Calls for the development of hands-on tools and mechanisms

Another finding that emerges from our research is that stakeholders think in very practical terms, and call for the development of a number of concrete, hands-on tools and mechanisms that may facilitate their work, and help advance PM. As an illustration, in paper I, the PM researchers suggested that harmonized European guidelines for the feedback of genetic research results to research participants should be developed [126]. To date, international guidelines exist which primarily recommend the feedback to research participants of clinically actionable research results, i.e. results of potential health utility that clinicians can use to guide prevention or treatment [153-155]. However, most of these guidelines do not provide practical and detailed guidance regarding, for instance, which criteria to use to determine the

“actionability” of results, which information about genetic variants to feed back to participants, and how to organize the feedback process [153-155]. Guidelines exist in Europe for reporting genetic results in clinical settings [156-158] but these guidelines encourage researchers to limit the likelihood of detecting clinically useful findings by applying filters when making use of genome sequencing technologies [156-158]. This strategy may be applicable in clinical settings but is not suitable for researchers who aim to discover new gene variants and may want to study as much of the genome as possible; the probability that they

“bump into” variants of health utility is therefore higher than in clinical settings. European clinical guidelines also primarily focus on discussing the technicalities of genetic testing but do not explain how to handle, for instance, different types of potentially clinically actionable variants [157].

The guidelines of the American College of Medical Genetics and Genomics (ACMG), published in 2013 and 2016 and developed for use in clinical settings, are one important exception to the general approach adopted in international documents [159, 160]. These

guidelines differ from other guidelines in the sense that they provide a list of pre-determined genetic variants that are known or expected to be pathogenic and that are recommended to be reported to patients undergoing clinical genome sequencing. During our workshop, we did not discuss in details the content of harmonized European guidelines for the feedback of genetic research results to research participants with the PM researchers. However, their request for more guidelines may indicate that concrete and specific guidance is needed at a greater level of granularity than is currently provided in today’s documents. This could be interpreted as a demand to develop harmonized European guidelines that are more in line with the ACMG guidelines [159, 160]. If developing a list of reportable variants is what the PM researchers had in mind, this would represent a change with respect to the situation presently prevailing in Europe - pragmatic guidance at a general level. This may, however, prove to be controversial as the ACMG guidelines have been widely criticized for being too top-down and short-sighted, not taking into consideration the patients’ situation, and encouraging opportunistic screening [161]. Furthermore, this would contradict results from a recent cross-national study conducted among genetics and genomics experts who, when asked about the type of guidance they would like to receive, agreed that general guidelines are preferable to a list of specific variants to report [162]. As I will discuss later, developing such a list would also generate a number of challenges. For instance, it may be difficult to reach agreement regarding the significance of the variants, and the types of variants to list according to latest scientific developments.

The stakeholders also called for the development of concrete mechanisms for broad and equitable access to PM. In paper I, the PM researchers expressed concerns that if harmonized European guidelines for the feedback of research results to research participants are not in place, situations may arise where “[…] some projects provide results to their participants,

while other similar projects do not provide results or decide to apply different criteria for doing so” [126]. This may lead to inequity in participant access to potentially clinically actionable or lifesaving information. In paper III, the PIO representatives emphasized that equitable access to PM should be the guiding principle for delivering PM to patients and citizens [125]. They experienced that patient access to new diagnostic tests and targeted drugs is fragmented and emphasized that access to PM should not depend on the patients’ financial ability to pay for such access but rather take place on the basis of the patients’ specific needs [125]. We did not discuss in-depth with the PIO representatives or the PM researchers which mechanisms to put in place to enable broad and equitable access to PM. However, we referred in paper II to some mechanisms that could be developed to adjust for potential disparities in access to PM, and reach out to those populations who normally do not have the prerequisites to benefit from new medical developments [121]. Mechanisms for instance include the implementation of community based participatory research programs, which contribute to inviting communities usually not included in research to participate in research [163], or the development of free and low-cost programs for accessing genetic testing. As an illustration, some public hospitals in the United States offer free BRCA testing and genetic counselling to patients who usually have limited access to health care [164]. Facilitating broad access to genetic testing can not only be done through the development of such mechanisms but also by

“creatively delivering genomic risk information” [165]. For instance, mechanisms exist, which were not discussed in our paper but that policymakers are currently considering, that may encourage people to endorse genetics and change behaviour. This for instance includes the delivery of health insurance vouchers upon submitting proof of follow-up with a counsellor [166] or the use of advisory notices accompanying genetic tests to inform that people undergoing similar tests have changed their life-style [165].

Although the mechanisms described above may contribute to facilitate access to PM, enabling PM is expected to raise a number of questions regarding, for instance, prioritization. Many considerations have to be taken when determining who gets access to what and who needs additional support to receive such access: the patients’ needs are clearly important but hardly any health care system has the financial resources to address all the needs of all patients without having to set limits and apply criteria for prioritization [167]. Furthermore, principles other than equitable access or addressing the patients’ needs, such as the cost-effectiveness of an intervention, may also have to be considered when deciding who gets access to what.

Discussing all issues surrounding equitable access to PM requires extensive work. However, a lesson that may be learnt from our consultations is that broad and equitable access to PM seems to be a recurrent concern among stakeholders. This suggests that more discussions are needed, probably at European level, following the principles of the RRI framework, to develop an overall, concrete and clear strategy for such access that aligns with European values for health care.

Finally, our research shows that stakeholders call for the development of concrete mechanisms for the funding of PM. In paper I, the PM researchers recommended to allocate specific funding of research grants to enable researchers and health care services to feedback genetic research results to research participants [126]. In paper III, the PIO representatives called for the allocation of specific funding for the development of PM, including biobanks and data sharing infrastructures, although they suspected that allocating such funding would be challenging [125]. It might not be surprising that central stakeholders of PM think that PM should receive more funding, and PM has already received a lot of attention from funders, including from the European Union. However, such call for funding raises an interesting question: what is sufficient funding to support the realization of PM? This was not discussed

in details in our consultations. One observation is that the funding of PM research and PM infrastructures, although existing, at least, in some European countries, is often fragmented and short-sighted. As an illustration, genomics research is generally funded through programs spanning three to five years. The same applies to the funding of biobank and data sharing infrastructures. This short-sightedness with regard to funding may have negative side effects as experienced by large-scale research projects which have been hindered to exploit valuable research data after project end because financial resources were lacking [168]. Generally, possible strategies pertaining to long-term funding of PM need to receive more attention in the public debate [169]. Until recently, the promoters of PM have primarily discussed practical tools and infrastructures to develop to enable PM, and shown limited interest in discussing the financial sustainability of PM. This could be because PM is assumed to reduce health care costs as the quality of treatment increases and less money is spent on developing drugs that do not work [170]. However, to achieve such savings, large investments must be made upfront. The feedback we received during our consultations is that significant concerns exist regarding how such investments may be secured in the future, and which areas of PM should be given priority in a context where health care systems are increasingly struggling to finance their core activities.