictures, slides, and so on) and transposes it into his/her own work without proper attribution to the original source. To be charitable, one can envision this may occur because of a certain naivety around the publication process and the ignorance of copyright law. If this is so, it is the obligation of colleagues, senior members of the group, and editorial board members to try to identify the issue when it occurs and correct it. It may be particularly difficult for authors whose native language is not English and who, I believe, in all good conscience, are trying to put together a manuscript in a language with which they are not familiar. Such persons also may not be aware of the implications of copying text without proper attribution. There is soft-
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ware available to identify plagiarism, and many journals are adopting this as a means to identify theft of text prior to acceptance for publication.30 Self-plagiarism For the purposes of this discussion, self-plagiarism is defined as the practice of substantial overlapping of text (and/or data) with another article(s) without full cross-referencing so that they share the same hypothesis, data, discussion points, or conclusions31 (http://publicationethics.org/static/1999/1999pdf 13.pdf [Committee on Publication Ethics]). As described by Cicutto,31 it may take several forms, including the publication of one article that overlaps substantially with another article published elsewhere, typically without acknowledgment (duplicate publication), or the partitioning of a large study, which could have been reported in a single article into smaller published articles/studies (salami publication). It is not difficult to see the attraction for this type of misconduct given the practice among academic institutions to reward productivity based on the numbers of articles published. However, in some cases, I believe it occurs unwittingly out of ignorance of the implications of the practice. Let us examine duplicate publications first. It is common for investigators to present their work, either as preliminary or complete information, at scientific meetings to avoid the inevitable time lag between submission and acceptance for publication (less of a concern now with the introduction of e-prints and publication ahead of press). This often is recorded as published abstracts or proceedings. Failure to disclose this at the time of publication of the main manuscript represents duplicate publication, and investigators should be aware of this. Moreover, for some high-profile journals (eg, The New England Journal of Medicine), such publication would prevent acceptance in that journal. Authors should be aware of journal policies in this regard to prevent disappointment. One solution being adopted is for the simultaneous publication of the manuscript in concordance with its presentation in a public forum. A discussion with the editor-in-chief should clarify the particular journal’s position in this regard. Next, let us examine the concept of salami publication; in short the division of one good manuscript into several manuscripts, each with a slightly different result addressed.31 It can take several forms, including presenting control data that appeared in an earlier publication; using tables or figures published in an earlier article in subsequent publications; publishing similar articles that deal with subgroups of data previously analyzed, discussed, and published as a larger group; publishing the data in two articles with one article written with a clinical focus and the other written with a basic science perspective; and publishing similar articles with different lead authors submitted to journals of the first author’s home country (local-foreign journal).31 Apart from the fact that this dilutes the original message, which may have been of more clinical import had the results all been presented together, such practice has significant implications for copyright law. The publication of previously published copyrighted material, in whatever form, without proper attribution, is an infringement of copyright law and subject to penalty. The message here is clear; if it comes from somewhere else, appropriate attribution should be provided. The previously mentioned software may help identify
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duplicate/salami publication, but readers also may play a role here by bringing the possibility to the editor’s attention. Encouraging/Condoning/Nonreporting Misconduct I believe that many instances of scientific misconduct can be prevented or identified in advance of publication. Many of the examples identified previously could be prevented by appropriate supervision and education of junior investigators32 (and in some cases senior investigators who may be unaware of the shifting ground that is considered scientific misconduct). I would hope that the instances in which deliberate scientific misconduct is being encouraged and/or condoned are few. It is the responsibility of all involved in the scientific enterprise to bring forth suspected instances of scientific misconduct. However, when it is identified before publication, if human research is involved, the respective REB should be notified because it is its role to provide oversight for ongoing human research. This may be extremely difficult in some situations (eg, a graduate student who discovers deliberate fabrication of data by a supervisor), but the consequences of condoning scientific misconduct are not trivial either. They include an overestimation of the magnitude of the effect size of the studied variable (eg, in Boldt’s case, the effectiveness of starch solutions in a variety of clinical scenarios, including use during cardiac surgery33-36; copyright infringement; loss of confidence of the public in the scientific enterprise; loss of reputation for the journals involved and subsequent ability to attract highquality articles (although to their credit many anesthesia journals, including Anesthesia and Analgesia, The British Journal of Anaesthesia, The Canadian Journal of Anesthesia, and The Journal of Cardiothoracic and Vascular Anesthesia have been transparent about the process and diligent in retracting articles identified as falling below the ethical standards required and should be commended for this approach); situations in which public monies have involved a wastage of precious resources that could have been directed to other worthwhile projects; and the wastage of time and money required to investigate such issues, which might have been better spent. Clearly, it is to no one’s advantage to allow scientific misconduct to go unrecognized and unreported. STEPS TO PREVENT SCIENTIFIC MISCONDUCT
The willful and deliberate performance of scientific misconduct likely is going to continue given the drivers for it (ie, publication, money, prestige), and its prevention will require the diligent oversight of all individuals involved in the conduct and reporting of scientific investigations. However, the uninformed and unintended performance of scientific misconduct, some instances such as have been identified earlier, can be prevented.4,9 I previously have outlined some of the ways I believe we can avoid the confusion surrounding some instances of scientific misconduct. In addition, the following are offered as aids to prevent accidental scientific misconduct (quoted from ref. 31): 1. Read the instructions for authors provided by the journal.
2. Acknowledge the contributions of others and the source of ideas and words regardless of whether paraphrased or summarized. 3. Enclose verbatim text/material in quotation marks. 4. Acknowledge sources used in the writing. 5. Understand the material completely and use your own words when paraphrasing. 6. Reference material when in doubt about whether or not the concept or fact is common knowledge. 7. Ensure that references are cited accurately. 8. Do not slice material into multiple separate articles if the results of a single complex study are best presented as a cohesive whole. 9. Alert the editors and readers when submitting a manuscript for publication containing research questions/hypotheses, methods, data, discussion points, or conclusions that have already been published or disseminated in a significant manner (such as previously published as an article in a separate journal or a report posted on the Internet). Editors should be informed in the cover letter, and readers should be alerted by highlighting and citing the earlier published work. 10. Alert the editors when submitting a manuscript for potential publication if there are any doubts or uncertainty about duplication or the redundancy of manuscripts originating from the same study. The authors should alert the editors of the nature of the overlap and enclose the other manuscripts (ie, published, in press/submitted, and unpublished) that might be part of the manuscript under consideration. Augmenting old data that was previously published with new additional data and presenting it as a new study can be an ethical breach and should be fully disclosed to the editors. 11. Write effective cover letters to the editor, especially regarding the potential for overlap in publication. The cover letter should detail the nature of the overlap and previous dissemination and ask for advice on the handling of the matter. 12. Become familiar with the basic elements of copyright law.
To these I would add the following: (1) research institutions should insist that their researchers/graduate students have undertaken formal training in ethical research and publishing; (2) before submission to a journal or granting agency, the article should be examined as part of an internal review process for the presence of plagiarism (this responsibility rests with the department head); and (3) university departments and the faculties of medicine should put in place structures that implement some form of oversight, independent from the investigator(s), for research conducted within their institutions. MEA CULPA
The fact is that some research is unethical, and some researchers are unethical. The role of the REB is to try to prevent unethical research from occurring and to provide oversight of the research as it evolves, with the primary focus on patient safety. However, REBs cannot uncover many aspects of scientific misconduct by unethical researchers. Journal editors, including the Editor-in-Chief and Editorial Board of the Journal of Cardiothoracic and Vascular Anesthesia, will do their part to identify misconduct and prevent publication of articles that are below the ethical standard, recognizing that we are not the “ethical police” and we will miss some of these events. However, I hope I have been able to convey the concept that the identification of scientific misconduct is everybody’s business, including you the reader. If you suspect it, report it; after all, it was the identification of a “too good to be true” figure in an article by a reader of Anesthesia
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and Analgesia that led to the identification of the fraud perpetrated by Dr Boldt. ACKNOWLEDGMENT The author thanks Dr Don Miller and Dr Tom Coonan for thoughtful commentary and review of the article.
Richard I. Hall, MD, FRCPC, FCCP Department of Anesthesia Dalhousie University Queen Elizabeth II Health Sciences Centre and The Capital District Health Authority Halifax, Nova Scotia, Canada
REFERENCES 1. Miller DR: Update to readers and authors on ethical and scientific misconduct: Retraction of the Boldt articles. Can J Anaesth 58:777781, 2011 2. Reilly C: Retraction. Notice of formal retraction of articles by Dr. Joachim Boldt. Br J Anaesth 107:116-117, 2011 3. Shafer SL: Editor’s note: Notices of retraction. Anesth Analg 112:1246-1247, 2011 4. Shafer SL: You will be caught. Anesth Analg 112:491-493, 2011 5. Dyer C: Researcher didn’t get ethical approval for 68 studies, investigators say. BMJ 342:d833, 2011 6. Gibbs NM: Retraction of articles with misleading information. Anaesthesiol Intensive Care 39:344, 2011 7. Retractions. J Cardiothorac Vasc Anesth 25:755-757, 2011 8. Steen RG: Retractions in the scientific literature: Is the incidence of research fraud increasing? J Med Ethics 37:249-253, 2011 9. Wager E, Williams P: Why and how do journals retract articles? An analysis of MEDLINE retractions 1988-2008. J Med Ethics 37:567570, 2011 10. Pfeifer MP, Snodgrass GL: The continued use of retracted, invalid scientific literature. JAMA 263:1420-1423, 1990 11. Shafer SL: Tattered threads. Anesth Analg 108:1361-1363, 2009 12. Miller DR: Publication fraud: Implications to the individual and to the specialty. Curr Opin Anaesthesiol 24:154-159, 2011 13. Sox HC, Rennie D: Research misconduct, retraction, and cleansing the medical literature: Lessons from the Poehlman case. Ann Intern Med 144:609-613, 2006 14. Wager E: Coping with scientific misconduct. BMJ 343:d6586, 2011 15. Trikalinos NA, Evangelou E, Ioannidis JP: Falsified papers in high-impact journals were slow to retract and indistinguishable from nonfraudulent papers. J Clin Epidemiol 61:464-470, 2008 16. Steen RG: Retractions in the medical literature: How many patients are put at risk by flawed research? J Med Ethics 37:688-692, 2011 17. White PF, Kehlet H, Liu S: Perioperative analgesia: What do we still know? Anesth Analg 108:1364-1367, 2009 18. Reinhart K, Takala J: Hydroxyethyl starches: What do we still know? Anesth Analg 112:507-511, 2011 19. Rice TW: The historical, ethical, and legal background of human-subjects research. Respir Care 53:1325-1329, 2008
20. Fischer BA: A summary of important documents in the field of research ethics. Schizophr Bull 32:69-80, 2006 21. Markman JR, Markman M: Running an ethical trial 60 years after the Nuremberg code. Lancet Oncol 8:1139-1146, 2007 22. Berger RL: Nazi science—The Dachau hypothermia experiments. N Engl J Med 322:1435-1440, 1990 23. Curran WJ: The Tuskegee syphilis study. N Engl J Med 289: 730-731, 1973 24. White RM: Unraveling the Tuskegee study of untreated syphilis. Arch Intern Med 160:585-598, 2000 25. Beecher HK: Ethics and clinical research. N Engl J Med 274: 1354-1360, 1966 26. Wilson RF: The death of Jesse Gelsinger: New evidence of the influence of money and prestige in human research. Am J Law Med 36:295-325, 2010 27. Reynolds SM: ORI findings of scientific misconduct in clinical trials and publicly funded research, 1992-2002. Clin Trials 1:509-516, 2004 28. Steen RG: Retractions in the scientific literature: Do authors deliberately commit research fraud? J Med Ethics 37:113-117, 2011 29. Hoffart J, Teichmann A, Wessler I: Biomedical research in Germany: The role of ethics committee and state medical association. Anesth Analg 112:501-503, 2011 30. Butler D: Copycat trap. Nature 448:633, 2007 31. Cicutto L: Plagiarism: Avoiding the peril in scientific writing. Chest 133:579-581, 2008 32. Leading by example. Nature 445:229, 2007 33. Delaney AP, Dan A, McCaffrey J, et al: The role of albumin as a resuscitation fluid for patients with sepsis: A systematic review and meta-analysis. Crit Care Med 39:386-391, 2011 34. Groeneveld AB, Navickis RJ, Wilkes MM: Update on the comparative safety of colloids: A systematic review of clinical studies. Ann Surg 253:470-483, 2011 35. Raja SG, Akhtar S, Shahbaz Y, et al: In cardiac surgery patients does Voluven(R) impair coagulation less than other colloids? Interact Cardiovasc Thorac Surg 12:1022-1027, 2011 36. James MF: Pro: Hydroxyethyl starch is preferable to albumin in the perioperative management of cardiac patients. J Cardiothorac Vasc Anesth 22:482-484, 2008