The International Committee of Medical Journal Editors (ICMJE) — which counts several prestigious periodicals among its members — is giving authors an offer they can’t refuse: Agree to share your clinical trial data with subsequent researchers or your manuscript will not be published. Though transparency has an innate appeal and the stated goal is a noble one —- “to improve the benefit to society from the efforts of patients who volunteer to participate in clinical trials” — there is a little of the devil in the proverbial details.
“Trial participants generously and selflessly volunteer their efforts, and put themselves at risk in clinical trials on the promise that the knowledge gained will be used to help others,” says Darren B. Taichman, MD, PhD, ICMJE secretary and executive deputy editor of the Annals of Internal Medicine. “Making sure that the data generated are made available to ensure the most is learned from them is part of keeping that promise.”
The ICMJE proposes that as a condition of consideration for publication of clinical trial studies in its member journals — which also include the New England Journal of Medicine and the Journal of the American Medical Association — authors would have to agree to share “deidentified individual-patient data (IPD) underlying the results presented in the article (including tables, figures, and appendices or supplementary material) no later than 6 months after publication.” The ICMJE proposal was outlined in an editorial1 published on Jan 26, 2016, in the three aforementioned journals and 10 others. “Sharing data should increase confidence and trust in the conclusions drawn from clinical trials, enable independent confirmation of results, and foster the development and testing of new hypotheses,” the committee states.
The “results” to be shared are defined as the IPD required to reproduce the article’s findings, including necessary metadata. The proposal is open for comments through April 18, 2016, at http://www.icmje.org/.
Those using data collected by others should seek collaboration with those who collected the data. “However, because collaboration will not always be possible, practical, or desired, an alternative means of providing appropriate credit needs to be developed and recognized in the academic community,” the ICMJE states. “We welcome ideas about how to provide such credit.”
Sponsors of clinical trials are in a position to support and ensure adherence to data sharing obligations, the proposal states. If data sharing agreements are not met, the editors may choose to request additional information; publish an expression of concern; notify the sponsors, funders, or institutions; or in certain cases, to retract the publication, the ICMJE states. “In the rare situation in which compliance with these requirements is impossible, editors may consider authors’ requests for exceptions. If an exception is made, the reason(s) must be explained in the publication.”
INFORMED CONSENT FOR THE FUTURE
The ICMJE anticipates that the new data-sharing requirement will go into effect for clinical trials that begin to enroll participants beginning one year after the proposed policy is finalized. If adopted as proposed, IRBs would need to determine that when researchers get consent from subjects, they are acknowledging that their data could be used by future researchers.
“Planning to responsibly share clinical trial data must assure the protection of trial participants’ rights, an area where the work of IRBs is essential,” Taichman says. “For example, IRBs will need to ensure that the consent process for trial enrollment includes appropriate information regarding the plan to and conditions under which data will be shared.”
Because informed consent regarding the sharing of de-identified participant-level data is not already in place for many currently ongoing trials, the proposed requirements for data sharing would apply only to those studies that start enrolling patients after the one-year grace period, he emphasized in comments to IRB Advisor.
“We do that often now — we ask for permission [for future use],” says Susan Rose, PhD, executive director of the Office for the Protection of Research Subjects at the University of Southern California, and member of the IRB Advisor editorial board. “It would become a mandatory question, but it shouldn’t be a big deal to make that happen.”
The ICMJE notes that by taking this action, they “join a growing consensus, [as] many funders around the world — foundations, government agencies, and industry — now mandate data sharing.”
However, details that have to be resolved include standardization of the definition of “clinical trial” among the various entities that oversee the research, Rose says. For example, the National Institutes of Health (NIH) definition of a clinical trial adopted in October 2014 is: “A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.”
In the editorial proposing the new sharing policy, the ICMJE defined a clinical trial as “any research project that prospectively assigns people or a group of people to an intervention, with or without concurrent comparison or control groups, to study the cause-and-effect relationship between a health-related intervention and a health outcome.”
“The NIH definition of clinical trials includes behavioral outcomes and this group says a health-related intervention and a health outcome,” Rose says. “So to me that looks like a different definition of clinical trials.”
In addition, the ICMJE requires studies to register at ClinicalTrials.gov, but the data fields are not particularly compatible with social and clinical behavioral research, she notes. Thus, a “translator” is needed describe the research in terms acceptable to the NIH website.
“Say [in a study] people are doing exercise to lose weight and to see if that makes them less hungry,” Rose says. “They’re not taking any drug, using a device or a biologic. If the study [researchers] want to get published in one of these [ICMJE] journals they have to register on ClinicalTrials.gov. But the data fields are not [compatible]. It would be really nice if ClinicalTrials.gov were more user-friendly to social and behavioral studies. These different definitions are a problem because we don’t know how to describe a health study with a behavioral come. The definitions have to be the same and they need to be agreed upon.”
Though specifics and challenges remain to be worked out, the ICMJE proposal is “an extremely important step in the right direction,” says Robert Klitzman, MD, professor of psychiatry and director of the Bioethics Master’s Program at Columbia University in New York City.
GREAT PROMISE, A FEW CAVEATS
“Unfortunately, evidence indicates that pharmaceutical companies have repressed data from trials that do not support their products,” Klitzman says.2 “The number of researchers who have fabricated results, and later had to retract their published papers, is also increasing. Hence, this announcement by ICMJE is very promising. Certainly, several details will have to be worked out — such as when, if ever, exceptions might be made. Moreover, not all journals are members of ICMJE — though most of the world’s top-tier journals are. Still, drug companies may decide to publish results in second-tier, non-member journals, and then distribute these articles to physicians who may not know the difference in policies.”
Klitzman called for more transparency in clinical trials and IRB oversight in his recently published book, The Ethics Police?. He also reported that researchers were frustrated by chronic delays in the approval process at present. (See the February 2016 issue of IRB Advisor.)
“Critics may argue that publication of results will be delayed [by the ICMJE requirements], but researchers can submit the data six months after publication, and presumably they will already have the data in a usable form,” he says. “ICMJE’s announcement did not address how to respond to potential arguments about the data being proprietary. This, too, will need to be decided. However, on balance, I think that this effort is vital and well worth considering.”
The one-year grace period should address issues that may delay research publication, Taichman says, but concedes that “new undertakings often require extra time” at the onset.
“But we cannot let the extra effort involved stop us from ensuring that we honor the contributions of trial participants by making the most of their data,” Taichman says. “And, there are benefits for researchers. Assuring trial participants that the most will be learned from their volunteer efforts should help encourage others to participate in trials.”
The ICMJE proposal would require authors to include a plan for data sharing as a component of clinical trial registration. The plan must include where the researchers will house the data and — if not in a public repository — the mechanism by which they will provide access. The committee references data-sharing plan elements outlined in a 2015 Institute of Medicine Report for additional details.3 ClinicalTrials.gov has also added a data-sharing component to its registration platform, the editors note.
“We encourage other trial registries to similarly incorporate mechanisms for the registration of data-sharing plans,” the ICMJE states. “[Researchers] who want to publish in ICMJE member journals (or nonmember journals that choose to follow these recommendations) should choose a registry that includes a data-sharing plan element as a specified registry item or allows for its entry as a free-text statement in a miscellaneous registry field. Authors may choose to share the deidentified IPD underlying the results presented in the article under less restrictive, but not more restrictive, conditions than were indicated in the registered data sharing plan.”
Just as the confidentiality of trial participants must be protected through the deidentification of IPD, the rights of investigators and trial sponsors must also be accommodated. In that regard, the ICMJE proposes the following safeguards:
- ICMJE editors will not consider the deposition of data in a registry to constitute prior publication.
- Authors of secondary analyses using these shared data must attest that their use was in accordance with the terms (if any) agreed to upon their receipt. They must reference the source of the data using a unique identifier of a clinical trial’s data set to provide appropriate credit to those who generated it and allow searching for the studies it has supported.
- Authors of secondary analyses must explain completely how theirs differ from previous analyses. In addition, those who generate and then share clinical trial data sets deserve substantial credit for their efforts.
Though signing off on the deal as a member of the ICMJE, the NEJM published an editorial that conceded that there are concerns about “research parasites” who had nothing to do with the design and execution of the study but use another group’s data for their own ends, “possibly stealing from the research productivity planned by the data gatherers, or even [using] the data to try to disprove what the original investigators had posited.”4
While noting such concerns, the editorial cites a study5 in the same issue by investigators who “worked symbiotically, rather than parasitically, with the investigators holding the data, moving the field forward in a way that neither group could have done on its own.”
The new authors hypothesized that certain colon cancers might create more aggressive tumors at greater risk of relapse and might be more likely to benefit from adjuvant treatment. Needing a large group of archived patient specimens and tissues, they collaborated with a research consortium funded by the National Cancer Institute. They found that 4% of patients had such tumors, which predicted poorer prognosis and greater benefit from of adjuvant chemotherapy. That generated a new hypothesis that, if proven, means that the vast majority of colon cancer patients can be reassured that “avoiding the unpleasantness of standard adjuvant therapy is unlikely to affect their outcome adversely,” the editorial authors noted. “No one expected that.”
Using the study as a case in point, the authors outlined the following key criteria for data sharing done right:
- Start with a novel idea, one that is not an obvious extension of the reported work.
- Identify potential collaborators whose collected data may be useful in assessing the hypothesis and propose a collaboration.
- Work together to test the new hypothesis.
- Report the new findings with relevant coauthorship to acknowledge both the group that proposed the new idea and the investigative group that accrued the data that allowed it to be tested.
REFERENCES
- Taichman, DB, Backus J, Baethge C. et al. Editorial: Sharing Clinical Trial Data: A Proposal From the International Committee of Medical Journal Editors. Ann Intern Med 2016: http://www.icmje.org/news-and-editorials/M15-2928-PAP.pdf.
- Klitzman, RL. (2015) The Ethics Police? The Struggle to Make Human Research Safe. New York: Oxford University Press.
- Institute of Medicine. Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk. Washington, DC: National Academies Press. 2015.
- Longo, DL, Drazen JM. Editorial: Data Sharing. N Engl J Med 2016;374:276-277.
- Dalerba P, Sahoo D, Paik S, et al. CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med 2016;374:211-222.
The International Committee of Medical Journal Editors — which counts several prestigious periodicals among its members — is giving authors an offer they can’t refuse: Agree to share your clinical trial data with subsequent researchers or your manuscript will not be published.
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