This chapter provides an overview of the key potential benefits and risks of data sharing and sets forth the guiding principles (as evolved from the Framework document; see Box 2-1) that informed the committee’s thinking as it considered the issues presented throughout the remainder of this report. These principles served as a lens through which the committee weighed the benefits and risks of data sharing and considered the roles and responsibilities of individuals and organizations that participate in and benefit from the clinical trials enterprise. Additionally, this chapter describes the committee’s approach for applying these principles to develop the conclusions and recommendations offered in the following chapters.
Potential Benefits of Data Sharing
Sharing of clinical trial data has great potential to accelerate scientific progress and ultimately improve public health by generating better evidence on the safety and effectiveness of therapies for patients. There have been some notable examples of how secondary analyses of shared data have benefited the public, for example, by showing that widely used interventions are ineffective or unsafe (Chan et al., 2014; Doshi et al., 2012; Kaiser et al., 2003; Nissen and Wolski, 2007) or by improving clinical care (Farrar et al., 2014; Gabler et al., 2012a,b; Ventetuolo et al., 2014a,b).
Evolution of Guiding Principles from the Framework Document
In the Framework document, released in January 2014, the committee set forth guiding principles that underpin responsible sharing of clinical trial data and posed a question to help direct its thinking for this final report: To whom do the benefits of clinical trial data belong? As detailed in Chapter 1, the Framework document encouraged the public and interested stakeholders to submit written comments, and the committee gathered further commentary through its public workshops. This chapter incorporates the insights and knowledge the committee gained over the course of the study and updates the guiding principles and approach to their application accordingly. The committee did not delete or add any principles after the Framework was released but did revise the supporting text to better align with this new understanding.
From the perspective of clinical trial participants, data sharing increases their contributions to generalizable knowledge about human health by potentially facilitating additional findings beyond the original, prespecified clinical trial outcomes. Conversely, if data are not shared, opportunities to generate additional knowledge from participants’ contributions are missed (Califf, 2013; Collyar, 2013; Hamblett, 2013; IOM, 2013; Mello et al., 2013; Terry and Terry, 2011).
From the perspective of society as a whole, sharing of data from clinical trials could provide a more comprehensive picture of the benefits and risks of an intervention and allow health care professionals and patients to make more informed decisions about clinical care. Moreover, sharing clinical trial data could potentially lead to enhanced efficiency and safety of the clinical research process by, for example, reducing unnecessary duplication of effort and the costs of future studies, reducing exposure of participants in future trials to avoidable harms identified through the data sharing, and providing a deeper knowledge base for regulatory decisions (Califf, 2013; Doshi et al., 2013; Eichler et al., 2012; Goldacre, 2013; IOM, 2013; Krumholz et al., 2014; Mello et al., 2013; Ross et al., 2012).
In the long run, sharing clinical trial data could potentially improve public health and patient outcomes, reduce the incidence of adverse effects from therapies, and decrease expenditures for medical interventions that are ineffective or less effective than alternatives. In addition, data sharing could open up opportunities for exploratory research that might lead to new hypotheses about the mechanisms of disease, more effective therapies, or alternative uses of existing or abandoned therapies that could then be tested in additional research (Califf, 2013; IOM, 2013;
Mello et al., 2013; Zarin, 2013). The risks of not sharing are inverse to these benefits and include unnecessary duplication of trials, which unduly exposes additional participants to experimentation; increased unwillingness of individuals to participate in clinical trials if the data resulting from those trials are withheld; bias in the body of evidence; and the inability of investigators to build on previous work, thereby slowing progress in understanding of human health.
Risks of Data Sharing
The potential benefits of sharing clinical trial data and the risks of not sharing need to be weighed against any potential harms from sharing.
First, data sharing could put clinical trial participants at increased risk of invasions of privacy or breaches of confidentiality. As a result, participants could suffer social or economic harms (IOM, 2013; Malin, 2014; Mello et al., 2013).1
Data sharing also could result in potential harms to society. For example, shared clinical trial data might be analyzed in a manner that would lead to distorted effect estimates or incorrect conclusions (although this could also occur with the original analyses) (Krumholz and Ross, 2011). For example, if multiple secondary analyses are carried out in an attempt to establish serious adverse effects but statistical analyses do not take these multiple analyses into account, some apparent adverse effects may be identified on the basis of chance alone. A potential consequence is that invalid analyses will lead to claims of risk that are not scientifically valid, which may in turn lead to lawsuits for negligence that, while without merit, are expensive to respond to and defend against.2 If spurious claims of risk are publicized in the lay media, they may be difficult to refute even if they are disproved in peer-reviewed articles. Such claims may harm the public by deterring appropriate use of beneficial therapies. Furthermore, investigators may find it highly burdensome in terms of time and effort to respond to invalid secondary analyses, as the investigators in the PLATO (Platelet Inhibition and Patient Outcomes) trial have documented (Wallentin et al., 2014). To further complicate matters, such invalid analyses may result not only from inadvertent errors in data analysis but also from conflicts of interest, including, in the United States, the prospect of monetary gain through qui tam lawsuits. Incorrect conclu-
1 This section draws on a paper commissioned by the Committee on Strategies for Responsible Sharing of Clinical Trial Data on “Concepts and Methods for De-identifying Clinical Trials Data,” by Khaled El Emam and Bradley Malin (see Appendix B).
2 Personal communication, Virtual WebEx Open Session, G. Fleming, to Committee on Strategies for Responsible Sharing of Clinical Trial Data, Institute of Medicine, regarding clinical trial data sharing: product liability, April 9, 2014.
sions or treatment recommendations for either whole patient populations or subgroups could produce suboptimal care, avoidable adverse effects, and unnecessary anxiety and result in possible discrimination (IOM, 2013; Spertus, 2012). Concerns about such future uses of their clinical trial data might also deter some individuals and/or communities from participating in future clinical trials (IOM, 2013).
The manner in which data are shared might undermine the incentives of clinical trial sponsors, clinical investigators, researchers, and other essential stakeholders to invest their time and resources in the development and clinical testing of potential new treatment practices (Dickersin, 2013; Rathi et al., 2012). For example, data sharing might allow confidential commercial information to be discerned from the data (EMA, 2014; Teden, 2013).3 Competitors might use shared data to seek regulatory approval for competing products in countries that do not recognize data exclusivity periods or do not grant patents for certain types of research (Kapczynski, 2014). The manner in which clinical trial data are shared also might harm the intellectual capital and professional recognition of academic clinical investigators who devote considerable effort and time to designing a clinical trial, recruiting and retaining participants, and collecting the primary data. If subsequent independent analyses failed to give appropriate recognition to the original investigators, those investigators would not have incentives to conduct clinical trials in the future.
The committee offers the following guiding principles as an essential foundation for any approach to sharing clinical trial data.
Maximize the Benefits of Clinical Trials While Minimizing the Risks of Sharing Clinical Trial Data
Understanding and balancing the benefits and risks of health interventions is an essential component of health care, clinical research, and the development of therapies. Similarly, sharing clinical trial data entails potential benefits and harms, as outlined above. Strategies for data sharing should maximize the benefits of sharing to those who give of themselves to participate and to society as a whole while minimizing the potential harms for all stakeholders. This guiding principle for responsible sharing of clinical trial data is derived from the ethical concept of beneficence.
3 E-mail communication, Advanced Medical Technology Association (AdvaMed), to A. Claiborne, Institute of Medicine, regarding strategies for responsible sharing of clinical trial data, March 21, 2014.
The International Conference on Harmonisation’s (ICH’s) Guideline for Good Clinical Practice (GCP) declares: “Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks,” and “the rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society” (ICH, 1996). Likewise, the U.S. Belmont Report articulates beneficence as a basic ethical principle and obligation of research involving human subjects. With respect to persons involved in clinical trials, beneficent actions “(1) do not harm and (2) maximize possible benefits and minimize possible harms” (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979, p. 6). Benefits include both the immediate knowledge gained from testing the hypothesis of a particular clinical trial and the broader utility of the study data in informing the development of effective and safe clinical care. As discussed in the Belmont Report, practitioners are faced with deciding “when it is justifiable to seek certain benefits despite the risks involved” (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979, p. 7). The potential utility of data should be factored into the balance of potential benefits and risks in making the decision whether to expose individual clinical trial participants to risk in order to seek benefits to society as a whole.
Internationally, the right “to share in scientific advancement and its benefits” and “to the protection of the moral and material interests resulting from any scientific . . . production of which [a person] is the author” are both recognized in the 1948 United Nations Universal Declaration of Human Rights.4 Of particular importance is that rights can be framed as positive access to the fruits of scientific research (Knoppers et al., 2014) as well as negative rights to privacy and antidiscrimination. The right of patients and the public to the benefits of scientific research is an alternative way of framing the idea that responsible sharing of clinical trial data should be guided by the goal of increasing scientific knowledge that leads to better therapies for patients (Knoppers et al., 2014).
Respect Individual Participants Whose Data Are Shared
The committee’s second guiding principle stems from the broadly articulated concept that respect for research participants is a fundamental principle of research ethics (ICH, 1996; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979).
4Universal Declaration of Human Rights, G.A. res. 217A (III), U.N. Doc A/810 (1948).
“Respect for research participants” is a term used to describe a bundle of obligations that researchers owe to clinical trial participants. This bundle is commonly understood to include informed consent to participate in a trial and protection of privacy and confidentiality; the committee adds to these components participant engagement throughout a research project.
Clinical trials are designed and carried out to answer research questions about the safety and efficacy of specific health interventions. The interventions that participants receive are determined by the study protocol, not by what their personal physicians consider best for them as individuals. In consenting to participate, clinical trial participants also accept that complying with the study protocol potentially entails inconvenience and risks (Lidz et al., 2004). Although participation in clinical trials, on the whole, may not be significantly more risky than ordinary clinical care or receiving the study intervention outside of the trial (Gross et al., 2006), the benefits and risks of the study arms in a specific trial are not known at the outset. In some instances, the intervention arm of a trial will be shown to have significantly worse outcomes than the control arm, a finding that cannot be predicted at the time of enrollment.
Respect Through Protections for Research Participants
Respect for research participants requires protecting their dignity, integrity, and right to self-determination; this includes, at a minimum, compliance with applicable regulations and ethical standards for the conduct of clinical trials and handling of the resulting data. Respect for research participants has historically been understood to require specific informed consent from participants (including consent for how their data will be used) before they enroll in a clinical trial in which the intervention will be carried out at the individual participant level (Childress et al., 2005; CIOMS, 2002; WMA, 2013).5 In addition, it could be argued that respect for clinical trial participants requires a broader concept of sharing information with participants and obtaining their ongoing consent or concurrence throughout the trial. For example, clinical trial staff might educate participants about the condition being studied, provide more information about study interventions over the course of the trial, and offer additional opportunities for participants to learn more. In addition, respect for participants might require that clinical trialists offer to inform participants of the overall results of the trial, in language that they can understand (Brealey et al., 2010; Fernandez et al., 2003, 2009); studies
5 Specific informed consent is not necessarily required for trials at the group level, such as certain cluster randomized trials (Weijer and Emanuel, 2000), or for certain comparative effectiveness trials (Faden et al., 2013).
indicate that this information is desired by most clinical trial participants. Respect for participants also requires that professional staff in a clinical trial prevent serious and imminent harms that they are uniquely situated to identify and prevent (NRC, 2005).
For existing trials, data sharing (particularly sharing beyond other investigators in the trial) may not have been discussed explicitly with participants during the consent process. Sharing of data without specific participant consent may be ethically acceptable and legally permitted in certain instances. If the shared data are anonymized, for example, current U.S. federal regulations on human research protections and U.S. health information privacy regulations (e.g., the Health Insurance Portability and Accountability Act [HIPAA])6 allow other researchers to use the data for research under certain conditions without consent from the original participants.7
Respect also suggests a need to protect the confidentiality and privacy of trial participants when data are shared. For example, additional protections may be needed when participant identifiers cannot be removed from data or must be included in shared data in order to address an important research question.
Respect Through Engagement
Respect also can be demonstrated and advanced through efforts to engage participants and their representatives in the development of the processes for sharing of clinical trial data, so as to build public trust in the value and importance of data sharing (CTSA, 2011). It is important to remember that individuals participating in clinical trials come from cultures and communities around the world in which power may be unequally and perhaps unfairly distributed (NRC, 2005). Representatives of communities and groups from which clinical trial participants are recruited can provide insight into the cultural and societal values and concerns pertinent to sharing of clinical trial data. Proactive input and feedback on plans for sharing clinical trial data can be obtained from representatives of research participants, disease advocacy groups, community advisory boards, and the public (Jiang et al., 2013). Such engagement also can help sponsors and investigators explain the rationale for data sharing to participants and the public in an accessible and understand-
6 Health Insurance Portability and Accountability Act of 1996, Public Law 104-191, 104th Cong. (August 21, 1996).
7 The U.S. example has been described here for illustrative purposes. The European Union also has strong data privacy protections that must be observed when clinical trial data are shared by its member states (European Commission, 2013).
able manner. The act of seeking and obtaining such input does not in itself constitute surrogate consent or authorization for data sharing. Rather, it demonstrates respect for participants by actively soliciting their concerns about data sharing, identifying its unappreciated benefits and risks that were not previously taken into account, and allowing participants or their advocates to suggest how the data sharing process might be improved (Stiles and Petrila, 2011).
Increase Public Trust in Clinical Trials and the Sharing of Trial Data
Public trust is an intrinsic value undergirding the biomedical science and health research enterprise, which is fundamentally aimed at improving human health. At a more instrumental level, trust also is essential for ensuring continued public support for clinical research and for fostering participation in clinical trials. The concept of public trust in clinical trials encompasses trust both in the scientific process of generating the data (i.e., that there is accountability for how the trials are carried out) and in the validity of the trials (i.e., that the reported findings are an accurate representation of the underlying data) (IOM, 2013). Sharing of clinical trial data could either enhance or reduce public trust in clinical research. The process used for data sharing should therefore be undertaken in a manner that enhances public trust in both the clinical trial process and the data sharing process.
Trust in Clinical Trial Data
By increasing the transparency of how a trial was designed and carried out and of the pathway to the conclusions derived from the trial, sharing of clinical trial data could increase public trust in the outcomes of that particular trial and of trials generally (Loder, 2013). Data sharing also could increase the usefulness and trustworthiness of clinical trial data and analyses of the data because clinical researchers who know that others will be using their data may be more thorough and more careful in their methodology and its documentation. Such additional attention to detail could also help reduce bias in the data and findings (Mello et al., 2013).
Sharing clinical trial data could enhance public trust by facilitating secondary analyses that could determine whether the final conclusions and summaries of clinical trials are robust, valid inferences from the original evidence, although this must be done in a credible and fair manner (Laine et al., 2007). Whether the inferences drawn from a particular trial are strong or called into question, efforts to demonstrate the widespread applicability of the study findings could enhance overall trust in the sci-
entific process and result in more evidence-based recommendations for clinical care.
Trust in clinical research could further be enhanced if sharing of clinical trial data were accompanied by public outreach and engagement to help the public understand that numerous judgments are needed to transform source data into analyzable data (CTSA, 2011), and that highly trained researchers may take different approaches to answering a research question or to analyzing a given data set. Discrepancies in researchers’ analytical approaches and interpretations are an expected part of scientific processes and discussions. Such outreach also could help the public better understand that findings from early clinical trials (i.e., phase I and early phase II trials) often are not definitive and that attempts to reproduce original analyses or to conduct meta-analyses using pooled data from multiple clinical trials can strengthen, modify, refute, or extend the original reports from a trial.
Trust in the Data Sharing Process
Sharing clinical trial data could carry the risk of undermining public trust in clinical trials under certain circumstances, for example, if multiple analyses were to yield conflicting conclusions (Califf, 2013). Public trust in clinical trials whose data are shared could be undermined unless the processes for sharing the data are clear, transparent, and accountable. To this end, established criteria for sharing clinical trial data, procedures for fairly adjudicating requests for data against those criteria, and accountability for both data holders and requesters in adhering to those standards are necessary. Clear, transparent, and accountable processes for data sharing also must include protection of participant privacy and respectful handling of individual participant data.
Sharing of clinical trial data should be carried out in such a manner that it does not repeat, in the data sharing context, well-documented historical examples of imposing disproportionate risks of clinical research on vulnerable groups and thereby undermining the trust of those groups in the overall clinical trial process (Bioethics Commission, 2011; Emanuel et al., 2008; Jones, 2008; Wertheimer, 2008). For example, data sharing ought to include protections for participant subgroups that are particularly vulnerable to breaches of confidentiality or other adverse consequences of data sharing. Clinical trial participants may be particularly vulnerable to harm if they have conditions, or are members of groups, that are commonly stigmatized (Bioethics Commission, 2011; Emanuel et al., 2008; Jones, 2008). In this regard, there may be justifiable and ethical reasons for handling some types of clinical trial data differently with respect to sharing so as to reduce the potential for unfair treatment of participants. For
example, whole genome sequencing data could be identifiable (Gymrek et al., 2013) and might be viewed as putting participants at heightened risk and warranting additional safeguards or protections for participants whose genomic data could be shared. As another example, persons with mental illness, communicable diseases such as HIV infection, injection drug use, and other conditions suffer severe stigma and discrimination in some communities and societies (Bierer et al., 2013; Emanuel et al., 2008).
Further, public trust could be increased if the public saw evidence that their perspectives had been incorporated into the data sharing process (whether by employing the mechanisms described above or by addressing specific community concerns). If analyses of shared data used methods and statistics that were not scientifically valid and led to biased conclusions, they could inappropriately undermine patient trust in valid conclusions about the trial intervention. Such mistrust could ultimately lead to seriously flawed clinical care decisions, unwarranted patient concerns about the quality of care, or avoidable patient anxiety.
Conduct the Sharing of Clinical Trial Data in a Fair Manner
Fairness, broadly articulated, is a core ethical principle that is applicable to the sharing of clinical trial data. In general terms, fairness entails persons receiving what is due to them or what they deserve (Beauchamp and Childress, 2009). Fairness requires similar treatment of people (whether as individuals or as part of groups, entities, processes, etc.) unless there are justifiable reasons to treat them differently. Where disagreements arise is in specifying what an individual or group is due or deserves, identifying sufficient reasons for differential treatment under what might be perceived by some as similar circumstances, and determining whether inequity (i.e., unfairness, unethical conduct) has occurred. Participants, sponsors, and investigators, in particular, have a stake in the fairness of data sharing.
Clinical trial participants could perceive fairness as including equitable distribution of the benefits of clinical research across different groups of participants and different communities. Pooling of shared data from several clinical trials could, for example, benefit groups that have been enrolled in clinical trials in such small numbers that the statistical power to draw valid inferences about risks and benefits for them in any single trial is limited. Among the underserved groups for whom data sharing might accelerate research are individuals with rare conditions or rare subtypes of common conditions and members of certain ethnic groups that historically have had low enrollment in clinical trials. Underrepresentation of these groups in clinical trials can lead to a weaker evidence base for clinical care decisions, as well as health disparities and discrimination (IOM, 2002).
Clinical trial sponsors and investigators who design and carry out clinical trials might believe that fairness includes appropriate recognition and reward for their work and protection of their legitimate interests. Investigators who make substantial investments of intellectual capital, time, and resources in a trial have an interest in carrying out additional analyses of the data they have collected and in receiving due credit when other researchers take advantage of those data. Sponsors that bring a new therapy to market have an interest in competitors not using shared data to gain an unfair competitive advantage or as the sole means of obtaining licensing in other countries without carrying out any original clinical studies. Appropriate protection of these interests could help provide incentives (or reduce disincentives) to share data and to conduct future clinical trials.
The committee next considered its approach for practical application of the above principles to the issues entailed in sharing clinical trial data. If each principle were to be given equal weight, many issues would be unresolvable, as the principles would be in conflict. For example, the principle of maximizing benefits to society could conflict with the principle of respecting participants in addressing the issue of whether participants should be given the opportunity to opt out of data sharing in the consent process. Therefore, the committee needed to develop a practical approach for weighing the principles, particularly in cases in which two or more are in tension.
To develop this approach, the committee returned to the original question posed in the Framework document: “To whom do the benefits of clinical trial data belong?” Note that this is a separate question from who has ownership of the data (described in Box 2-2). The benefits of clinical trial data could be regarded as belonging primarily to the public: the data benefit patients and the public through the advancement of science and clinical knowledge that leads to improved patient care. From this perspective, some might argue that sharing clinical trial data ought to be a prima facie obligation. That is, the default policy—the presumption—should be sharing, with justification needed to restrict or recognize an exception to sharing.
On the other hand, the benefits of clinical trial data could be regarded as belonging primarily to the organizations and individuals who invested resources and time to plan and carry out the clinical trial and analyze the data. The rationale here could be providing fair rewards for investment and work, or it could be instrumental: new tests and therapies would not be developed if organizations and individuals lacked appropriate incen-
Ownership of Clinical Trial Data
With respect to ownership of clinical trial data, academic institutions that receive research grants might claim ownership over the data collected during the research in order to comply with regulatory requirements (Drazen, 2002). Private funders of clinical trials might claim they own the resulting data, particularly if the data will form part of a submission to the U.S. Food and Drug Administration (FDA) for regulatory approval. The language of research grants and contracts and the wording of informed consent forms signed by participants in clinical trials also could delineate ownership or disposition of the data. For example, the U.S. National Institutes of Health (NIH) includes data sharing requirements in the terms and conditions of research grants (NIH, 2003).
It is also important to note that the owner of property does not always have absolute dominion over it; others may have legal access to it under certain conditions for certain purposes. Moreover, property may be taken for public use without consent of the owner, subject to constitutional requirements for due process and fair compensation (Evans, 2011). Ultimately, the question of who owns the data is less important than the question of the rights and responsibilities of data holders.
tives to do so. From this perspective, the policy presumption could be that sharing of clinical trial data should be undertaken only if those who carried out the trial are appropriately incentivized and their interests and rights are protected. Some might argue that sharing of clinical trial data should be optional and voluntary, at the discretion of the organization and individuals who invested resources and time in conducting the trial.
The committee’s position is that the benefits of data sharing belong primarily to the public in the form of valid scientific knowledge and improvement of clinical practice and public health. However, these benefits are not necessarily best attained by full open transparency. Rather, transparency is a means to these goals of scientific knowledge and improvements in clinical care and public health, not a goal in and of itself (Schauer, 2011). The legitimate interests of stakeholders—particularly their concerns about the potential risks and costs of data sharing—need to be recognized and addressed in a fair manner. If full open transparency of clinical trial data carries on balance more risks than benefits, it does not serve the public good.
Rather, the public good is served by policies that seek to attain the benefits of data sharing to advance science and improve clinical care while mitigating its risks to stakeholders.
Finally, the committee was mindful that its estimation of the balance of benefits and risks will likely change over time. As discussed in
Chapter 1, the clinical trial ecosystem—the methods and technologies for conducting and reporting trials; the expectations of participants and the public for increased involvement and transparency; and the attitudes of clinical trial investigators, sponsors, and funders toward sharing clinical trial data—is rapidly evolving. Consideration of the benefits and risks of data sharing needs to be forward looking and take into account not only the risks of sharing but also the potential harms of not sharing in this changing environment.
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