Ethicists

The development of the consensus statement was underpinned by a five-year research project funded by the Canadian Institutes of Health Research [14] (link). The project used a mixed methods approach incorporating both empirical work and ethical analysis. The empirical work included interviews with key informants, review of published CRTs [15] (link), a survey of trialists, and a survey of REC chairs. Based on the empirical work, as well as the practical experiences of research team members, the team identified six questions specific to CRTs in need of further analysis: How should research participants be identified? From whom, how, and when must informed consent be obtained? Does clinical equipoise apply? How does one determine if the benefits outweigh the risks? Who are gatekeepers, and what are their responsibilities? How ought vulnerable groups be protected [16] (link)? The research team conducted an ethical analysis of each issue, which led to a series of discussion papers laying out principles, policy options, and rationales for proposed ethics guidelines [17] (link)–[20] (link). The research team posted these papers on a wiki (http://crtethics.wikispaces.com) and publicized the wiki in the discussion papers and surveys.
To develop the consensus statement from this process, the research team organized a two-and-a-half-day meeting of a multidisciplinary expert panel that took place in Ottawa, Canada, in November 2011. The research team identified the constituencies and perspectives that needed to be represented within the expert panel, including ethicists, cluster trialists, consumer representatives, RECs, policy makers, funding agencies, and journal editors. Potential expert panel members were identified by consultation with colleagues, via searches of the relevant literature and the Internet, and from respondents in the key informant interviews, trialist survey, and REC chair survey. In addition to six of the members of the research team, 26 external individuals were approached, of whom 13 agreed to participate. (See Text S2 for a list of the 19-member expert panel.) External members were invited as individuals rather than as representatives of their home organizations.
The research team made the discussion papers available to the expert panel in advance of the meeting. The first day of the consensus process was an open meeting with a simultaneous webcast, attended by individuals from the same constituencies and sources used to identify the expert panel. Eighty people participated in person, and a further 20 participated by webcast. The research team presented the results of the empirical studies and the ethical analyses of the six questions, and three expert discussants and the audience commented on the presentations. The open meeting served to further familiarize the expert panel with the content of the materials developed by the research team, and allowed them to hear issues raised about the materials by the broader audience. Video of the open portion of the consensus meeting is available via YouTube (http://www.youtube.com/user/mtaljaard55).
Over the next one and a half days the members of the expert panel met in closed session to discuss the identified issues and to develop recommendations. The expert panel was chaired by Professor Martin Eccles, an experienced small group leader with expertise in chairing guideline development groups. Initial discussions established the “rules of engagement” for the expert panel process. The expert panel agreed about how debate should be conducted and how they wanted the chair to run the process. The expert panel agreed to achieve consensus, where possible, through discussion and would document disagreements; they did not wish to use a majority voting system. Draft recommendations based upon the background papers were presented to the expert panel, and members were asked to identify issues in need of clarification and discussion. Full discussion of these issues was facilitated by the chair with the aim of achieving consensus on the underlying principles, but not necessarily specific wording. All expert panel members actively participated in the discussion. Some draft recommendations were substantially revised during the process. There were no substantive disagreements requiring presentation of dissenting views.
A writing group, consisting of seven members of the research team, then reviewed the results of the meeting and produced a first draft of the consensus statement. The writing group circulated the draft to the expert panel in December 2011 and asked for comments on both the principles and specific wording of the recommendations. Responses were received from all participants, and a point-by-point response to all comments (available on request) was produced and the draft consensus statement revised accordingly. In February 2012, the writing group posted the revised consensus statement on the wiki and invited the expert panel, participants of the open meeting, respondents in the key informant interviews, trialist survey, and REC chair survey, and other contacts of the research team to comment. Again, the writing group produced a point-by-point response to all comments (available on request) and revised the consensus statement. In June 2012, the final draft of the consensus statement was sent to the expert panel for approval, which was given by all members with no dissention.

The survey instrument included 4 optional open-ended questions that allowed participants to respond in detail to the topic of the questionnaire (Textbox 1).
Open-ended questions were strategically placed within the survey to minimize the risks of prompts excessively influencing participants’ responses in a negative or positive direction. Question 1 was embedded in the survey after a series of closed-ended questions about where GPs practiced and the percentage of patients in their practices that GPs estimated could access full online access to their health records (Multimedia Appendix 1). Question 2 was embedded after a series of 10 Likert-scale questions encompassing a range of both positively and negatively valenced items with respect to the effects of ORA on patient care, for example, “Among my patients who read their full GP health record on the web a majority will: (a) Better understand their health and medical conditions; (b) Worry more...” Question 3 was inserted after a series of 8 Likert-scale questions, which encompassed a balance of positive and negatively valenced items on the effects or ORA on GPs’ practice, for example, “I will be/already am less candid in my documentation” and “Medical care will be/is delivered more efficiently.” Finally, question 4 was embedded at the end of the survey after the participants’ demographic questions. Thematic qualitative data analysis was used to investigate these responses [42 (link),43 (link)].
We carried out inductive thematic coding of the data [44 ]. Responses were analyzed by 2 members of the research team (CB and JT). CB is a philosopher of medicine and health care ethicist from the United Kingdom, and JT is an informatician and psychiatrist from the United States with experience in sharing online access to patients’ health records [45 (link),46 (link)]. The comment transcripts were initially read numerous times to achieve familiarization with the participant responses. Next, an inductive coding process was used, in which brief descriptive labels (“codes”) were applied to each comment. Multiple codes were applied to the comments with multiple meanings. Comments and codes were reviewed and compared to investigate similarities and differences. First-order codes were grouped into second-order themes, which were further divided into third-order categories to provide a descriptive summary of responses. CB and JT met to discuss coding decisions, and subsequently, minor revisions were made.

OSCRO established policy and procedural guidelines in 2008, formally defining the use of human embryos and their derivatives at OHSU, informed by the National Academy of Sciences’ (NAS) Guidelines. These policies and guidelines permitted the procurement of gametes and embryos for research purposes, the creation of fertilized and SCNT human embryos specifically for research, genetic manipulation of human gametes and embryos, creation of human embryonic stem cell lines and molecular analyses. Together, OSCRO and the OHSU IRB worked concurrently to review and monitor applications for research studies involving human embryos at OHSU.
Human embryo and embryonic stem cell research policies and principles at OHSU were vetted over the course of a decade informed by the NAS guidelines, and subsequently affirmed by new guidelines released in 2015 by the Hinxton Group, the International Society for Stem Cell Research (ISSCR), and 2017 recommendations by the NAS and National Academy of Medicine joint panel on human genome editing. As a part of the review process, OHSU convened additional ad hoc committees to evaluate the scientific merit and ethical justification of the proposed study: the OHSU Innovative Research Advisory Panel (IRAP) and a Scientific Review Committee (SRC). Members of both committees were independent and their names were kept confidential from the research team; OHSU Research Integrity supervised all committee meetings, documentation, and formal recommendations.
IRAP Committee was tasked with deliberating ethical considerations related to using gene correction technology in human embryos for basic research at OHSU. The committee was composed of eleven members from internal and external sources: a lay member, a clinical ObGyn physician, three bioethicists, an OHSU Institutional Ethics committee member, three former OSCRO members, a clinical geneticist, and a clinician. Upon completion of the review, the IRAP recommended allowing this research “with significant oversight and continued dialog, the use of gene correction technologies in human embryos for the purpose of answering basic science questions needed to evaluate germline gene correction prior to the use in human models,” at OHSU.
The established track record of the study team to uphold strict confidentiality and regulatory requirements paved the way for full OHSU IRB study approval in 2016, contingent upon strict continuing oversight, which includes: a phased scientific approach requiring evaluation of results on the safety and efficacy of germline gene correction in iPSCs before approving studies on human pre-implantation embryos; external bi-annual monitoring of all regulatory documents regarding human subjects; bi-annual Data Safety Monitoring Committee review; and annual continuing review by the OHSU IRB. The DSMC is required to remain active for the length of the approved IRB protocol and consists of four members: a lay member, an ethicist, a geneticist, and a reproductive endocrinologist. This committee conducts full review of all donations, the subsequent uses of these samples, and participant adverse events. The DSMC provides formal recommendations to the study team and IRB at the completion of each meeting.

The interviews were transcribed verbatim. The transcripts were reviewed independently by IO and CG. Both IO (sociologist and medical ethicist) and CG (health services researcher) are specialized in qualitative research methods and interviewing techniques. CG carried out an independent analysis of all transcripts using MAXQDA software while following Kuckartz’s steps of content analysis [18 ]. In the first step, the data was coded separately, moving from concrete passages to more abstract levels of coding, including emerging themes. C.G. and I.O. then discussed the codes and C.G. re-coded potentially unclear passages again. Critical reviews and plausibility checks of each analysis of each interview were performed in order to help us to become aware of our own backgrounds and potential bias (reflexivity) [19 (link)]. The codings were then reviewed by a third independent researcher to ensure inter-rater reliability. After two interviews, a preliminary coding guide was developed which was adapted continuously throughout the analysis, adding new codes emerging from the material, if necessary. In research group meetings, all findings were critically tested and discussed. In this way, any discrepancies could be resolved.
For this paper, C.G. translated the quotes and back-translated them to eliminate any confusion of meaning [20 (link)].