Randomized clinical trials (RCTs) represent the best study design for minimizing bias when studying the effectiveness of a treatment. RCTs also are the building blocks of systematic reviews and meta-analyses, which allow more generalizable conclusions to be drawn about therapeutic efficacy1, provided that the RCTs themselves are well-designed and implemented, and provided that the data are available for such analyses.
Unfortunately, study details and results from all of the RCTs that have been performed often are not available, and meta-analyses can include only those data that the authors can find. Many prospective trials are started but never finished, and many more are completed but never published2-5. Published RCTs therefore make up only a subset of the universe of RCTs performed, and compelling evidence suggests that a positive study outcome (among other non-scientific factors) increases the likelihood that a study will be published6.
Selective publication of this sort, sometimes called publication bias or positive-outcome bias, is harmful for at least two reasons. First, if two studies—one showing positive results and one showing no difference between interventions—have been performed, but the positive study is more likely to be published (and therefore available for meta-analysis), then meta-analyses will tend to inflate the apparent benefits of a treatment and de-emphasize its harms7,8. This may lead to the inappropriate adoption of new interventions that are less effective than they seem and that almost always are more expensive. Second, when no-difference studies are performed but not published, a wasteful duplication of resources is likely to ensue when clinicians set out to conduct trials that unbeknownst to them have already been carried out.
A systems-level solution exists, and has for some time. RCTs should be registered in one of the numerous publicly available, free, searchable, well-maintained clinical trial repositories before the first patient is enrolled9-11. In addition to mitigating positive-outcome bias and reducing the likelihood that expensive, time-consuming trials will needlessly and unknowingly be repeated, prospective registration helps journals to minimize data dredging by allowing verification that the end points reported were the end points initially proposed by the researchers12. Prospective registration also allows patients to identify trials in which they may wish to enroll, and it can help institutional review boards find research germane to the studies that they evaluate13.
For several years, The Journal of Bone and Joint Surgery, The Bone & Joint Journal, and Clinical Orthopaedics and Related Research have either required or encouraged trial registration but permitted it to be done retrospectively (that is, after the study had been completed). We now all concur that this is not sufficient. Retrospective registration merely to allow a paper to be considered for publication by a journal does not facilitate the identification of no-difference findings, minimize data dredging, help patients find care, or support ethics panels in their important work. The International Committee of Medical Journal Editors (ICMJE) has required that its member journals insist on prospective registration for more than a decade now14. It is time for the leading journals of orthopaedic surgery to do likewise.
With that in mind, as of now The Journal of Bone and Joint Surgery, The Bone & Joint Journal, and Clinical Orthopaedics and Related Research require registration in a publicly searchable clinical trials registry prior to publication of RCTs, and the trial registry number will be published in the electronic and print versions of these papers. Through the end of 2017, which we consider a transition period, this registration may take place either prospectively or retrospectively, but as of January 1, 2018, authors of all RCTs that began after the publication of this editorial must demonstrate proof of prospective registration to be considered for review by any of our three journals.
We understand that there will be rare situations in which prospective registration is not possible or not appropriate, and we will be receptive to such claims. In these situations, the authors will be expected to explain in the limitations section of the paper the reasons for non-registration, and the editors will add a note to the title page of such a paper explaining why the exception was permitted. However, simple omission of prospective registration will not be considered a suitable excuse; the principles at stake here are too important.
We encourage all orthopaedic journals to join us in setting and maintaining this important community research standard.
Note: The authors would like to acknowledge, for their contributions to this important policy and the editorial that articulated it, the Senior Editors of Clinical Orthopaedics and Related Research (Matthew B. Dobbs, MD; Mark C. Gebhardt, MD; Terence J. Gioe, MD; Paul A. Manner, MD, FRCSC; Raphaël Porcher, PhD; Clare M. Rimnac, PhD; and Montri D. Wongworawat, MD) as well as its Managing Director (Lee Beadling, BA); the Editorial Board of The Journal of Bone and Joint Surgery (Jean-Noël A. Argenson, MD, PhD; Thomas W. Bauer, MD, PhD; Thomas D. Brown, PhD; Charles R. Clark, MD; Charles M. Court-Brown, MD, FRCSCEd[Orth]; Lars Engebretsen, MD, PhD; Andrew Green, MD; Anil K. Jain, MS, FAMS, FRCS; Michelle A. James, MD; Bernhard Jost, MD; Jeffrey N. Katz, MD, MSc; Eng Hin Lee, MD, FRCSC; Elena Losina, PhD; Stephen Lyman, PhD; Konstantinos N. Malizos, MD, PhD; Robert G. Marx, MD, MSc, FRCSC; Sanjeev Sabharwal, MD, MPH; Bruce Sangeorzan, MD; Christoph J. Siepe, MD; Paul D. Sponseller, MD; Stephen R. Thompson, MD, MEd, FRCSC; Daisuke Togawa, MD, PhD; and James P. Waddell, MD, FRCSC) and its Editors Emeritus (Vernon T. Tolo, MD, and James D. Heckman, MD); and the Editorial Board of The Bone & Joint Journal (Matthew Costa, PhD, FRCS[Tr&Orth]; Richard Carey Smith, BSc[Hons], MB, BS, MRCS, FRCS[Orth], FAOrthA; Melina Dritsaki, BSc, MSc, PhD; Xavier Griffin, FRCS[Tr&Orth], PhD; Nicholas Parsons, BSc, MSc, PhD; Daniel Perry, FRCS[Orth], PhD; and Dirk Stengel, MD, PhD, MSc).
*The authors of this editorial are the Editors-in-Chief of Clinical Orthopaedics and Related Research, The Journal of Bone and Joint Surgery, and The Bone & Joint Journal, respectively; in the interest of setting a common standard among leading general-interest orthopaedic journals, this editorial is being published concurrently in all three of those journals.
Disclosure: All ICMJE Disclosure of Potential Conflicts of Interest forms for Clinical Orthopaedics and Related Research Editors are on file with the publication and can be viewed on request; the Editors’ disclosure statements also appear each month in print on the masthead of Clinical Orthopaedics and Related Research. The ICMJE Disclosure form for the Editor of JBJS is provided with the JBJS online version of this article, and the ICMJE Disclosure form for the Editor of The Bone & Joint Journal is available with the BJJ online version of this article.
2. Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. 2003 Jan 22-29;289(4):454-65.
3. Emerson GB, Warme WJ, Wolf FM, Heckman JD, Brand RA, Leopold SS. Testing for the presence of positive-outcome bias in peer review: a randomized controlled trial. Arch Intern Med. 2010 Nov 22;170(21):1934-9.
4. Lièvre M, Ménard J, Bruckert E, Cogneau J, Delahaye F, Giral P, Leitersdorf E, Luc G, Masana L, Moulin P, Passa P, Pouchain D, Siest G. Premature discontinuation of clinical trial for reasons not related to efficacy, safety, or feasibility. BMJ. 2001 Mar 10;322(7286):603-5.
5. Rosenthal R. The ‘‘file drawer problem’’ and tolerance for null results. Psychol Bull. 1979;86(3):638-41.
8. Hopewell S, McDonald S, Clarke M, Egger M. Grey literature in meta-analyses of randomized trials of health care interventions. Cochrane Database Syst Rev. 2007;2:MR000010. Epub 2007 Apr 18.
12. Rifai N, Bossuyt PM, Ioannidis JP, Bray KR, McShane LM, Golub RM, Hooft L. Registering diagnostic and prognostic trials of tests: is it the right thing to do? Clin Chem. 2014 Sep;60(9):1146-52. Epub 2014 May 22.
14. De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, Kotzin S, Laine C, Marusic A, Overbeke AJ, Schroeder TV, Sox HC, Van Der Weyden MB, International Committee of Medical Journal Editors. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med. 2004 Sep 16;351(12):1250-1. Epub 2004 Sep 8.