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Editorials |

Clinical Trial Registration Promotes Patient Protection and Benefit, Advances the Trust of Everyone, and Is Required FREE TO VIEW

Richard S. Irwin, MD, FCCP
Author and Funding Information

Affiliations: Northbrook, IL ,  Dr. Irwin is Editor in Chief of CHEST.

Correspondence to: Richard S. Irwin, MD, FCCP, Editor in Chief, CHEST, 3300 Dundee Rd, Northbrook, IL 60062-2348; e-mail: rirwin@chestnet.org



Chest. 2007;131(3):639-641. doi:10.1378/chest.07-0088
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Published online

Because CHEST has signed on to adhere to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals of the International Committee of Medical Journal Editors (ICMJE), we have endorsed the following principles: (1) investigators are required to register their clinical trials (other than phase 1 trials) in a public trials registry that is managed by a not-for-profit organization, free of charge for both registrants and users, and electronically searchable; (2) trial registration has been applied to trials that started recruiting on or after July 1, 2005, or, for trials that were ongoing by the July date, registration had to be completed before September 12, 2005; (3) a clinical trial has been defined as any research project that prospectively assigns human subjects to intervention or concurrent comparison or control groups to study the cause-and-effect relationship between a medical intervention (eg, drugs, devices, surgical procedures, behavior treatments) and a health outcome; and (4) clinical trials must be accurately and appropriately registered (eg, by filling out the minimum 20-item data set defined by the World Health Organization) before enrollment of the first patient to be considered for publication. Additionally, CHEST reserves the right to decline papers if, in its discretion, it deems the disclosure at the registry to be incomplete or inaccurate. Although these principles were first published in 20041and they have been incorporated into the CHEST Instructions to Authors (www.chestjournal.org), we and others2 continue to receive manuscripts reporting results of clinical trials that have not been registered or that have been inaccurately registered.

With a goal of trying to improve the ability of our potential authors to write in the most understandable and communicative manner possible and to be successful in publishing their studies,3we launched our “Medical Writing Tips” series in March of 2006. In two separate articles in this series, we stressed the importance of following the journal-specific Instructions to Authors4and the Uniform Requirements,5a guide to writing, publishing, and editing in international biomedical publications generated by the ICMJE. While the Uniform Requirements (www.icmje.org) and our Instructions to Authors emphasize that trial registration is required, they do not provide guidance in practical terms on how to register a clinical trial. Zarin and Kesselman6 have closed this loop in the process in this issue of CHEST (see page 909). In their Medical Writing Tip article entitled “Registering a Clinical Trial in ClinicalTrials.gov,” they answer commonly asked questions such as what policies regulate clinical trials registration, which trials should be registered, and how do I register my trial? They also address the key issues to consider when registering a trial and how to avoid the most frequent problems. While the writing tip of Zarin and Kesselman,6 focuses on registering a trial in the US-based ClinicalTrials.gov, most of the principles discussed will also apply to the registration of trials in other registries such as the UK-based International Standard Randomised Controlled Trial Number Register.

Because we perceive that it is not commonly understood why clinical trial registration that is open to everyone should be required, we take this opportunity to summarize and expand on some of the more important reasons that have been articulated by Sim and colleagues7(Table 1 ). Because they have access to the medical literature9 and the lay press (which has recently brought to light problems in published medical studies),10the general public around the globe has become distrusting of the clinical research industry. The public has become acutely aware that scientific misconduct occurs, is not a new phenomenon,11and is not limited to the pharmaceutical industry or to the clinical scientific industry. The perception is that professional integrity on the part of investigators and clinicians has deteriorated12and that agencies such as the Food and Drug Administration cannot protect them.13 Clinical trial registration facilitates transparency, a necessary element in restoring the public trust. If distrust leads to lower enrollment in trials with a consequence of slowing innovation, restoration of the public trust will likely benefit medical science and innovation.

Transparent clinical trial registration has the potential to allow editors, reviewers, and institutional review boards another opportunity to understand the context of study results to discover and control “design bias” (ie, when a trial is designed with a high likelihood of being positive) as well as “publication bias.” A study with design bias is unethical because it is contrary to the concept of “equipoise” or the “uncertainty principle,” a central ethical principle of clinical research. The principle of equipoise holds that a subject may be enrolled in a randomized controlled clinical trial only if there is true uncertainty about which trial arm is most likely to benefit the patient. Scholarly surveys of approximately 1,000 randomized controlled clinical trials published over the past 15 years have suggested that systematic bias has favored products (medical and surgical) made by the company funding the research.1418 These publications suggest that “design bias” has been a real and ongoing concern and that we need to guard against it as we go forward. These same surveys also suggest that publication bias has been pervasive in our scientific publications over the past 15 years.9,12,18 Publication bias occurs when sponsors do not allow studies unfavorable to their products to be published or allow only selective reporting of favorable studies. An egregious example of this has recently come to light.9 Other potential forms of publication bias include publishing funded research in supplements as proceedings of symposia (eg, peer review is less intense or not at all), promoting interpretive spin of data that exaggerates benefits or minimizes risks of the company’s products, and duplicating publication of positive results. Because subjects enroll in studies to benefit medical science and society and negative studies further medical knowledge, we believe it is unethical to fail to submit negative studies for publication. In the spirit of full transparency, we will become ever more vigilant in guarding against publishing studies with “design” and “publication” biases. With respect to the latter, CHEST and the American College of Chest Physicians have decided to only publish industry-sponsored supplements that advance the field and do not contribute to publication bias, and we will continue to publish high-quality studies with negative findings. Contrary to the perception of many, negative findings are often published in high impact journals.,18

A transparent clinical trial registration process has other obvious benefits. Minimizing design and publication biases can help to ensure the integrity of evidence-based medicine. In this regard, it is very important that negative results are not lost to the body of general knowledge. Letting others know very basic information about ongoing trials can potentially promote the efficiency of clinical research by reducing unnecessary duplication of research and facilitate the planning of a different trial for which grant funding might be better utilized. While some7 have argued that public disclosure of certain of the minimum 20 data set items may potentially adversely affect academic and commercial competitive advantage, there does not appear to be convincing evidence that this is the case. The fact that an ever-increasing number of companies are registering their trials speaks against the concern that disclosure threatens innovation. According to Sim and colleagues,7 “openness might promote rather than stifle innovation.” We agree; for all the reasons (Table 1), clinical trial registration is needed. Because clinical trial registration promotes patient protection and benefit, and advances the trust of everyone, it is required according to the principles of the ICMJE for a trial to be considered for publication in CHEST.

Dr. Irwin has no personal or financial conflict to disclose.

Table Graphic Jump Location
Table 1. Reasons for Clinical Trial Registration

References

DeAngelis, CD, Drazen, JM, Frizelle, FA, et al (2004) Clinical trial registration: a statement from the International Committee of Medical Journal Editors.JAMA292,1363-1364. [PubMed] [CrossRef]
 
DeAngelis, CD, Drazen, JM, Frizelle, FA, et al Is this clinical trial fully registered? – a statement from the International Committee of Medical Journal Editors.N Engl J Med2005;352,2436-2438. [PubMed]
 
Barron, JP Introducing “Medical Writing Tips of the Month:” a new section inCHEST.Chest2006;129,506-507
 
Welch, SJ Preparing manuscripts for online submission: basic information and avoidance of common pitfall.Chest2006;129,822-825. [PubMed]
 
Barron, JP The uniform requirements for manuscripts submitted to biomedical journals recommended by the International Committee of Medical Journal Editors.Chest2006;129,1098-1099. [PubMed]
 
Zarin, DA, Kesselman, A Registering a clinical trial in ClinicalTrials.gov.Chest2007;131,909-912. [PubMed]
 
Sim, I, Chan, A-W, Gulmezoglu, AM, et al Clinical trial registration: transparency is the watchword.Lancet2006;367,1631-1633. [PubMed]
 
Graham, DJ COX-2 inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense.JAMA2006;296,1653-1656. [PubMed]
 
Steinman, MA, Bero, LA, Chren, M-M, et al Narrative review: the promotion of gabapentin: an analysis of internal industry documents.Ann Intern Med2006;145,284-293. [PubMed]
 
Armstrong D. Financial ties to industry cloud major depression study. The Wall Street Journal Online. July 11, 2006. Available at: wsj.com. Accessed July 13, 2006.
 
Nylenna, M, Simonsen, S Scientific misconduct: a new approach to prevention.Lancet2006;367,1882-1884. [PubMed]
 
Miller, FG, Brody, H Professional integrity industry-sponsored clinical trials.Acad Med2005;80,899-904. [PubMed]
 
Institute of Medicine urges reforms at FDA [editorial].Lancet2006;368,1211. [PubMed]
 
Yaphe, J, Edman, R, Knishkowy, B, et al The association between funding by commercial interests and study outcomes in randomized controlled drug trials.Fam Pract2001;18,565-568. [PubMed]
 
Lexchin, J, Bero, LA, Djulbegovic, B, et al Pharmaceutical industry sponsorship and research outcome and quality: systematic review.BMJ2003;326,1167-1170. [PubMed]
 
Fries, JF, Krishnan, E Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development.Arthritis Res Ther2004;6,R250-R255. [PubMed]
 
Bhandari, M, Busse, JW, Jackowski, D, et al Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials.Can Med Assoc J2004;170,477-480
 
Ridker, PM, Torres, J Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000–2005.JAMA2006;295,2270-2274. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Reasons for Clinical Trial Registration

References

DeAngelis, CD, Drazen, JM, Frizelle, FA, et al (2004) Clinical trial registration: a statement from the International Committee of Medical Journal Editors.JAMA292,1363-1364. [PubMed] [CrossRef]
 
DeAngelis, CD, Drazen, JM, Frizelle, FA, et al Is this clinical trial fully registered? – a statement from the International Committee of Medical Journal Editors.N Engl J Med2005;352,2436-2438. [PubMed]
 
Barron, JP Introducing “Medical Writing Tips of the Month:” a new section inCHEST.Chest2006;129,506-507
 
Welch, SJ Preparing manuscripts for online submission: basic information and avoidance of common pitfall.Chest2006;129,822-825. [PubMed]
 
Barron, JP The uniform requirements for manuscripts submitted to biomedical journals recommended by the International Committee of Medical Journal Editors.Chest2006;129,1098-1099. [PubMed]
 
Zarin, DA, Kesselman, A Registering a clinical trial in ClinicalTrials.gov.Chest2007;131,909-912. [PubMed]
 
Sim, I, Chan, A-W, Gulmezoglu, AM, et al Clinical trial registration: transparency is the watchword.Lancet2006;367,1631-1633. [PubMed]
 
Graham, DJ COX-2 inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense.JAMA2006;296,1653-1656. [PubMed]
 
Steinman, MA, Bero, LA, Chren, M-M, et al Narrative review: the promotion of gabapentin: an analysis of internal industry documents.Ann Intern Med2006;145,284-293. [PubMed]
 
Armstrong D. Financial ties to industry cloud major depression study. The Wall Street Journal Online. July 11, 2006. Available at: wsj.com. Accessed July 13, 2006.
 
Nylenna, M, Simonsen, S Scientific misconduct: a new approach to prevention.Lancet2006;367,1882-1884. [PubMed]
 
Miller, FG, Brody, H Professional integrity industry-sponsored clinical trials.Acad Med2005;80,899-904. [PubMed]
 
Institute of Medicine urges reforms at FDA [editorial].Lancet2006;368,1211. [PubMed]
 
Yaphe, J, Edman, R, Knishkowy, B, et al The association between funding by commercial interests and study outcomes in randomized controlled drug trials.Fam Pract2001;18,565-568. [PubMed]
 
Lexchin, J, Bero, LA, Djulbegovic, B, et al Pharmaceutical industry sponsorship and research outcome and quality: systematic review.BMJ2003;326,1167-1170. [PubMed]
 
Fries, JF, Krishnan, E Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development.Arthritis Res Ther2004;6,R250-R255. [PubMed]
 
Bhandari, M, Busse, JW, Jackowski, D, et al Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials.Can Med Assoc J2004;170,477-480
 
Ridker, PM, Torres, J Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000–2005.JAMA2006;295,2270-2274. [PubMed]
 
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