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Ann Thorac Surg 2006;82:6-12
© 2006 The Society of Thoracic Surgeons
a South Florida Thoracic Surgery, Hollywood, Florida
b Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina
Accepted for publication January 17, 2006.
* Address correspondence to Dr Block, South Florida Thoracic Surgery, 1150 N. 35th Avenue, Suite 440, Hollywood, FL 33021 (Email: block{at}sfthoracic.com).
Presented at the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10–12, 2005.
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Abstract |
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METHODS: We reviewed all reports of research involving human subjects published in these journals during the first 6 months of 2002, the first 6 months of 2003, and the last 6 months of 2004 (n = 273, 291 and 288 for each time period, respectively with a total of 852).
RESULTS: Ethical process was mentioned in 346 of 852 (41%) investigations. Comparing US and non-US studies, the rates of mentioning ethical process for prospective studies were 76 of 83 (92%) and 178 of 216 (82%), respectively, and for retrospective studies were 75 of 220 (34%) and 18 of 334 (5%), respectively. Between 2002 and 2004, the rates of mentioning ethical process for prospective studies increased from 79 of 101 (78%) to 80 of 89 (90%), and for retrospective studies it increased from 17 of 172 (10%) to 59 of 199 (30%).
CONCLUSIONS: There was a significant increase in mention of ethical process from early 2002 to late 2004; however, documentation of appropriate ethical process in human research published in cardiothoracic journals remains less than ideal. The main burden of ensuring ethical process in human investigations rests with researchers, their institutions, and institutional review boards; however, editors can help rectify this problem by requiring adherence to national and international standards in the human subjects' research studies they publish. In adhering to ethical standards, investigators respect the research subjects' right of self-determination and foster public confidence in human research.
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Introduction |
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This environment has left many investigators uncertain about the need for such ethical processes as informed consent and formal review of their activities. Although mechanisms such as institutional review boards (IRBs) are in place in the US (US) and many other countries to oversee ethical conduct of research with human subjects at the institutional level, medical journals can encourage the use of these ethical guidelines. Both The Annals of Thoracic Surgery (ATS) and The Journal of Thoracic and Cardiovascular Surgery (JTCVS) subscribe to the guidelines of the International Committee of Medical Journal Editors. These guidelines stipulate that publication of research involving human subjects requires assurances that "the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation...and with the Helsinki Declaration..." [2]. Both journals have explicit requirements to document ethical process in their instructions for authors. Both have also recently published editorials regarding ethical conduct of research [3, 4].
Our purposes in carrying out this study were to assess the degree to which recent human research articles published in these two journals adhere to current ethical guidelines, to review the applicability of these guidelines to the spectrum of research activities in cardiothoracic surgery, and to observe if the recent editorial effort by both journals correlated with an improvement in documentation of the ethical process.
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Material and Methods |
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The types of research were defined as either retrospective or prospective. Retrospective studies were divided into three categories:
Prospective studies were divided into five categories:
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Results |
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Comment |
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Our findings suggest that recent editorials in both ATS and JTCVS that highlighted the importance and relevance of ethical process to research with human subjects have been effective. The frequency of mentioning ethical process increased for the periods studied, yet there remains a substantial difference between authors from the US and those from other countries. These differences are worthy of further comment.
We recently reviewed the historical development of the ethical guidelines for human research, including the Nuremburg Code, the Declaration of Helsinki (hereinafter referred to as Helsinki), [5] and the Common Rule in the US (Title 45, Section 46 of the Code of Federal Regulations) [6]. The Common Rule was developed to guide human research conducted in the US, yet two thirds of the reports covered in this review were written by non-US investigators. The International Committee of Medical Journal Editors has adopted Helsinki as the minimal standard for non-US investigations, and both ATS and JTCVS subscribe to the International Committee of Medical Journal Editors guidelines for publication of research. Therefore, both journals hold non-US research involving human subjects to the standards set by Helsinki's guidelines. Law and regulation bind US investigators to the Common Rule when federal funding is connected to the research, but nearly all IRBs apply the same standards to all research in their jurisdictions, regardless of funding. Although the Common Rule's regulatory requirements are explicit and comprehensive, Helsinki is more general and concise.
Helsinki provides principles to guide research, but also requires investigators to abide by their national requirements (Principle 9). Cultural, historical, and political differences clearly shape national perspectives on this issue, and not surprisingly the specifics of relevant national regulations (when they exist at all) vary widely between countries. Helsinki nevertheless limits the authority of national research practices or guidelines: "No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration." For example, informed consent and voluntary participation in research have been clearly identified as universal ethical principles, and because of the potential for human rights abuses in authoritarian states, these principles trump cultural, social, and political considerations [5].
To understand the requirements for research activities, investigators must be familiar with current ethical guidelines, and both the federal Common Rule and Helsinki are relevant to the design and execution of human subject research and to the editorial process.
When Does Clinical Activity Become Research?
Helsinki does not explicitly define research. Most of the document addresses prospective experimentation on human subjects, but it also states, "Medical research involving human subjects includes research on identifiable human material or identifiable data" (Principle 1); this clause brings retrospective studies within the purview of the general guidelines.
In the US, the Common Rule is more specific, defining research as "... a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge" [7]. The Common Rule exempts such routine activities as "medical care, quality assurance, quality improvement ... and simple data collection" [8]. Database generation and prospective observational studies are not included in this list of exemptions and could be characterized as either a routine activity or as research. The use of databases is widespread, so consideration of their status as research is worthwhile.
When Does Data Collection for Databases Become Research?
Helsinki does not address the status of databases as research; however, the Common Rule is helpful in this regard. The key test of when data collection becomes research is whether or not data are being collected for the specific purpose of testing a hypothesis and contributing to generalizable knowledge. The intended use of the data determines whether or not its collection constitutes research. If there is "clear advance intent" [10] to analyze the data and publish the results, the data collection itself constitutes research. Thus, prospective studies, even when they are "purely observational or involve only the collection of data ... do not qualify for exemption ... " [9].
The database of The Society of Thoracic Surgeons may help to clarify the activities that constitute research. Its data are collected prospectively, there is advance intent to use the data for analysis of results, and it can be used to test hypotheses and generate publications that contribute to generalizable knowledge. Is this research? Is informed consent necessary? The question of whether the database constitutes research turns on the difference between the intended and the potential uses of the collected data. The principle intent of the database of The Society of Thoracic Surgeons is to provide information to individual surgeons for quality assurance and quality improvement purposes, an activity that the Common Rule clearly exempts from IRB review. Thus, collection of the data is not considered research, and informed consent and IRB review are not necessary. However, once the data exist they can and should be used to answer research questions. It is at this point that consideration by an IRB may be required. For example, if an investigator wishes to use the database retrospectively to measure the impact of renal failure on length of hospital stay and plans to publish the findings, then IRB approval or exemption is necessary before initiating the database query.
When is Informed Consent Required?
Obtaining the informed consent of human subjects is a fundamental obligation of all clinical investigators. Helsinki describes precisely what information must be conveyed and how consent must be documented (Principles 20, 22–26), but it mentions no exceptions to the requirement for informed consent. The document focuses heavily, though not exclusively, on prospective studies, mentioning investigation of human materials and data only once (Principle 1), almost as an afterthought. It is unclear whether consent is required for such retrospective studies, and therefore it should not be surprising if the perception of the need for ethical review of such studies is lower in countries that rely only on Helsinki as an ethical standard.
In contrast, the Common Rule specifies that informed consent may not be required if "the research involves no more than minimal risk to the subjects" and if obtaining informed consent is either impractical or will have an adverse affect on the research [10]. Retrospective studies typically meet these criteria, so informed consent is usually not required. In certain prospective investigations, such as observational studies that pose little physical risk to subjects, the obligation to obtain consent may be unclear. Although it is unlikely that patients would object to participating in such studies, not asking for their consent recruits them as study subjects without their knowledge, infringing on their decision-making autonomy, albeit marginally. Moreover, obtaining consent even when not absolutely required might prove beneficial. Actively involving patients enlists them as partners in research and provides them with a positive experience. Americans overwhelmingly support medical progress through scientific research; patients often express a desire to participate in research, if not for their own benefit then for the benefit of others [11–13]. Not asking patients for their consent to participate in medical research may be a lost opportunity.
Privacy and Confidentiality in Retrospective Studies
Helsinki protects privacy and confidentiality: "Every precaution should be taken to respect the privacy of the subject [and] the confidentiality of the patient's information..." (Principle 21). Moreover, the document further emphasizes the importance of privacy and confidentiality by identifying "research on identifiable human material or identifiable data" as medical research, implying that nonidentifiable material or data is not medical research and does not require research protections.
Under the Common Rule, the need for IRB review of retrospective research that uses existing materials (ie, charts, data, specimens, an so forth) hinges in part on the potential for violation of confidentiality. For example, research with publicly available materials is exempt. However, retrospective chart reviews and analyses of pathology specimens use materials that are not publicly available, so such research can be exempt only if the investigator completely dissociates the material from its source (the subject), recording information "in such a manner that subjects cannot be identified directly or through identifiers linked to the subjects" [14].
Uncertainty Regarding Ethical Review
Whenever there is uncertainty as to whether an expedited review is appropriate, or even if the review is necessary, US investigators should solicit IRB advice; often a telephone call to the IRB is sufficient to make the determination. Unfortunately the IRB is often viewed as (and, lamentably, sometimes is) "an entity whose approval is an obstacle to be overcome rather than a group of research colleagues whose counsel is valuable" [15]. International investigators should follow both their national ethics policy and guidance provided by Helsinki. Understanding the ethical principles that underlie guidelines and regulations allows investigators to better understand mandates that otherwise seem arbitrary and onerous.
Opportunities for Journal Editorial Boards
The responsibility for adhering to ethical process rests with the investigators. The institutions in which they carry out their research and review boards, where available, share in this responsibility and assist investigators in meeting it. Journal editors and (by extension) reviewers also have a role. Because publication in a peer-review journal confers legitimacy and is the principle means for dissemination of scientific knowledge, the editorial process provides an opportunity to encourage the application of fundamental ethical principles to the research of human subjects. Both ATS and JTCVS require authors to document ethical process, yet the majority of investigations published in the two journals in the time periods we studied failed to follow editorial instructions. This does not necessarily mean that the investigators failed to observe ethical standards, only that they failed to document what they did or did not do. Without such documentation, the possibility that ethical norms were transgressed remains open. For this reason, documentation itself should be considered an integral part of the process that includes observing ethical standards.
Editorial insistence that investigators follow the journal's instructions may enhance the quality of studies published in the cardiothoracic surgery literature. For example, both journals require authors to describe their ethical processes in the Methods section, thus encouraging researchers to follow ethical guidelines in carrying out investigations. If documentation is absent, an editor's request for a clarifying statement could settle any question about process.
Although the guidelines of the International Committee of Medical Journal Editors recommend rejection of studies that fail to adhere to ethical guidelines, we believe that the ATS policy to handle such situations is more appropriate and useful. The ATS editors accept scientifically worthy papers that lack ethical process, but attach an editorial comment to the end of such papers when published [5, 16]. The comment points out the ethical flaw, explains how the flaw was weighed against the scientific value of the study, and expresses support for ethical process in research involving human subjects. The authors may be requested or required (at the discretion of the editor) to comment on the ethical transgression. This policy simultaneously endorses ethical process and promotes open discussion of ethical flaws in the design and execution of human investigations. This creates an educational opportunity for both the authors of the paper and its readers who are potential authors. The editors of ATS used this approach when they published a prospective randomized trial from China that contained valuable information, but lacked both a consent process and ethical review [5, 17]. The alternative of not publishing educates only the authors, keeping the larger scientific community ignorant of the transgression.
Conclusion
The fundamental human right to self-determination underlies all clinical investigation. We must, as a matter of international and US ethics and law, respect the right of human research subjects to determine how others use their bodies and their personal information. When investigators follow ethical guidelines, they build the trust that is critical to the long-term success of the research enterprise. Journals can play an important part in helping investigators reach that goal. Our investigation shows that by assuming their rightful role as champions of ethics in research, journal editors have succeeded in promoting the application and documentation of ethical process, and that further progress is needed.
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Discussion |
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DR BLOCK: Well, I think the New York Times test is a good one. How would you feel if the New York Times had an article tomorrow on the front page saying that 50% of the studies in our journal involving human subjects had no documentation of ethical review? It is important because of our obligations to our subjects, but also because if we do not pay attention to it, then we are liable to see increasing restrictions on our ability to conduct clinical research and increasingly intrusive government regulations. The recent data suggest that it is more an issue of education than anything else. It is not that investigators do not want to do it. I think it is more a recognition that we need to do it for studies that historically we have not recognized needed ethical review.
DR MICHAEL MACK (Dallas, TX): Mark, I have two questions. First, do you think this is a matter of people not doing it or is it a documentation issue, or not able to be determined?
DR BLOCK: I think if people went to the trouble to do it, they would document it. I think it is more an issue of not doing it. And to some degree it may be that investigators feel that if they have this interesting idea, they just want to look at some charts, and if I go through the trouble of going to the IRB, they may say no, it is going to be a hassle, I will just do it.
DR MACK: This issue has been discussed on the editorial boards of both journals. Do you think that the editors should go to the extreme of refusing to publish papers that do not have ethical process documentation?
DR BLOCK: There needs to be a balance. I think it depends on the significance of the report. An excellent example is one of the prospective randomized trials in 2003 published in The Annals. It was a Chinese study on radiation therapy after esophagectomy. Patients were randomized to no radiation therapy versus radiation therapy. There was no ethical review, no consent, nothing, just a prospective randomized trial. And I know that discussions went back and forth, and ultimately the paper was published, but there was an accompanying editorial to comment on the fact that there was no ethical review. That really presents an important educational opportunity. And I think it is useful to publish the research, but still point out the fact that we are missing some fundamental issues here. It presents an educational opportunity instead of just sweeping it under the rug.
DR JOHN R. BENFIELD (Los Angeles, CA): This is really an important paper. I was going to ask whether you are sure that lack of documentation is the same as lack of ethical process, but that question has already been asked. Frankly, I was surprised to hear you say that you think that lack of documentation did reflect lack of process. Therefore, I ask why you are so sure? Secondly, I would like to hear how you defined lack of ethical process during your reviews? These crucial questions may be answered in your manuscript, but I did not hear them clearly addressed in your presentation.
DR BLOCK: It was a lot of reading, reading through all those papers from start to finish looking for any documentation anywhere, any language saying IRB approval, the protocol adhered to the Helsinki declaration; even some studies that said we obtained informed consent, and even in those studies it was not clear that the informed consent was just for the surgical procedure or informed consent to participate in this research trial. Any language that even stated some form of review or consent process was considered ethical process. So it was fairly loose criteria. In the paper we also applied strict criteria and we discuss the differences we found. We had separate criteria for the 2004 studies in which we asked if the language clearly documented ethical review or was it fairly loose, nonspecific language. It is not that hard to do this type of analysis. When you read through the papers, once you think about it, it is fairly obvious whether there was any attention at all to some external ethical review of the protocol. I am not saying that the investigators are not paying attention to their ethical responsibilities, only that they are not in the best position to make an objective judgment about the ethical underpinnings of their study. That is why there are external boards constituted to do precisely that. It is the responsibility of investigators to solicit the opinion of those external boards, the IRB in the US, so that we can insure there is objective validation that we are adhering to these ethical standards. If an investigator goes to the trouble of doing that, I find it hard to believe they would not document it in their manuscript. Furthermore, the publication guidelines of both journals clearly document the requirement to include such language in the manuscript.
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46.116(d)]..46.101(b)(4)]..This article has been cited by other articles:
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  R. M. Sade "Surgical research or comic opera" redux. Ann. Thorac. Surg., October 1, 2006; 82(4): 1173 - 1174. [Full Text] [PDF]
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