Respect Through Research Participant Protections

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 is carried out at the individual participant level (Childress et al., 2005; CIOMS, 2002; WMA, 2013).⁵ For existing trials, data sharing (particularly sharing beyond other investigators in the trial) might not have been explicitly discussed with participants during the consent process. Sharing of data without specific participant consent might be ethically acceptable and legally permitted in certain instances. For example, if the shared data are de-identified, 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] of 1996)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. Questions have been raised about the sufficiency of commonly used de-identification methodologies (Benitez and Malin, 2010; El Emam, 2013; McGraw, 2012); consequently, additional protections may be needed.

Respect Through Engagement

Respect can also be demonstrated and advanced through efforts to engage participants and their representatives in the development of processes for sharing of clinical trial data (CTSA, 2011). For example, new policies and procedures regarding data sharing and subsequent additional analyses (particularly for specific trials or classes of trials as relevant) could be developed with input and feedback from representatives of research participants, disease advocacy groups, community advisory boards, and the public (Jiang et al., 2013). Such an approach would also include dissemination of information and calls for input about data sharing policies and procedures and a rationale for data sharing that is accessible and understandable to the public. The act of seeking and obtaining such input would not in itself constitute surrogate consent or authorization for data sharing. Rather, it would respect participants by actively seeking to identify concerns about and potential unappreciated benefits of data sharing that were not previously taken into account, and allow participants or their advocates to suggest how the process of data sharing might be improved (Stiles and Petrila, 2011).

Potential Benefits

International ethical standards identify beneficence as a basic ethical principle and obligation of research involving human subjects. The International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 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). Benefits include both the immediate knowledge gained from answering the hypothesis of a particular clinical trial and the broader utility of the study data in informing development of effective new interventions. 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, 1979, p. 5). The potential utility of data is a component in the balance of potential benefits and risks when making the decision to expose individual participants to risk in order to seek benefits to society as a whole.

Clinical trials are designed and carried out to address research questions about the safety and efficacy (or effectiveness) of one or more 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, might not be significantly riskier than ordinary clinical care or receiving the same intervention outside the trial (Gross et al., 2006), in a specific trial the benefits and risks of the study arms 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.

From the perspective of clinical trial participants, data sharing increases their contributions to generalizable human health knowledge by potentially facilitating additional findings beyond the original, predefined clinical trial outcomes. Thus, if data are not shared, opportunities are missed to generate additional knowledge from their contributions (Califf, 2013; IOM, 2013; Mello et al., 2013).

From the perspective of society as a whole, sharing data from clinical trials, if it were to yield additional results that contribute to the scientific knowledge base, could provide a more accurate, less biased, and more comprehensive picture of the benefits and risks of an intervention. Sharing clinical trial data could potentially lead to enhanced efficiency and safety of the clinical research process by, for example,

• reducing duplication of efforts and costs of future studies;
• reducing exposure of participants in future trials to avoidable harms that can be identified through data sharing;
• providing a deeper knowledge base for regulatory decisions;
• supporting the development of clinical practice guidelines; and
• allowing health care professionals and patients to make more informed decisions about clinical care.

The usefulness of clinical trial data would be enhanced if, in addition to sharing the protocol, manual of operations, statistical analysis plan, a copy of the case report forms, and metadata about the analyzable data file, the data user could ask the data generator questions regarding logistical and practical issues such as the conduct of the clinical trial or data analyses. The usefulness of shared clinical trial data might also be enhanced if data were collected in a standardized manner, where scientifically indicated (Califf, 2013; IOM, 2013; Mello et al., 2013).

In the long run, proponents have suggested that sharing clinical trial data could 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 opportunities for exploratory research that might lead to hypotheses about the mechanisms of disease, more effective therapies, or alternative uses of existing or abandoned therapies that could be tested in additional research (Califf, 2013; IOM, 2013; Mello, 2013).

Potential Harms

These potential benefits of clinical trial data sharing need to be balanced against any potential harms. Data sharing could place clinical trial participants at increased risk for invasions of privacy or breaches of confidentiality, which could then lead to social or economic harms to the participants (IOM, 2013; Mello et al., 2013).

Data sharing could also result in potential harms to society. For example, shared clinical trial data might be analyzed in a manner that leads to biased effect estimates or invalid conclusions (although this might also occur with the original analyses) (Krumholz and Ross, 2011). Incorrect conclusions or treatment recommendations for either whole-patient populations or subgroups could produce suboptimal care 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 clinical trials.

Clinical trialists and sponsors of clinical trials could also suffer potential harms due to the administrative and financial burden of data sharing, which they might regard as an unfunded mandate. The manner in which data are shared might undermine the incentives of clinical trial sponsors, clinical investigators, coordinating centers, researchers, and other essential stakeholders to invest 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 (CCI) to be discerned from the data (Teden, 2013). Competitors might use shared data to seek regulatory approval of competing products in countries that do not recognize data exclusivity periods or that do not grant patents for certain types of research. The manner in which clinical trial data are shared might also 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 fail to give appropriate recognition to the original investigators, there will not be incentives for investigators to share clinical trial data.

Trust in Clinical Trial Data

By increasing the transparency of trial design and conduct and the pathway to trial conclusions, sharing clinical trial data might increase public trust in the outcomes of specific trials and of clinical trials generally (Loder, 2013). Data sharing might also increase the usefulness and trustworthiness of clinical trial data and analyses because clinical researchers who know that others will be using their data might be more thorough and more careful in their methodology and its documentation. Such additional attention to detail might also help to reduce bias in the data and findings (Mello et al., 2013).

Sharing clinical trial data could enhance public trust by facilitating confirmatory analyses that could determine whether the final conclusions and summaries of clinical trials are robust and valid inferences from the original evidence, although this must be done in a credible and fair manner (Laine et al., 2007). Whether the inferences from a particular trial are strong or weak, activities seeking to demonstrate widespread applicability of the findings could enhance overall trust in the scientific process and in the resulting evidence-based recommendations for clinical care.

Trust in clinical research could be enhanced further if sharing clinical trial data were accompanied by 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 might take different approaches to answering a research question or to analyzing a given dataset. Different analytical approaches and interpretations of data by researchers are an expected part of the scientific process and discussions. Such outreach could also help the public better understand that findings from individual clinical trials are often not definitive, and that attempts to replicate original analyses or the conduct of meta-analyses using pooled data from multiple clinical trials can strengthen, modify, refute, or extend the original reports from a trial. Moreover, trust would be enhanced if additional analyses using data from a clinical trial were easily connected with the publications from the original 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 yield conflicting or invalid conclusions (Califf, 2013). Public trust in clinical trials where data are shared might be undermined unless there are clear, transparent, and accountable processes for the data sharing, including established criteria for clinical trial data sharing, procedures for fairly adjudicating requests for data against those criteria, mechanisms for ensuring or confirming the integrity of data when they are collected and analyzed by different parties, and accountability for both data holders and requesters in adhering to those standards. Clear, transparent, and accountable processes for data sharing would also include protection of patient privacy and respectful handling of individual patient data. Further, public trust could be increased if the public sees evidence of the incorporation of its perspectives (whether through the mechanisms described above or by addressing specific community concerns). If analyses of shared data use inappropriate methods and statistics and lead to biased conclusions, they can undermine patient trust in valid conclusions about the study intervention. Such mistrust might ultimately lead to seriously flawed clinical care decisions, unwarranted patient concerns about the quality of care, and avoidable patient anxiety.

Fairness in Exposure to Potential Risks of Data Sharing

Clinical trial data sharing should be carried out in a fair manner so that it does not repeat, in the data sharing context, well-documented historical examples of placing disproportionate risks of clinical research on vulnerable groups (Bioethics Commission, 2011; Emanuel et al., 2008; Jones, 2008; Wertheimer, 2008). For example, data sharing should include protections for participant subgroups that are particularly vulnerable to breaches of confidentiality or other adverse consequences of data sharing. Clinical trial participants could be particularly vulnerable to harm if they have conditions, or are members of groups, that are often stigmatized. In this regard, there might be justifiable and ethical reasons for handling some types of clinical trial data sharing differently to reduce the potential for unfair treatment of participants. For example, whole-genome sequencing data could be identifiable (Gymrek et al., 2013), which might be considered to put participants at heightened risk, and additional safeguards or protections for participants whose genomic data could be shared might be warranted.

Fairness in the Distribution of the Potential Benefits of Research

Clinical trial data sharing could increase fairness in clinical research by helping to distribute the benefits of clinical research more equitably across different groups of participants and communities. Pooling shared data from several clinical trials could, for example, benefit groups who have been enrolled in clinical trials in such small numbers that the statistical power in any single trial to draw valid inferences about risks and benefits is limited. Among the underserved groups for whom data sharing might accelerate research are individuals with rare conditions, rare subtypes of common conditions, and members of certain ethnic groups that historically have 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, clinical investigators, and coordinating centers that design and carry out clinical trials might consider fairness to include appropriate recognition, protection, and reward. Investigators who make substantial investments of intellectual capital, time, and resources have an interest in carrying out additional analyses of the data they have collected and in receiving due credit when others take advantage of these data. In addition, there are administrative burdens when sharing data with others that need to be fairly distributed among those who collect and control clinical trial data, those who seek access to shared data for additional research, and society. Appropriate protection of these interests could help provide incentives (or reduce disincentives) to share data and to conduct future clinical trials.