CIRM considered the management of individual findings while drafting a model informed consent document for the CIRM iPS Cell Initiative. The evaluation was conducted in consultation with CIRM's Scientific and Medical Accountability Standards Working Group. This working group comprises scientists, patient advocates, ethicists and clinicians, and its charge includes recommending 'ethical procedures for obtaining cells for research' [9
]. The evaluation process involved examining recruitment and consent protocols for iPS cell derivation, a literature review, and testimonials from primary researchers collecting specimens, organizations operating biological repositories, secondary researchers and patient donors. Working group deliberations and follow-up research produced the following conclusions.
iPS cell derivation can introduce unknown changes to donor cells
The iPS cell derivation process can introduce unknown changes to the donor cells. Existing guidelines focus on a repository research system where biological specimens, biomarkers and/or associated data correlate with the donor's native genotype at the time of sample collection. For example, a blood sample in a research repository may have identical genetic characteristics to a sample that would be collected for a diagnostic test.
The degree to which the iPS cell genotype differs from that of the original tissue donor is not fully understood. iPS cells have demonstrated significant genetic variability upon reprogramming and subsequent culture. While some of this variability may be attributed to pre-existing differences among somatic cells within the donor [10
], a number of additional factors have been identified that can influence this property - including the introduction of somatic cell coding mutations [11
] and of changes to the allelic copy number [12
] during reprogramming and cell culture. To what extent this variability could be ameliorated is not yet clear.
The behavior and phenotype of iPS cells and their derivatives in the research setting may also reflect epigenetic changes and other forms of variability that can be introduced during the reprogramming process [13
]. While many such alterations would be represented in the underlying genetic code, there remains a theoretical possibility that future research on reprogrammed cells will identify nongenetic correlates that would be of interest as an incidental finding.
No protocols exist to harmonize results from research utilizing iPS cell lines
Protocols do not exist to harmonize results from research laboratories utilizing iPS cell lines, with clinical (Clinical Laboratory Improvement Amendments-approved) laboratories necessary to validate findings.
The CIRM iPS Cell Initiative will operate in a jurisdiction governed by the Clinical Laboratory Improvement Amendments. These regulations impose a number of quality assurance requirements designed to ensure the analytical validity of a particular assay. No protocols exist currently to validate findings derived from iPS cells.
Incidental findings of complex disease are difficult to interpret
Incidental findings of a complex trait or disease are difficult to interpret. There is broad acknowledgement that returning findings to a patient constitutes an exceptional circumstance that warrants special consideration. The National Heart Lung and Blood Institute Working Group on Reporting Genetic Results in Research Studies has suggested a decision-making framework for such a circumstance that takes into account relative disease risk and penetrance [5
]. This framework is designed to make a determination of whether some type of efficacious clinical or lifestyle intervention (action-able) is available.
With the CIRM iPS Cell Initiative there may be incidental findings related to the targeted disease or an undiagnosed complex condition. Polygenic diseases are multifactorial, resulting from a poorly understood confluence of pleiotropic gene effects and often the environ-mental history to which a cell or individual has been exposed. Methodologies for the quantification of relative risk and penetrance for such disorders are limited and generally have not been sufficiently validated.
Suggesting individual results may propagate therapeutic misconception
Suggesting that individual results may emerge can propagate a therapeutic misconception. Obtaining consent to return findings is an essential prerequisite to providing individual research results. However, obtaining consent for the return of findings may contribute to a therapeutic misconception [19
]. Researchers implementing iPS cell derivation protocols involving donors with polygenic neurologic disease cited examples suggesting that a therapeutic misconception may persist with some donors despite a comprehensive consent process [20
Researchers have different obligations
Physicians have different obligations to patients than researchers have to donors. Findings will occur in secondary research laboratories utilizing cells provided by the bank. These laboratories will have no relationship with the cell donors. The purpose of the CIRM iPS Cell Initiative is to support research designed to create generalizable knowledge to help patient populations in the future. Obligations of researchers to donors whose cell derivatives they study are fundamentally different from contexts where there is a direct relationship with patients. The obligation to other results does not necessarily extend to investigators or scientists who have no clinical relationship with the patient. Further, imposing such an obligation may result in liability to the researcher [21