Sharing Clinical Trial Data Maximizing Benefits, Minimizing Risk (2015) / Chapter Skim
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4 The Clinical Trial Life Cycle and When to Share Data
4 The Clinical Trial Life Cycle and When to Share Data
Pages 91-138
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From page 91... ...
. Publication in peer-reviewed scientific journals is currently the primary method for sharing clinical trial data with the scientific and medical communities, as well as the public (often through media coverage of published findings)
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Many discussions of the sharing of clinical trial data to date have failed to specify which of the many clinical trial data elements or data sets might be shared at different time points in the life cycle of a trial. To address this shortcoming, this chapter briefly describes the major stages of the clinical trial life cycle and then offers specific definitions and descriptions of the individual participant data, metadata, and summary data that are generated at each stage.
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2. Participant enrollment: Clinical trial data originate from patients and healthy volunteers who participate in studies.
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94 SHARING CLINICAL TRIAL DATA FIGURE 4-1 Overview of the clinical trial life cycle.
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.4 Thus, as the committee examined what clinical trial data should be shared and when, it was useful to consider clinical trials in these two broad categories: (5a) those intended to support a regulatory application5 and (5b)
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meet protocol-specified criteria. In addition to physiologic and clinical measurements, other types of health data are increasingly being collected in clinical trials, including quantified sensor data (e.g., readings from remote monitoring devices, including smartphone apps)
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Raw data sets are large and complex, include potentially sensitive individual participant data, and are not needed for most secondary analyses of shared clinical trial data. For example, raw data from MRI and computed tomography (CT)
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A second concern is that the clinical trial team often plans to publish a series of secondary analyses, particularly in large clinical trials. Often junior members of the team who are assigned to be lead author on one of these 6 Best practice is to conduct the analyses on blinded data with dummy codes representing treatment arms.
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These 20 items, however, are a small subset of the metadata and additional documentation developed for clinical trials, which include the data sharing plan, protocol and all amendments, the SAP and all amendments, analytic code, and other documents described in Box 4-1 and in the following pages.
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Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final data set, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (in cluding the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use) , and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting
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To be useful to potential secondary users of a clinical trial data set, the data sharing plan needs to be publicly available and readily accessible. One means of accomplishing this goal is to make data sharing plans a 21st element in the WHO trial registration data set.
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It may be amended during the trial while the data are blinded but is finalized before the analysis is completed and the data are unblinded. The SAP drives the primary analyses of the analyzable data set.
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For many clinical trials, the SAP-defined analyses may not use all of the data available in the analyzable data set. Moreover, as discussed earlier, publications of clinical trials in peer-reviewed journals generally draw on only part of the analyzable data set.
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Such examples illustrate the importance of demonstrating statistical reproducibility. Sharing of the analytic code along with the analytic data set also aligns with the principles of transparency and accountability that underlie effective sharing of clinical trial data.
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Subsequent journal publications may address in greater detail a specific aspect of the primary analysis that was not included in the primary publication or analyze outcomes in particular prespecified subgroups of participants. Each journal publication is supported by a specific analytic data set corresponding exclusively to the data used to generate the tables and figures in the publication (which will be a subset of the full analyzable data set)
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4) The committee agrees that sharing the analytic data set supporting a publication is an integral part of the process of communicating results through publication.
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udson and ollins state in an editorial in the H C Journal of the American Medical Association (JAMA) , When research involves human volunteers who agree to participate in clinical trials to test new drugs, devices, or other interventions, this principle of data sharing properly assumes the role of an ethical man 7 Adverse events are "unfavorable changes in health, including abnormal laboratory findings, that occur in trial participants during the clinical trial or within a specified period following the trial" (ClinicalTrials.gov, 2014)
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. The committee appreciates that, in a similar manner, adoption of recommendations for sharing clinical trial data (beyond public posting of summary results)
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Some of the supporting clinical trials included in a regulatory submission do not directly contribute to the evaluation of the effectiveness of the intervention; for these studies, sponsors may be permitted to submit an abbreviated CSR (FDA, 1999)
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Many treatment decisions are based on evidence from past clinical trials, and thus the potential benefits from sharing those data should not be ignored. However, sharing data from legacy clinical trials also presents particular risks and challenges, which need to be balanced against the potential benefits.
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Although it is legally acceptable to share the trial data without the consent of the trial participants (for example, if the data have been deidentified) , Research Ethics Committees may or may not allow data sharing that is contrary to the consent form even if the data are de-identified.
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When Data Packages Should Be shared As discussed previously, vast amounts of data from clinical trials currently are never made public or shared beyond the original investigator team or company, although, as noted in previous chapters, this situation is beginning to change. This section presents the committee's findings and conclusions regarding when the various types of clinical trial data detailed above should be shared.
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It would be desirable for stakeholders in clinical trials to convene after some experience with sharing clinical trial data has been gained, perhaps in 3 to 5 years, so they can reconsider, based on evidence, the timing of data sharing and the conditions under which various types of data should be shared. In deliberating on when the various types of clinical trial data should be shared, the committee found it helpful to summarize the benefits and concerns, discussed in detail in Chapter 3, associated with the timing of data sharing from the perspectives of key stakeholders: • Benefit patients and future research participants.
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. As discussed below, the committee determined that most clinical trial data should not be shared routinely before study completion.
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, full statistical analysis plan (including all amendments and all documentation for additional work processes) , and analytic code.
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They are strongly urged to do so for major and significant clinical trials whose findings will influence decisions about clinical care.
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When reporting the primary results of clinical trials, investigators routinely report a variety of participant characteristics. Reporting these characteristics enables readers to assess the types of patients to whom the results apply, and investigators sometimes use such characteristics to adjust analyses for differences among participants across the trial arms.
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The committee was mindful of these countervailing goals of sharing clinical trial data soon after publication and appreciates that the scientific community is divided over when the analytic data set supporting a publication should be shared. It is likely that some trialists believe they need 1 year to carry out secondary analyses they were planning.
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If a well-designed, adequately powered trial showed that a widely used practice was less effective or less safe than another widely used alternative, and if the differences would have great clinical significance, the trial findings could strongly influence clinical practice. In such a case, shortening the time before clinical trial data are shared would be justified so that other investigators could reproduce the published findings or employ different valid analytic approaches.
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Trials Not Part of Regulatory Application As noted previously, the results of many clinical trials remain unpublished long after the trial's completion. Fewer than half (46 percent)
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. From these findings, the committee concluded that steps should be taken to encourage timely publication of clinical trial results and sharing of clinical trial data after the study investigators have had a fair opportunity to publish their findings.
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As discussed previously, fair sharing of clinical trial data necessitates that sharing be valued independently as a duty of scientific citizenship. Thus, as the academic reward system recognizes and affords fair credit for sharing data that enable other investigators to publish findings, the committee anticipates that the calculus for how much total credit can be obtained by sharing data earlier will evolve to favor more rapid sharing.
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The committee also recognizes that what stakeholders consider acceptable for a moratorium period may change over time as more experience is gained with sharing clinical trial data, particularly if data are collected prospectively on the outcomes of such a data sharing policy. Such outcomes might include the Kaplan-Meier curves on the percentage and types of trials published as a function of time since trial completion, as well as investigators' willingness to lead or participate in other clinical trials.
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Regulatory Approval Regulatory authorities such as the EMA and the FDA have a more comprehensive view of clinical trial data than do other secondary users of shared data. These two agencies make extensive efforts to understand, challenge, and reanalyze submitted data.
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Given regulatory agencies' broad perspective on the data, their public health mandate, and their accountability as government agencies, the committee believes, as noted earlier, that it is beneficial to allow regulators a "quiet period" as they carry out their review, during which clinical trial data need not be shared with other secondary users, even beyond the 18-month period after study completion. The committee concludes that a "post-regulatory data package" -- consisting of the CSR (redacted for commercially or personal confidential information)
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In such cases, sharing clinical trial data may help other researchers studying and other sponsors developing similar products. The design of trials on these other products may be modified by the results of the abandoned trial, for example, if the results suggest safety or efficacy endpoints.
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Box 4-4 presents three case examples of the timeline for sharing clinical trial data. Sharing Data with Participants Clinical trial participants are interested in certain types of trial data, sometimes for purposes other than carrying out secondary analyses.
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The trial is completed on July 1, 2014. Because this is a regulatory trial, the post-regulatory data package should be released 18 months after study completion (December 31, 2015)
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As in the case of baseline individual data, some data collected during a trial come from tests that are routinely available in clinical practice, such as tests ordered to assess endpoints or monitor adverse events. Abnormal findings may require follow-up by the participant and his or her physician in real time -- for example, if there is evidence of cancer recurrence.
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For levels of new biomarkers for the study drug or for innovative tests not yet used in clinical care, individual results may be of uncertain significance and little direct clinical benefit until clinical trial data have been analyzed. For example, a trial may be assessing the predictive power of new biomarkers or the sensitivity of a new imaging technique.
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Such outreach and collaboration may also increase public understanding of and trust in the clinical trial process. Conclusion: Investigators can help uphold public trust in clinical trials and adhere to current best practices and legal standards by • xplaining to trial participants what data will be shared with them e and with other interested parties and when, as part of the informed consent process; and • s appropriate, making individual participants' own data collected a during the course of a trial available to them following study comple tion and data analysis.
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From page 133... ...
should be shared no later than 6 months after publication. Regulatory application: • For studies of products or new indications that are approved, the post-regulatory data package (including the full analyzable data set and clinical study report redacted for commercially or personal confidential information, together with the full protocol, full sta tistical analysis plan, and analytic code)
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2013. Clinical trial data sharing and challenges to data sharing: Current and future.
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:867-872. European Union Clinical Trials Register.
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2014. Considerations of informed consent in the discussion of clinical trial data sharing -- domestic issues.
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Paper presented at IOM Committee on Strategies for Responsible Sharing of Clinical Trial Data: Meeting One, October 22-23, Washington, DC. Temple, R., and G
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