The Inherent Ethical Challenge of First-in-Human Pluripotent Stem Cell Trials

KEYWORDS::

• ethics
• first-in-human trials
• induced pluripotent stem cells
• iPS cells
• pluripotent stem cells
• research ethics
• risk–benefit
• social value
• translational medicine

Pluripotent stem cells have great potential for regenerative medicine, but the inherent uncertainty of first-in-human trials combined with the technical complexity of pluripotent stem cells make early-phase pluripotent stem cell trials ethically very challenging. The first clinical studies using human embryonic stem cells are currently in early phases [1,101,102]. Moreover, only 6 years after the publication of Takahashi and Yamanaka‘s seminal article showing the derivation of induced pluripotent stem (iPS) cells from adult human fibroblasts [2], the first trial using iPS cells have been announced for a study in patients with macular degeneration (MD), a common cause of blindness. The upcoming clinical study will enroll six patients over 50 years of age with severe age-related MD, for whom conventional treatment has failed. Skin cells will be isolated from study participants, induced to become pluripotent and subsequently differentiated into retinal cells. The developed autologous retinal pigment epithelium (RPE) will then be transplanted to engraft with patient cells. From a safety perspective, age-related MD is ideal as a model system for a first-in-human iPS cell trial, as the retina is accessible for monitoring, it is immune privileged and is isolated by the blood–ocular barrier (although the RPE is part of this barrier) [3]. Notwithstanding these advantages, many safety and ethical issues warrant attention as failure of a premature trial could jeopardize the safety of participants and impede the development of crucially needed therapies because of a social outcry, as was the case in early gene therapy trials. Our aim here is to identify some of the ethical concerns for the purpose of a public debate as well as for enhancing the ethical acceptability of this forthcoming first-in-human iPS cell trial. We argue to proceed cautiously, but only after further (pre)clinical evidence has improved the risk–value balance.

The inherent ethical challenge of first-in-human trials

The principle that risks to research participants must be proportional to anticipated benefits is common to all international documents on ethical conduct in clinical research. Although this balance is difficult to ascertain at all stages of clinical research, it is particularly challenging for first-in-human studies for two reasons. First, risks cannot be reliably evaluated; indeed, the aim of these trials is risk assessment. Moreover, for ‘first-in-kind‘ trials such as iPS cell studies, risks are extremely unpredictable due to the absence of drugs similar in mode of action, and the lack of precedent for this novel intrusion in the human body. Second, research participants are not expected to gain any direct benefit in early phase trials [4], particularly because of the dose-escalation regimen. In the absence of direct medical benefit, justification for exposing research participants to possible harms is sought in the ambiguous concept of ‘social value‘ [5], which often refers to the possible therapeutic value of the intervention tested that would hopefully follow a successful trial, and the instrumental or knowledge value inherent in the trial itself. Instead of balancing risks and benefits, it is therefore better to speak of balancing risks and potential value for first-in-human trials. Although the value of stem cell treatment to future patients with MD could be high, the progressive value of early phase trials is low because the likelihood of advancing to Phase II/III trials is small [6]. Researchers should therefore make as many efforts as reasonably possible not only to minimize risks, but also to maximize the value of a trial, in order to improve the risk–value balance – and one should keep in mind that the risk minimization and value maximization do not have to be compatible [7].

Reducing risks to research participants

Besides the unpredictable risks inherent in every first-in-human trial, the forthcoming iPS cell trial brings additional concerns; the ex vivo cultivation of the iPS cell-derived RPE takes place over a 10-month period and the grown tissue can thus become contaminated with harmful viruses, bacteria and fungi. Furthermore, iPS cell technology could enhance the risk of cancer; accidentally transplanted nondifferentiated stem cells can cause teratomas, whereas genetic aberrations in the DNA of iPS cell-derived retinal cells can cause malignant neoplasms [8]. These genetic aberrations are the product of the process of inducing pluripotency in somatic cells, the selection procedure of rapidly proliferating cell lines in vitro, and/or the pre-existing genetic changes present in the diverse populations of somatic cells from adults [9,10]. An increased understanding of the molecular details of cell reprogramming is crucial in preventing (epi)genetic alterations in iPS cells that give rise to increased cancer risks. Indeed, consensus on a reliable and safe reprogramming protocol seems a prerequisite for moving to the clinic [11]. In addition to this hiatus in knowledge, most preclinical data have been collected using mice and/or rats, both lacking a macula, possibly rendering data on (lack of) harmful side effects (as well as on efficacy) less reliable.

Although the research team of the RIKEN center in Kobe (Japan) has completed a preclinical trial using primates, they observed their study primates for a relatively short time. Teratomas, which may be detectable in a short time frame, were not found; however, malignant neoplasms may go undetected for years, as may teratomas, thus necessitating long-term monitoring of the study primates. More importantly, the results of the primate trial have not yet been published and can thus not be scrutinized by the research community, nor can they be replicated to validate the results. It is precisely a lack of transparency that can damage the reputation of a research field, as was the case for gene transfer interventions.

In addition, risks of novel interventions are better evaluated when reviewers can consult data on similar interventions [5]. Awaiting further results from the current first-in-human embryonic stem cell trial for MD [1] may improve the risk evaluation of iPS cell trials, and thereby possibly reduce harm.

Increasing social value

What further steps can maximize the value of the forthcoming trial? One could choose appropriate end points. Finding efficacy in preclinical studies is a precondition for obtaining approval from research ethics committees (or institutional review boards); however, efficacy is often defined in surrogate end points rather than clinical benefit [12]. In the case of iPS cells in MD, scientists for example could examine the engraftment success of iPS cells, the electrical responses of the RPE or phagocytosis functioning. Although these are necessary for the RPE to be effective, the social value of the study is ultimately an improvement of future patients‘ quality of life. Even an improvement in vision on the visual acuity chart does not necessarily affect quality of life. Involving patients and patient support groups, such as AMD Alliance International, on which clinical end points are worth assessing in a trial would be an excellent way to improve the social value of a study. After all, patients are both end users of biomedical innovations and experiential experts and therefore bring knowledge and experience different from researchers.

Furthermore, it is important to ensure that research participants are aware of the fact that research is conducted not to treat them, but to obtain generalizable information. This will prevent both therapeutic misconception, that is, misunderstanding of patients regarding the purpose of a study, and therapeutic misestimation, that is, underestimation of patients regarding the risks or overestimation regarding the benefits due to incorrect understanding of the trial [13]. As medical research is increasingly viewed as access to first class novel therapies, and as patients expect medical teams to act in their best interest, it is not surprising that patients may enroll in trials hoping for a cure. Although informed consent is a necessity for ethical research, it does not abdicate moral responsibility from researchers. Participants should be made aware of the risks, and lack of information of risks. A consent form should also contain a section on the disclosure of significant (genetic) information detected during research that could influence the patients‘ quality of life [14].

The guidelines for the clinical translation of stem cells from the International Society for Stem Cell Research (ISSCR) leave room for a justification of attempting innovative stem cell-based treatment in a small number of seriously ill people. Although the patients who will be enrolled in the impending trial have severe MD, this is not life threatening, which invites the question of whether this is the right participant group for a first iPS cell trial.

Proceed with caution

In summary, by acquiring a more favorable risk–value balance the ethical acceptability of the first-in-human iPS cell trial can be enhanced. Risks can be minimized, among others, by extensive monitoring during the study and by increasing the internal and external validity of preclinical evidence. Simultaneously, choosing clinically relevant outcome measures can maximize potential social value. The decision to make the leap from bench to bedside should be taken by an expert community after consideration of the available evidence [15]. Rigorous review and interdisciplinary discussion are essential, including a transparent public debate. The recent process on mitochondrial gene transfer may serve as an example of transparent and socially aware innovation [15,103].

In translational iPS cell research many of the ethical challenges of innovative cutting-edge interventions are magnified. Due to the unique risks of pluripotent stem cells, the relative unreliability of animal models, the potential vulnerability of research participants, the tremendous scientific and commercial stakes, and the high public expectations, we advise to proceed with caution.

Acknowledgements

The authors would like to thank N Geijsen for his valuable comments and critical reading of the manuscript.

Financial & competing interests disclosure

AL Bredenoord is supported by The Netherlands Organisation for Health Research and Development Veni grant 016.136.093. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

AL Bredenoord is supported by The Netherlands Organisation for Health Research and Development Veni grant 016.136.093. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.