While issues of equitable access and research regulation are undeniably important, there is a risk that by only focussing on access and affordability, global health research stakeholders run the risks of leaving researchers, patients, regulators, and policymakers with limited information on other possible ethical, legal and social issues that may arise during the design and implementation of gene therapy trials in Africa, including how to ensure that somatic gene therapy is conducted in a responsible and ethically sound manner. This paper aims to address this gap by shedding light on other important and potential ethical, legal, and social challenges of gene therapy trials for SCD in Africa (Table 1).

Table 1 Summary of ethical and social considerations for somatic gene therapy in Africa.Transparency in communicating risks and adverse events of gene therapy

Somatic gene therapy for SCD carries potential risks, such as gene silencing, gene toxicity, phototoxicity and inadvertent germline transmission of DNA [40, 41]. Additionally, some studies reported a possible risk of developing leukaemia and myelodysplastic syndrome [42, 43]. Emerging evidence hints at the possibility of off-target editing with unforeseen long-term consequences [44]. While efforts are underway to minimise these risks, patients and their caregivers, research ethics committees and research regulators would need clear and honest communication about the possibility of these different risks, even if they are transient. This includes detailing how risks will be monitored and managed by the trial team, and how they compare to the risks associated with existing standards of care and other advanced therapies for SCD.

Given the rapidly evolving nature of SCD gene therapy and the unpredictable clinical course of SCD, it is also important to acknowledge the current lack of comprehensive information on the long-term benefits of gene therapy for SCD. Such open and honest communication is essential for informed decision-making by patients and their caregivers, as well as in fostering trust between potential participants and researchers. Furthermore, understanding public perceptions of these risks is crucial as it can facilitate risk communication during informed consent and community engagement and public education on gene therapy for SCD.

Therapeutic mis-estimation and uncertainties about gene therapy

The possibility of a life free from the pain crises and complications associated with SCD, can create high expectations regarding the potential benefits of gene therapy [24]. As a consequence, there is a possibility that patients and their caregivers may perceive the risks associated with gene therapy as minimal compared to the long-term physical and psychological discomfort caused by SCD. This phenomenon, known as therapeutic misestimation, can lead to an underestimation of the actual risks of gene therapy and an unrealistic conviction of experiencing only the benefits (therapeutic optimism).

Several factors may contribute to therapeutic misestimation and optimism, such as religious beliefs, the hope for a miraculous cure and sensational or hyped media coverage of successful gene therapy trials. Consequently, some patients and their caregivers may consent for gene therapy without fully considering the potential risks and complications. In light of these, it is imperative for researchers, healthcare providers, and the media to communicate the experimental nature of gene therapy and the potential risks accurately, and without exaggeration, so as to enable potential participants to make decisions based on a realistic understanding of the procedure and its potential outcomes. Also, reserachers should work closely with genetic counsellors and patient advocacy groups to develop mechanisms and platforms for providing support sharing experiences, and facilitating peer-to-peer discussions, which can help individuals gain a more balanced perspective on gene therapy as well as enable informed decision making for participation in gene therapy trials.

Criteria for selection of participants, withdrawal from study and discontinuation of trial

It is likely that gene therapy trials  for SCD will become available in Africa within the next decade. Consequently, it is essential to establish clear criteria (e.g., disease severity, comorbidities, age) for selecting patient-participants, procedures or withdrawal from the trial and conditions for discontinuation of the trial. In the United States, current protocols for SCD gene therapy exclude children based on the low SCD childhood mortality rates in the region [45]. However, this exclusion criteria may be debatable in sub-Saharan Africa, where many children living with SCD do not reach their fifth birthday due to limited access to comprehensive care [8, 46] and may benefit more from gene therapy. The worsening of SCD with age further complicates the decision-making process, especially as there is limited information on health-related quality of life across the lifespan of individuals living with SCD in Africa. If the goal of SCD gene therapy is to improve overall health-related quality of life, there may a valid case for including children in SCD gene therapy trials in Africa. This would provide data on how gene therapy compares to existing standards of care for SCD in African countries or other advanced therapies. It would also enable a comparison of outcomes, and help patients and their families make more informed decisions regarding their preferred intervention.

While it is standard practice that participants can withdraw from a clinical trial at any time, this can be tricky for gene therapy trials once the actual procedure has commenced. Possibility of withdrawal only seems possible in terms of withdrawing their data from the study. Addressing the challenge of withdrawal, may require tailoring consent as a dynamic process, where in the initial stages, the focus is more on improving patients and caregiver’s knowledge of gene therapy trials, such that before the intervention is administered, the patient would have had enough time to reflect on, and make an informed decision about their participation in the trial.

As with study withdrawal, discontinuation, or premature termination of a gene therapy trial, be it for reasons related to serious adverse events, access to participants or logistical challenges can lead to uncertainties for trial participants. Also, considering that long term follow up is required to ascertain risk post-trial and detect potential delayed side effects, investigators will need to inform participants about the alternative care and psychosocial support that would be made available to trial participants.

Informed consent: comprehension and balancing hope and uncertainty

While gene therapy has been presented as a potential one-time cure for SCD, there are risks related to gene silencing, gene toxicity, phototoxicity, uncertainties (even if transient) around germline transmission of DNA, and viral shedding. It is important to acknowledge the current lack of comprehensive information on long-term benefits, including clarity on whether gene therapy will prevent occurrences of chronic organ dysfunction and failure in SCD [47]. It is important to ensure that the optimism of scientists and clinicians do not influence the final decision of patients and that potential trial participants are clear about the potential benefits, risks and uncertainties of gene therapy. To this effect, informed consent for SCD gene therapy should be designed such that the first stage involves education of patients (or parents/guardians) about the procedures, potential benefits and risks, possibilities of withdrawal and procedures for long term monitoring, followed by assessment of literacy and comprehension. We recommend that the planning stages of gene therapy trials/research for SCD in Africa should prioritise the development and testing of consent documents and educational materials with patient support groups, as this could enable patient participants and their caregivers to have fore knowledge of gene therapy, its limitations and risks, even before they are approached to be part of a trial. The co-creation of these documents and materials with patient support groups will not only help improve understanding and decision making, but also foster discussions amongst various stakeholders on the ethical and social aspects of somatic gene therapy for SCD.

Decisional conflict based on varying concerns and priorities for parents and their children, especially mature minors, and young adults

Consent for gene therapy involving minors, especially adolescents can present complex moral dilemma often involving conflicting decisions between parents and their children regarding trial participation. For example, a mature minor living with SCD may be more optimistic about the potential of a cure even if their parents are reluctant to consent. In designing gene therapy trials, it is important to appreciate that both perspectives-those of the adolescent and the parents-are valid, and stem from distinct concerns. Therefore, when developing educational and patient engagement interventions it is imperative to consider these divergent viewpoints.

Minimising decisional conflict in consent between parents and mature minors would require that mechanisms to assess the ability of mature minors and their parents to understand relevant information, appreciate the potential risks and benefits and to make an informed decision. Providing psychosocial support to both parents and adolescents/young adults to help them cope with the challenges that come with decisional conflict will also be key. The MacArthur Competence Assessment Tool for Clinical Research [48], is an example of a literacy and decision making assessment tool that could be used to access the ability of mature minors and young adults to provide informed consent for SCD gene therapy trials. Bearing in mind that the cultural context in Africa plays a major role in decision making within families, engagements with SCD patient support groups can help identify culturally and appropriate strategies to navigate decisional conflict in gene therapy trials in Africa. Open and inclusive discussions with adolescents/young adults their caregivers, health care providers ad patient support groups could also help clarify expectations and clarify concerns ultimately leading to decisions that are in the best interest of the minor or young adult.

Appropriate standards of care for SCD gene therapy trials in Africa

Patients who participate in gene therapy trials will require complex care before, during, and after the trial, it is necessary to establish and communicate to ethics committees and potential participants, the standards of care that was considered in the design of the trial and what will be available to trial participants at the end of the study. Comprehensive SCD healthcare is not available in many African countries and Hydroxyurea, which has been described as the go to drug for improving the quality of life of persons living with SCD [49], is not yet accessible to many patients in Africa [12, 50, 51]. Also, considering that long term follow up is required to ascertain risk and delayed adverse events, investigators will need to inform participants about the measures in place to ensure quality care, and in the case of discontinuation of the trial their commitment to ensuring that trial participants receive support and comprehensive care. SickleInAfrica [52], have proposed multi-level standards of care guidelines for SCD in Africa [53]. However, broad stakeholder engagement would be required to improve access to basic SCD medications and interventions as listed for example in the SickleInAfrica standards of care guidelines for SCD. Without wide access to basic care for SCD in Africa, SCD gene therapy trials in Africa risk being flagged as exploitative or extractive research.

Bounded Justice: Inequities in global access to SCD gene therapy trials

It would be an injustice in global health if a continent that bears 75% of the global SCD burden is unable to access a cure for SCD when it becomes available or be able to access and participate in trials for a cure. Currently, there are no SCD gene therapy trials ongoing in Africa and there is an ongoing debate on whether limited research resources should be allocated to gene therapy, when access to basic lifesaving interventions such as prophylactic penicillin, hydroxyurea and folic acid is still a major challenge in many African countries [54]. Policy makers in many African countries may also contend that there are cost-effective treatments that could improve the quality of life of persons living with SCD. Nonetheless, the high upfront cost of gene therapy should not be reason for tardiness in promoting gene therapy trials for SCD Africa, considering that the lifetime cost (by age 50) of managing a patient living with SCD exceeds eight million USD (Leonard et al., 2020). This health economics argument can be persuasive, especially for those who can afford it. Alternatively, individuals living with SCD may advocate for access to gene therapy from a critical utilitarian perspective-that it will improve their quality of life. This is exemplified in the story of Jimi Olaghere who, in 2020, consented to an SCD gene editing trial in the USA [22]. Jimi explained how SCD infiltrated every aspect of his life including having to leave his parents in Nigeria to stay with relatives in the USA in order access better care, but how as he got older, his pain episodes were frequent, excruciating and he would sometimes wake up in intensive care feeling disappointed to still be alive [55]. A year, following his participation in the gene therapy trial (watched by his parents in Nigeria via a live stream), Jimi says he is now able to plan for decades in the future, unlike before. Many SCD patients in Africa and their caregivers are likely to share similar sentiments as Jimi and, therefore, advocate for researchers, funders and governments to prioritise gene therapy for SCD.

A major contributing factor to global inequities in access to gene therapy for SCD has to with broader national health system challenges in many African countries. This includes a dearth of infrastructural capacity for specialised clinical care. Currently, available gene therapies for SCD require chemotherapy and bone marrow transplant, yet these services are largely unavailable or not fully functional in many African countries [56, 57]. The consequence is that the wealthy will travel to high income countries to access gene therapy, leading to the unintended consequence of “genetic tourism”. Medical tourism, of which genetic tourism, is a subset also raises ethical and legal issues that will also need to be considered in discussions on the governance of gene therapy. It would be important to define, and be transparent, about how priorities for SCD gene therapy trials would be made in Africa. At the early stages priority areas should undoubtedly be on building ethics and regulatory and biosafety capacity, patient education and public engagement and clinical infrastructure to host SCD gene therapy trials. Thereafter, the focus can shift to finding affordable costing models, and by extension equitable access to SCD gene therapy.

Global and public health agencies together with pharmaceutical companies have a moral obligation to uphold the concept of non-abandonment and give equal value to the lives of persons living with this long term and incurable condition, by allowing them access to specialised care even if it would preclude allocation of scientific and public health resources in the most cost-effective way [58]. Similar arguments have been made for rare medical conditions [59] and orphan drugs for SCD [60]. Otherwise, we may witness a situation where the most vulnerable, would have travel to HICs to access gene therapy for SCD, exposing them to the unintended consequence of “genetic tourism”, including exploitation by commercial services. This exploitation make take the form of extravagant claims about the outcomes of gene therapy, commercial and commercial health services downplaying the risks involved and providing little clarity on follow up procedures, especially for medical tourists .