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1 Introduction

Scientific and policy debates on the issue of disclosing research results and incidental findings to participants have evolved over time. Scientific advances, including the continued refinement of whole genome and exome sequencing techniques, have helped this issue to maintain momentum. As a means of ensuring a robust informed consent process, a number of jurisdictions have adopted consent requirements that address disclosure of research findings in a variety of research contexts including genetic testing or genomic analysis [1–4]. Likewise, some institutions recommend or require disclosure of specific information regarding general and individual research results as well as incidental findings to participants [5–8]. However, policies remain scant and overall directed (if not conflated) to the general context of clinical genomics and genetic research. At the same time, across jurisdictions and studies, policies are often open to (conflicting) interpretations [9–11], particularly with respect to their implementation processes, thereby calling for greater guidance to facilitate a consistent approach [12].

All together, policies co-exist with a complex, dynamic, and polarized academic debate centered on the emergence of a context-specific “duty” to disclose qualified research findings to participants in genetic and genomic studies [13, 14]. As reflected in normative instruments and ethical guidelines, such duty is framed within the spectrum of liberal to restrictive approaches: this is, from a loose, discretional professional responsibility conferred to researchers and/or biorepositories, to an ethical duty if not a (seldom) legal obligation [15–17]. Underpinning such ethical duty is the core bioethical principle of autonomy, beneficence, and non-maleficence; principles which must be carefully weighted in their implementation [14, 18, 19]. Equally important, such duty is based on the notions of reciprocity and solidarity [20–22], understood as a shared view of both providing equitable mechanisms for respecting participants’ interests (including the ones from patient advocacy communities) and for promoting scientific progress by recognizing the intrinsic nature of the research enterprise, that is, as an endeavor directed at producing generalizable knowledge [23].

Seemingly, consensus exists on the need to clarify existing policies and to provide further guidance with respect to: (1) distilling the nature (i.e., professional or ethical duty, legal obligation), (2) length and (3) scope of responsibilities for disclosing (4) qualified findings (e.g., general, individual or incidental; Table 4.1) within (5) a context-specific setting [24] (e.g.. primary, secondary research, biobanking). However, such consensus (and apparent certainty) ends when attempting to develop detailed guidance surrounding such issues. In fact, even the essential conditions for disclosure (from analytical and clinical validity, clinical utility and actionability to personal utility; Table 4.2), and terminological and definitional issues (e.g., are there incidental, unanticipated or unexpected findings?; Primary or secondary variants?) remain contentious [7, 25–28].

Table 4.1 Typology of findings
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Table 4.2 Disclosure criteria
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Adding to the difficulty of finding guidance is the fact that there are only a small number of empirical studies assessing the views of stakeholders [29, 30]. These studies are often methodologically and contextually diverse, making the generalization of their conclusions questionable. Moreover, such studies are often directed to a selected group of stakeholders, leaving gaps with respect to the perspectives of other key stakeholders such as biobankers, funders, policy-makers and members of oversight bodies. In addition, there is a lack of studies systematically analyzing the uptake of disclosure policies and protocols, or on their impact after implementation (e.g., logistical and financial costs).

1.1 The Stem Cell Context

As stated above, scientific inquiry, policy debates, and normative activity in this area have focused primarily on the genetic/genomic research and clinical contexts, which only to a certain extent are suitable for extrapolation to the stem cell field. While aware of the risks of falling into an exceptionalistic view [31, 32], it is maintained that the particular complexities of stem cell research and banking warrant special consideration. To that end, recently adopted stem cell-specific policy guidance seeks to acknowledge that the vast range of pluripotent stem cell research related studies and the diversity of banking initiatives—in which pluripotent stem cell lines are continuously immortalized, transformed, and distributed [33–35]—are important factors to consider when drafting protocols for authenticating, disclosing, and managing research and incidental findings [23].

As the stem cell field continues to grow, and particularly since the discovery of induced pluripotent stem cell lines from somatic tissues, there is a rejuvenated interest in biobanking. In general, biorepositories are considered vital research infrastructures providing primary material for stem cell research (i.e., collection sites for tissues for subsequent stem cell line derivation). Stem cell repositories specifically constitute a resource for access to authenticated, quality-controlled, and ethically sourced pluripotent stem cell lines. They “play an intermediary role promoting scientific utility and clinical safety while at the same time developing procedures to advance participants interests” [36].

Scientific advances, together with evidence (albeit anecdotal) of donor-participant support for a system of sustained interaction via the disclosure of qualified research findings [37, 38], are providing a compelling rationale for governments and scientific institutions to adopt prospective policies in the area of disclosure. In this chapter, we will provide an overview of stem cell-specific policy recommendations addressing the scientific, ethical, and legal implications of mandating the disclosure of individual research results, including incidental findings.

2 Stem Cell Research and Banking: Disclosing and Managing Results and Incidental Findings

Robust and effective infrastructures and processes to support a system for validating, managing, and disclosing (or justifying withholding) research and incidental findings are required. They are predicated in the establishment of prospective protocols that take into account the context, type, duration, and nature of the relationship between the research participant and the researcher (or the biorepositories) [39–41]. Indeed, amongst many important factors, the specific research context is the one with greatest impact on establishing whether an ethical—or even a legal—duty could or should be established towards individuals and institutions situated at the different stages of the research cycle [42, 43]. Certainly, such systems are sustained within the framework of an equally robust informed consent process, as illustrated in policies and ethical guidelines adopted across jurisdictions [23, 44]. In the spirit of reciprocity, such policies urge primary stem cell researchers and cell repositories to adopt prospective protocols governing the management of information and its release back to donors as a way of addressing stakeholder expectations [23, 45].

As captured by guidelines issued by the International Society for Stem Cell Research [46], reciprocity towards research participants (and society in general) entails acknowledging their right to access information [47–49]. This is translated in the professional responsibility of researchers to communicate general research results so as to promote transparency and scientific and ethical integrity in the field [50]. For example, comprehensive research findings (whether negative, inconclusive, or positive) should be published in peer-reviewed publications and plain-language summaries should be made available to the public [7, 23].

Furthermore, any system supporting the disclosure (or justifying the withholding) of qualified research and incidental findings must establish clear thresholds that would inform the what, to whom, and when to provide such disclosure. Such systems must also acknowledge that the thresholds of clinical and analytical validity, clinical utility (and perhaps personal utility), together with actionability, entail evolving standards. As such, they require a mechanism for the ongoing monitoring of scientific progress. In the particular context of pluripotent stem cell research, systems also require the development of mechanisms to (a) ensure robust traceability [49, 51] and (b) enable confirmation of the direct relevance of cell line data with respect to the donor. In this order of ideas, the following sections provide an overview of three institutional policies that outline systems to enable the disclosure of research results and incidental findings arising in the context of pluripotent stem cell research and banking.

2.1 The International Stem Cell Forum and the Ethics Working Party

The International Stem Cell Forum (ISCF) (www.stem-cell-forum.net) was established under the auspices of the UK Medical Research Council with the objective of promoting global good practice and international collaboration to accelerate progress in stem cell research. The ISCF’s membership consists of nineteen funders of stem cell research from around the world [52]. One of the ISCF’s initiatives is the Ethics Working Party (EWP), an independent body mandated to prospectively identify, discuss, and analyze the ethical and policy issues arising in stem cell research.

To that end, and considering the need for ethical deliberation and further policy guidance, in 2011 the ISCF EWP adopted a Policy Statement [23] on the disclosure and management of general, individual, and incidental research findings. The Policy Statement (Table 4.3) is narrowly tailored to address stem cell lines derived from human embryos and from somatic tissue via induced pluripotent stem (iPS) cell techniques from adult donors. It proposes a framework with criteria for future policy that is mindful of local ethical and legal constraints, while at the same time recognizes and respects the specific needs and interests of the particular donor population involved (i.e. children/minors, affected individuals, adults who lack the capacity to consent, healthy volunteers).

Table 4.3 ISCF EWP policy statement recommendations
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The ISCF EWP Policy Statement supports a context-specific system for communicating qualified research findings (as defined in Table 4.2) to participants and donors of human biological materials. Such a system should be founded in robust and prospective donor informed consent that allows for the possibility of identifying and re-contacting donors while protecting their privacy. Moreover, the Policy Statement highlights the significant implications (e.g., financial, ethical, legal, scientific, etc.) of extending a duty to disclose certain research and incidental findings beyond primary researchers and cautions against this practice. Furthermore, it also cautions against any return of donor/participant-specific results (particularly with respect to human embryonic stem cell lines) when the genetic/genomic findings have not been validated by confirmatory testing.

In sum, the ISCF EWP only foresees the possible communication of individual and incidental findings for human pluripotent stem cell research (e.g., iPS cell and hES cell lines) in the terms described in Table 4.3.

2.2 The California Institute for Regenerative Medicine

In 2004, and following the passage of Proposition 71 [53], the California Institute for Regenerative Medicine (CIRM) (www.cirm.ca.gov) was created with the mission to support and advance stem cell research and regenerative medicine in California (United States). To achieve its core objectives, CIRM funds strategic stem cell research projects with the goal of “the discovery and development of cures, therapies, diagnostics, and research technologies to relieve human suffering from chronic disease and injury” [54]. To further fulfill its mandate, CIRM launched the iPS Cell Initiative designed to support disease modeling, target discovery as well as drug screening and development [7, 45] for prevalent, genetically complex diseases. The iPS Cell Initiative will support access to high quality human iPS cell lines through a biobanking resource model. To that end, it will recruit approximately 3,000 disease-specific donors for the derivation of an estimated similar number of new iPS cell lines [55].

After extended deliberation and analysis [7, 56, 57] by CIRM’s Medical and Ethical Standards Working Group, prospective recommendations for the management of research findings arising in the context of the iPS Cell Initiative were developed. The guidance is directed at knowledge gained from the derivation, banking, and distribution of disease-specific iPS cell lines. Consistent with the ISCF-EWP Policy Statement cited above, CIRM proposes a system based on a robust and prospective consent process seeking specific approval to communicate relevant research findings to somatic cell donors.

CIRM’s recommendations are designed to maintain an avenue of communication with donors without creating unrealistic expectations. In the case of genetically induced stem cell lines, thresholds for clinical and analytical validity, clinical utility, and actionability are indeterminate at this time, which limits the usefulness of disclosing individual research results. Several scientific and ethical considerations are mentioned [7], including:

  • The nature and behavior of the genotypic and phenotypic data arising from an iPS cell line and its derivates, which does not necessarily correlate with the cell donor’s native genotype at the time of sample collection.

  • The absence of established and harmonized protocols for clinically validating results from research utilizing iPS cell lines (e.g., Clinical Laboratory Improvement Amendments—CLIA Act).

  • The difficulty of interpreting findings for complex diseases and determining their actionability (e.g., mechanisms for quantifying relative risk and penetrance of complex diseases and undiagnosed complex conditions are yet to be validated).

  • The risks of increasing therapeutic misconception.

  • The conflation between research and clinical care, which in turn blurs the fundamentally different obligations of primary/secondary researchers and physicians.

To that end, CIRM recommends adopting a priori informed consent and research protocols that foresee the potential disclosure of:

  • General (aggregated) research results: CIRM foresees disseminating aggregated non-identifiable results from iPS cell research via pre-established mechanisms mediated by the iPS cell repository. It further suggests the possibility of establishing mechanisms to “actively alert researchers or clinicians at the collection site to new findings without the need to associate the results with specific donors” [7]. Such alerts would allow the collection site teams to evaluate the potential clinical relevance of any particular finding and incorporate this knowledge into future (general) clinical care decisions.

  • Individual research results: Collection sites recruiting patient cohorts should consider mechanisms for donor re-contact in the event qualified individual research results that emerge from future studies.

  • Incidental findings: The disclosure of incidental genetic findings based on the analysis of genetically reprogrammed iPS cells is scientifically and ethically inappropriate at this time.

Altogether, CIRM’s approach is designed to promote and protect the interest of patient donors by creating mechanisms to allow research findings to feedback to the patient-care environment. Ultimately, the efficacy of this approach will depend, to some degree, on the efficacy of iPS cell to model disease and inform the development of new therapeutic approaches.

2.3 The International Stem Cell Banking Initiative

The International Stem Cell Banking Initiative (ISCBI) [58]—established by the ISCF—is a global, interoperable network of stem cell banks, working jointly towards identifying and harmonizing best practices for banking, characterization, and testing of pluripotent stem cell lines [35, 59]. ISCBI’s vision and mission is “to create a solid scientific and ethical framework for international stem cell banking and research” [60]. Important harmonization and standardization work has been carried out by ISCBI. In 2008, ISCBI adopted its first best practices: the “Consensus Guidance for Banking and Supply of Human Embryonic Stem Cell Lines for Research Purposes” [41]. The Guidance document seeks to be comprehensive in managing a wide-range of aspects involved in a bio-resource. A set of best practices for clinical grade pluripotent stem cell lines is currently being developed by ISCBI [61]. The new guidelines, set to be published in mid 2014, will establish an international set of standards for stem cell lines destined to be used in clinical translation as well as clinical trials; and will cover procurement, characterization, testing, maintenance, and shipment. It is envisaged that ISCBI will have an important role to play in shaping research and its clinical translation by creating the foundations of stem cell banking [60].

With respect to the specific topic of disclosure of clinical significant information, ISCBI’s policy adheres to the rationale and the recommendations developed both by the ISCF-EWP and CIRM. To that end, its new guidelines will recommend that biorepositories, in addition to determining the scope of donor’s informed consent, also ascertain whether protocols for the disclosure of individual research results and/or incidental findings to somatic cell and gamete donors, have been adopted. Finally, ISCBI’s guidance also cautions against such disclosure in the absence of validated assays enabling the determination of clinical significance or personally actionable information.

3 Conclusion

As this brief chapter illustrates, the debate surrounding the disclosure of individual, general, and incidental findings to participants in stem cell research studies has been stimulated by recent normative guidance on the subject. Solid scientific and ethical justifications have been provided in support of mechanisms that could allow for context-specific and qualified disclosures. Whether based on a doctrine of fiduciary duties, ancillary care or on the fundamental ethical principles of autonomy, beneficence, and non-maleficence [18, 62], such systems warrant a cautious approach cognizant of current scientific uncertainties. Moreover, to fully meet public expectations and to respect the interests of researchers, patients, and research participants alike, a transparent and balanced approach of the benefits and risks—as understood or considered by the different stakeholders—is required. In addition, given that any system for disclosure is necessarily predicated on obtaining voluntary, informed, and understanding informed consent, mechanisms to improve genetic/genomic and stem cell literacy amongst stakeholders are much needed. To that end, the research agenda remains complex and vast.