Neuroscience Trials of the Future: Proceedings of a Workshop (2016)

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6 Ethical Considerations Highlights • As clinical trials continue to transform, ethical considerations that need to be addressed include respecting the autonomy and privacy of patients, protecting and securing patient data, and balancing the risks and benefits of individuals against the risks and benefits to the community of patients at-large (Kaufmann). • Patient engagement, improved communication, and transparency are key to encouraging patients to agree to share their data, de- spite the risk of re-identification (Rockhold). • Data should be thought of as something patients donate rather than something that is collected (Chiauzzi). • PatientsLikeMe’s Clinical Trial Awareness tool is one example of a patient recruitment tool in which patients are matched with clinical trials for which they may be eligible (Chiauzzi). NOTE: These points were made by the individual speakers identified above; they are not intended to reflect a consensus among workshop participants. Petra Kaufmann, director of the Office of Rare Diseases Research and Division of Clinical Innovation at the National Center for Advancing Translational Sciences (NCATS), began with the admonition that the field has a moral obligation in neuroscience trials to explore change, giv- en the stagnant drug development environment for some disorders. Changes are coming, she continued, as a result of technological advances 53 

54 NEUROSCIENCE TRIALS OF THE FUTURE as well as the changing landscape in health care, where electronic medi- cal records are enabling novel ways of using data. Yet as the field ex- plores changing how clinical trials are conducted, several participants noted that a number of ethical considerations need to be addressed, in- cluding respect for the autonomy and privacy of patients, ensuring that they are safe from the risk of exposure of their data, and balancing the risks and benefits of the individual against the risks and benefits to over- all patient community. In addition, she suggested that as opposed to par- allel systems of data collection in the context of clinical care, research, and regulatory approval, it would be more ethically sound to have better alignment of these data streams in order to maximize the usefulness of those data. This would call for more attention to both data protection and human subjects protection, yet while there appears to be momentum across the field for more data sharing, cultural barriers remain. Indeed, the technology to share data is available, but incentives are not yet aligned with that goal, said Kaufmann. DATA PROTECTION Throughout the workshop, several participants highlighted the need for data sharing in a variety of contexts. In the context of ethics, data pri- vacy and data protection are particularly important. Frank Rockhold, sen- ior vice president of Global Clinical Safety and Pharmacovigilance at GlaxoSmithKline (GSK) at the time of the meeting, and now professor of biostatistics and bioinformatics at Duke University School of Medicine, noted that large datasets are already available and accessible, even as guidelines for data protection are still evolving. For example, www.clinicalstudydatarequest.com (CSDR) is an independent custodian of anonymized patient-level data from clinical trials that has amassed data from more than 1 million patients. The Wellcome Trust, Multi- Regional Clinical Trials Center at Brigham and Women’s Hospital, Har- vard University, along with others, have launched an initiative to support this effort by creating and implementing a sustainable, centralized inter- national data-sharing platform. According to Rockhold, one of the cen- tral issues of large databanks is how to safely share information. CSDR established an independent review panel to determine whether research- ers should be granted access to these data, based on the scientific ra- tionale and significance of the proposed research as well as the qualifications of the investigators and other criteria (Strom et al., 2014). 

ETHICAL CONSIDERATIONS 55 In addition, the Institute of Medicine conducted a study on Sharing Clin- ical Trial Data: Maximizing Benefits, Minimizing Risk addressing these issues (IOM, 2015). Rockhold posited that data privacy should be thought of as a proba- bility issue. Despite several different levels of de-identification before data are incorporated into a shared database, the risk of re-identification will never be zero unless the data are stripped of so much information that their value is essentially zero. Moreover, the patient’s perception of risk and harm from re-identification, and thus the patient’s benefit‒risk assessment, may be very different from the perception of sponsors, clini- cians, and other stakeholders, said Rockhold. In addition, the potential benefits for the patient contributing the data may be vastly different from the potential benefits to future patients. Thus, the appropriate balance between providing valuable data and protecting the privacy of those who donated those data will shift with different studies, populations, and over time. Statisticians have created complex probability models to assess the risk of re-identification under different scenarios (Dankar et al., 2012; Wan et al., 2015). Yet communicating what these probabilities mean in real life to patients remains a challenge. Adding to the complexity, laws regarding data privacy can differ among countries, as well as variations in individuals’ perception and fear of exposure, make it especially chal- lenging to establish a workable worldwide system, said Rockhold. Despite these challenges, he said most patients are willing to accept some small level of risk if it means their information can be reused to help somebody in the future. In addition, Rockhold argued that by not reusing data, we are violating our commitment to patients to search for better treatments. Recently, GSK added a statement to their informed consent documents indicating that as a condition of enrolling in trials, patients had to accept that their data would be shared publicly despite the small risk of re-identification; little resistance to this requirement was encountered. For studies conducted before this statement was added to the informed consent, the company enlisted the help of data privacy and legal experts to estimate the probability that patients would have agreed to share their data, although in a few cases the informed consent explicit- ly precluded sharing of information. Ironically, said Rockhold—although for rare diseases it is especially difficult to de-identify information and thus, these data are frequently not shared—many rare disease patient groups have indicated support for data sharing. There are also certain data, such as the name of the investigator, 

56 NEUROSCIENCE TRIALS OF THE FUTURE that are typically not shared because they increase the risk of re- identification. Other approaches to lessen the risk of re-identification include the use of a trusted third party to carry out the de-identification process, encrypting information, and anonymizing the information and then discarding the key. This latter approach, however, precludes the possibility of going back to the dataset to answer new questions. Indeed, each of these steps to protect data may diminish their usefulness. Greg Koski proposed another model, which he called the “Fidelity” model for patient engagement. It allows patients to place their personal health information, genomic information, among others, in a secure per- sonal account, which they control and can invest in ways they choose to support research. This approach, he said, truly empowers patients and equalizes the power differential between those who do the research and those who depend on it. HUMAN SUBJECTS PROTECTION Koski said he and many others believe the current approach to hu- man subjects protection is dysfunctional and inappropriate for our cur- rent environment and needs to be fundamentally reconsidered. For example, he said that the research community is beginning to recognize that including research use under HIPAA restrictions has impeded re- search and that it may be time to review and revise these restrictions. Furthermore, he argued for moving to a model based on a paradigm of professionalism rather than protectionism, built on the assumption that well-trained, committed individuals will do what’s right according to general standards of responsible behavior. This model would also create an environment that aligns physicians and others for doing things proper- ly. Moreover, he and others argued for more patient-centric approaches that recognize patients as more than clinical trial participants. Emil Chiauzzi, research director for PatientsLikeMe, offered a differ- ent perspective on a truly patient-centered approach as it might apply to clinical trials with regard to data sharing and privacy. The PatientsLikeMe1 platform operates in the service of patients rather than patients serving to provide the research community with data. This includes considering the patient experience over a long period of time, and thinking of data as something patients donate rather than something that is collected. 1 For more information, go to https://www.patientslikeme.com (accessed June 3, 2016). 

ETHICAL CONSIDERATIONS 57 At the time of the workshop, approximately 400,000 patients were registered to use the PatientsLikeMe platform. Approximately 2,500 dis- eases are represented with varying levels of data density across those diseases. Both structured data from validated measures and unstructured, qualitative data are captured; in both cases these are real-world longitu- dinal data provided by patient report. The site allows people to track their diseases, monitor symptoms and reactions to medication, and share their information with people who have similar conditions. These data are also used by research partners who seek to gain insight into disease processes, medication adherence, and other aspects of the patient experience. The data-sharing agreements for these studies typically remove identifiers such as name, address, and e-mail address. Qualitative data are less fre- quently shared because they are difficult to de-identify, said Chiauzzi. Patients are informed through the user agreement that there are no guarantees with regard to data privacy. Moreover, Chiauzzi noted that people who join PatientsLikeMe have already bought into the social me- dia concept and thus have somewhat different views compared to the general population with regard to privacy. Yet there is still a need to ex- plore privacy in a more nuanced way in terms of conditional and person- al factors; thus, PatientsLikeMe is working with research partners to develop measures to assess individual affinity for different aspects of privacy, protection, and data sharing. PatientsLikeMe also includes a Clinical Trial Awareness tool that matches patients with clinical trials for which they may be eligible. As noted in previous chapters, the use of social media for recruitment in clinical trials raises some concerns about blinding and sharing different kinds of medical advice (Glickman, 2012). Chiauzzi suggested that there may be a way to leverage that kind of patient-to-patient communication in a positive way. PatientsLikeMe is now involved in an oncology study in which it is providing a collection point for people to have conversa- tions as a way to encourage retention. This site also provides a mecha- nism for investigators to communicate with study participants.