Early‐phase clinical trials in oncology for adults in France: A preliminary empirical bioethics study

The last few years have seen the improvement of cancer management through the arrival of a continuous stream of innovative new molecules known as ‘targeted therapies’ and ‘new immunotherapies’.1 One characteristic common to all these treatments is a specific link to a precise cellular and/or molecular profile. Some of these treatments are already improving therapeutic results for certain types and subtypes of cancer.2 However, a non-negligible proportion of these molecules remain inaccessible to patients other than through clinical trials, particularly early-phase clinical trials.3 The aims of such clinical trials were initially limited to identifying toxicities associated with the molecules tested, but they now extend to the evaluation of efficacy and possible therapeutic benefits for participants. We performed a preliminary empirical bioethics work at national scale in France, with specific protocolization,4 based on a non-systematic literature review, to deal with the ‘macro-bio-ethical issues’. Bioethics is a discipline that deals with ‘bio-ethical issues’, that is, tensions between medical and/or biological practices, such as early-phase clinical trials, and moral values and/or standards. A ‘moral value’ is an attitude concerning what we should or should not be (e.g. to be equal or not to be inequal, etc.), whereas a ‘moral standard’ concerns actions we should or should not do (e.g. to do equally or not to do unequally, etc.). We speak of ‘macro-bio-ethical issues’ if the work is performed at the scale of societies and/or countries, such as France, rather than at the scale of individuals and/or institutions (N.B. the issues at this lower level are described as ‘micro-bio-ethical issues’).5, 6 ‘Empirical bioethics’ concerns bioethics studies performed in the field with an appropriate approach (e.g. a qualitative approach, etc).7 The approach used in this preliminary empirical bioethics work was ‘qualitative’,8 as no mathematical or statistical method was used for document sampling, or for data collection or analysis. Instead, we performed a manual analysis of a small sample of documents, from which we were able to collect relevant secondary empirical data and information. For this reason, the study is also described as ‘preliminary’. Our approach was also ‘normative’,9 in that it was not limited to the empirical identification and description of macro-bio-ethical issues (N.B. in which case, it would have been exclusively ‘descriptive’). We searched for concrete solutions by applying a particular ethical theory: ‘global bioethics’.10 We were, thus, able to resolve the issues, that we had empirically identified and described, in a pragmatic manner, according to real or potential consequences for two bio-ethical objectives assumed in the framework of this theory to be common to all humanity: ‘survival’ and ‘happiness’ (N.B. encompassing ‘quality of life’, ‘well-being’, etc.). In other words, as described in our previous studies,11 we did not apply the ethical theory of ‘principlism’ (i.e. autonomy, beneficence, non-maleficence and justice), at any point, from the identification to the resolution of these issues. This work was performed jointly by the ethics and oncology departments of a single hospital. From the sampling of documents to the writing of the article, including the collection, processing and analysis of data and of the sample, this work took about 4 months, running from mid-September 2023 to mid-January 2024. Two of the principal investigators are bioethicists with expertise in empirical bioethics. They were assisted by an undergraduate project student. The other two principal investigators are oncologists with expertise in early-phase clinical trials. The oncologists were, therefore, both judges and active parties, but they supplied the clinical, scientific and technical expertise that the bioethicists lacked. Documents were sampled through a non-systematic literature review,12 performed online with Google Scholar, in English and French. We first delimited the search without orienting it by manually testing several combinations of key words. We manually restricted the search to the period 2013–2023, and targeted empirical research studies in the human and social sciences on the access of adults to early-phase clinical trials for cancer treatment in France, published in English and/or French, preferably in scientific journals, to ensure the collection of relevant secondary empirical data and information, particularly on social and ethical aspects. At saturation point, nine articles were included (n = 9).13-21 We identified another 12 articles,22-33 but we excluded them as they did not respect all the predefined selection criteria. They nevertheless contributed to our general reflections. We collected various secondary empirical data and information for each study to characterize our sample more accurately and to facilitate the subsequent content and thematic analyses. These data were recorded manually, on paper and/or on a computer, in a manner identical to that of the source text or with certain reformulations to facilitate their comprehension and analysis. The articles were downloaded, stored in a computer folder and then printed. The secondary empirical data and items of information collected were manually processed in an Excel file. No specific confidentiality protection measures were required. We performed content and theme analysis, from which we were able to identify and describe the principal macro-bio-ethical issues and solutions to them, by applying global bioethics, as explained above. Triangulation between investigators made it possible to ensure that the analysis was both reliable and credible, whilst, of course, remaining open to criticism. The content and thematic analyses have been summarized in a single table (N.B. see Table 1). Based on the content, we were able to highlight three principal themes (Table 1). The first corresponds to a tension, at national level, between the care delivered in early-phase clinical trials and equality of access to care. This is, thus, a first macro-bio-ethical issue, as defined above. In this situation, we are confronted with the opposition between a medical and biological practice (i.e. early-phase clinical trials), and the application, in the framework of care, of the principle of equality, which could be understood in this context as a moral value (i.e. to be, or considered, equal), and a moral standard (i.e. to do in an egalitarian, or equitable, manner), with respect to cancer patients (Table 2A). In our sample,13, 18, 19, 21 we essentially identified social inequalities, in the broad sense of the term (i.e. organizational, professional, individual, etc. Table 1C), particularly in terms of the care pathway (i.e. the location at which the patient is managed), geographic location (i.e. place of residence), sex (i.e. male or female), and/or age (i.e. under or over the age of 70 years) of the cancer patient potentially suitable for the type of clinical trial concerned (Table 1G,I). The second theme corresponds to another tension, at the same scale, in clinical trials of this type involving both care practices and research, this time between the goals of care, which aims to achieve individual benefit, and those of research, which aims to achieve a collective benefit. In this second macro-bio-ethical issue, there appears to be a definitive confrontation between a medical/biological practice (i.e. early-phase clinical trials) and liberty, which can be interpreted here as a moral value (i.e. to be, or considered, free), and a moral standard (i.e. to do in a free, autonomous or responsible manner), with respect to the patient-participant and doctor-researcher (Table 2B). Indeed, a common thread running through our sample is the notion that if these trials involve both care and research there is an obligation to inform the patient-participant of this duality, and to consider the patient-participant's liberty, and to allow this individual to act autonomously in the full knowledge that the imperatives of care frequently outweigh those of research in this type of clinical trial (i.e. individual benefit > collective benefit).14 Another thread running through this sample is the notion of the liberty of doctor-researchers and their responsibility for their actions with respect to the patient-participant.16 The third theme identified corresponds to a significant tension in early-stage clinical trials between care, research and industrial practices, relating in particular to the divergence between the goals of industrial practices and those of care and research practices. This constitutes a third major macro-bio-ethical issue relating to loyalty as a moral value (i.e. to be, or considered, loyal), and a moral standard (i.e. to do loyally), in situations in which doctors are required to act simultaneously as carers, researchers and, in reality, entrepreneurs (Table 2C).20 Of course, there could be a conflict of loyalty between the doctor-carer, who should be loyal and act loyally with respect to the patient, and the doctor-researcher, who owes such loyalty and loyal behaviour to society. However, both ultimately act in the public interest, in the fight against cancer, the first at individual level and the second at collective level. By contrast, the doctor-entrepreneur also integrates a private interest, the accumulation of profits for industry, which provides the funding for most of these trials and promotes international competition between doctors for access to its innovative molecules. A second potentially more problematic conflict of loyalty (N.B. or even a conflict of interest) could, thus, emerge if economic profitability becomes more important than therapeutic efficacy in these trials. As a solution to the first issue identified, we could envisage a better ‘geographic deployment’ across all territories (Table 2A). This solution echoes one of the articles in our sample (Table 1A), except that the justification here is evidently not solely a respect for justice (N.B. which can be seen, in this article, as a synonym, or almost so, of equality, as either a moral value or a moral standard).13 According to the ethical theory applied here, the justification for this solution lies, above all, in its positive consequences for the survival and/or happiness of the adult cancer patients included in these trials, which are very real for some, particularly if supportive care is added, according to our sample and others.14, 15, 19, 26, 27, 30 Moreover, there is an almost categorical imperative in France to render equality effective in almost everything, which makes it preferable to act on deployment rather than selection criteria or the matching of patients in these trials, given that changes in deployment would provide greater equality than modifications to selection criteria and patient matching.13 This might increase the social and political acceptability of these trials, thereby enhancing their development and acting on the consequences mentioned above. However, the execution of this solution remains problematic due to the restricted allocation of resources to certain territories (Table 2A).17 As a solution to the second issue, we could envisage a better ‘digital deployment’, particularly in terms of dynamic consent (Table 2B).34 Initially, this would involve explicit written, but electronic consent procedures, making it possible to consent, study-by-study, to the reuse of one's samples and data stored in a biobank, and to provide better information and educational content and interactive tools.35 Applied to early-stage clinical trials, this would make it possible, in particular, to adapt content and/or interactions to the profile of the patient-participant, to improve the patient-participants' ability to evaluate and understand the situation, and/or their literacy, thereby improving, in practice, their consideration of their liberty and making it easier for them to withdraw their consent. However, it would also make it possible for doctor-researchers to act in a more responsible manner, thanks to an associated computer platform improving the transparency of selection and matching procedures and even improving patient-participant involvement in decision-making. As a result, all these measures could potentially enhance some of the positive consequences mentioned above, or even lead to others, notably through improvements to the relationship of confidence between the stakeholders, underlying the bio-ethical pertinence of this solution. The spread of telemedicine,36 and the possible transformation of cancer into a chronic disease,13 add to this relevance. Nevertheless, this solution faces obstacles in the form of the digital divide,37 and the absence of coordination at national level for these studies.17 Finally, we can envisage improvements in ‘public deployment’ as a solution to the third issue. This would not necessarily imply ‘more academic trials’ (Table 2C). In France, particularly in oncology, so-called ‘academic’ clinical trials sponsored by hospitals and/or public institutions are now in the minority relative to so-called ‘industrial’ trials sponsored by pharmaceutical laboratories.20 One of the principal reasons for this is that industrial laboratories have the means to finance a larger number of clinical trials of this type in parallel. It would not, therefore, be easy to invert this ratio in practice, particularly in the current economic situation, in which the country is under increasing pressure to reduce public spending. Above all, it is not clear that this would have any positive, real and significant consequences for the survival and happiness of the adult cancer patients included in these trials. Firstly, it would be financially easier, and potentially better in terms of performance from a bio-ethical perspective, to reinforce some of the decision-making powers of ethics committees (i.e. institutional review boards, etc.),33 to ensure that the public interest outweighs private interests in such cases of conflicts of loyalty, which would also favour social and political acceptance in a country like France (Table 2C). Secondly, in terms of the relevance and impartiality of the decisions of ethics committee, it would be better for these decisions to be based on empirical bioethics studies published in scientific journals, rather than solely on the opinions and/or convictions of committee members. However, this would require a corresponding increase in the capacity to train and engage more bioethicists dedicated full-time to this work, rather than limiting ethics committee membership to volunteers with various degrees of training in bioethics, and empirical bioethics in particular. (Table 2C)5 In other words, professionalizing bioethics could be at least a part of the solution to these conflicts of loyalty, yielding better results at lower cost. The macro-bio-ethical issues and solutions envisaged here should be evaluated in empirical bioethics studies based on primary empirical data. Provided that the same ethical theory is applied, at least two aspects should be studied in parallel to increase the bio-ethical pertinence of these solutions. Indeed, in this preliminary empirical bioethics study, we did not take into account individual and collective criteria for these patients (e.g. culture, personality, etc.), or the environmental impact of these trials (e.g. global warming, etc.), as recommended in global bioethics.5 The first of these aspects relates to criteria for patient survival and happiness at the individual and collective levels, particularly in a French society that is secular by law but multicultural in reality.11 The second aspect, the environmental impact of these trials, encompasses their carbon footprint, waste management, and the pollution of air, water and/or soil.11 These studies could make use of pre-existing cohorts, and/or create new specific cohorts for studies of these solutions and/or aspects, allowing for mixed studies and the combination of patients, professionals and third parties directly or indirectly concerned by clinical trials of this type. HCS, PB, CH and JB are the principal investigators. They contributed to the conception of the paper, the drafting of sections and discussions about how the different sections should be refined and integrated. TP is an undergraduate trainee who helped collect and process the data. We thank Foch Hospital and our colleagues for support. Foch Hospital. HCS, TP and CH have no conflicts of interest to declare for the submitted work. PB has received personal fees from Astellas (educational sessions) and Pfizer (travel expenses to ASCO 2023), all outside of the submitted work. JB has received personal fees from AstraZeneca, Bristol-Myers Squibb, MSD, Janssen Cilag, Daiichi and Sanofi Aventis (advisory board, educational symposium and honorarium), all outside of the submitted work. The datasets used and/or analysed in this study are available from the corresponding authors on reasonable request.