Registering your research: What’s required?

Over the past 12 months, the editorial team at the Journal has spent a great deal of time assessing our processes and procedures on a granular level. We have examined both quantitative and qualitative evidence to determine what we are doing well and where we could improve, primarily with the aim of better supporting osteopathic medical research, the authors who conduct it, and the patients who participate in it. Over the course of that self-examination process, we found some areas for necessary and exciting operational change, many of which were discussed in the Editorials from our January [1] and February [2] issues. We also found some opportunities for more consistent enforcement of our existing policies, one of which I would like to highlight here: our requirements for clinical trial registry [3].

Our current policy states, as it has for many years, that we require prospective clinical trial registration for every research study involving human subjects, in alignment with the Declaration of Helsinki [3]. However, 16 years after this policy was introduced at the Journal [4], we still receive submissions with unregistered clinical research, particularly when the intervention being tested relates to osteopathic manipulative treatment (OMT). When we query about it, authors often respond that they did not consider their trial to be clinical because it did not involve a device or pharmaceutical. Conversely, our Editors often assume trials have been registered, even when an author does not provide the information, because our policy has been in place for so long. While we have instituted some procedural guard rails during submission and peer review to avoid these dichotomous assumptions, it is important for readers and authors alike to understand the reasoning and history behind this requirement.

In 1964, the 18th General Assembly of the World Medical Association took place in Helsinki; the group adopted and published a document entitled “Ethical Principles for Medical Research Involving Human Subjects,” otherwise known as the Declaration of Helsinki (DOH) [5]. The DOH, which has been referred to as a “cornerstone of ethics in biomedical research,” [6] still acts as a succinct, direct “set of principles … to protect human participants and conduct research in an ethical manner.” [6] As such, the first edition of the DOH focused primarily on informed consent [7], partially in direct response to the disturbing information exposed at the Nuremburg trials about unconscionable experiments in Nazi Germany, after which the Nuremburg Code was developed [7], [8].

The DOH has undergone several rounds of both minor revision and major additions, beginning with the second edition, developed in a Tokyo meeting in 1975, which introduced “arguably the single most important addition in terms of the ensuing conduct of medical research … the requirement that independent committees review research protocols,” [7] thus bringing institutional review board (IRB) approval into the conversation. In the fifth edition, which came out of the 2000 meeting in Edinburgh, the committee offered a “major logical re-framing” [7] of human subject research categories. According to a 2004 summary in the British Journal of Pharmacology, “The pre-2000 versions of the Declaration effectively dichotomized research into therapeutic (potentially benefiting the subject directly) and nontherapeutic (no direct benefit to subject). In the Edinburgh (2000) revision the new category of ‘Medical Research Combined with Medical Care’ [was] recognized as a subset of ‘all medical research involving human subjects’” [7].

Most important for the context of this Editorial, the 2008 meeting in Seoul brought the seventh revision of the DOH, which mandated clinical trial registry with the following statement: “Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject” [9], [10]. That statement still stands in the current version [5]. Calls for clinical trial registry requirements have a long history dating back to at least the 1980s [9]; a few years prior to the mandate in the DOH, in 2004, the International Committee of Medical Journal Editors (ICMJE) also issued a statement amplifying those calls [11]. A mere month after the ICMJE statement was recorded in the Annals of Internal Medicine, the Editor-in-Chief of the Journal of the American Osteopathic Association, Gilbert E. D’Alonzo, Jr. (DO), published an Editorial [2] in our pages announcing the same policy. He felt that the ICMJE statement would “substantially change the way in which clinical trials will qualify to be published in the peer-reviewed medical literature in the future,” and believed that “this process must be extended beyond pharmaceutical trials and beyond ICMJE member journals, … [to] include any clinical trial that could be used to influence the thinking of patients, researchers, clinicians, and other experts who take care of patients, write clinical care guidelines, or even decide on insurance-coverage policy” [2]. He also clearly stated, “I thought that it was directed at the pharmaceutical industry, but after careful consideration, I find that it involves all forms of clinical investigation involving human subjects, including nonpharmaceutical research such as osteopathic manipulative treatment” [2]. I strongly urge our readers to find Dr. D’Alonzo’s full Editorial on our website (www.jaoa.org) or through the MEDLINE/PubMed database; he shares important personal anecdotes about his own experience with medical research that place the need for clinical trial registry in crucial context.

Clinicaltrials.gov, the public database operated by the US National Library of Medicine and one of the most common sources for clinical trial registry, has published a straightforward list of the ethical justification for registry requirements [12]. By registering their work in a publicly-accessible registry database, whether required by journals like ours or not, authors can: (1) fulfill ethical obligations to participants and the research community; (2) provide information to potential participants and referring clinicians; (3) reduce publication bias; (4) help editors and others understand the context of study results; (5) promote more efficient allocation of research funds; and (6) help institutional review boards (IRBs) determine the appropriateness of a research study [12]. Incidentally, the World Health Organization’s website [13] also offers a very helpful list of primary and partner registry databases where researchers can submit their methodology and results.

Our Editors have now renewed their commitment to strictly enforcing the policy has been in place for more than 16 years at JAOA and now Journal of Osteopathic Medicine: all articles submitted to us describing prospective research involving human subjects must provide proof of clinical trial registry. Articles without that designation will be rejected. We have adopted an interim policy of allowing ex post facto registration for some articles because we realize the accepted convention of a priori registration is still not well known throughout osteopathic medicine, but this policy will not be permanent.

It is my hope (a hope shared by our current Editor-in-Chief, Ross D. Zafonte [DO] and our Section Editors) that this Editorial will serve to advance understanding and knowledge in the osteopathic medical community about not just the requirement for research registration, but also the ethical value of it.