One Size Fits All?: Ethical Considerations for Examining Efficacy in First-in-Human Pluripotent Stem Cell Studies

The 1962 amendments to the Food, Drug, and Cosmetic Act of 1938 changed the drug authorization process of premarket notification to a mandatory approval system. It gave the US Food and Drug Administration (FDA) the power to refuse the marketing of a drug based not only on safety but, thereafter, also on efficacy. The requirement of substantial evidence of efficacy by adequate and well-controlled investigations conducted by experts qualified by scientific training and experience made it possible for the FDA to introduce standards in research.1Daniel C Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Prince-ton University Press, Princeton, NJ2014Google Scholar This led to the categorization of drug research into three phases in the Investigational Drug Regulation of 1963, thereby establishing a codified, prospective research design.1Daniel C Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Prince-ton University Press, Princeton, NJ2014Google Scholar In 1964, Investigational New Drug (IND) forms were created for each of the three phases, embedding them more firmly into medical research. From the onset of this system, discussions have taken place about the appropriateness of phasing experiments in the drug approval process,2US Department of Health, Education, and Welfare Review Panel on New Drug Regulation. Interim Reports, vol. II, section A. Washington, DC, 1977Google Scholar but by the 1970s it was the textbook example for clinical research. Currently, the phasing of research even plays a role in the financial markets—transitions between phases mark the largest movements in pharmaceutical stock value.1Daniel C Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Prince-ton University Press, Princeton, NJ2014Google Scholar It is thus not surprising that critique of and changes to drug development often take place within the context of the phasing research paradigm. Phase I studies are designed to determine the maximum tolerated dose (MTD) of a drug and are potentially followed by phase II trials, which investigate whether the drug at the MTD has any promising effects. Phase III trials establish whether the new drug is more efficacious than available treatments, usually in randomized controlled trials. The assumption behind finding the MTD in phase I studies is the existence of parallel but offset dose-toxicity and dose-efficacy relationships for small-molecule drugs. However, for new biopharmaceuticals, this is not necessarily the case. For instance, the pharmacology of replication-competent viral vectors may display nonclassic dose–response curves because of complex interactions modulated by the innate and adaptive immune systems.3Le Bœuf F Batenchuk C Vähä-Koskela M Breton S Roy D Lemay C et al.Model-based rational design of an oncolytic virus with improved therapeutic potential.Nat Commun. 2013; 4: 1974Crossref PubMed Scopus (35) Google Scholar Similarly, the relationship between dosing and toxicity and effectiveness may be less predictable for cell-based interventions because the cells mediate multiple, potentially competing effects. For example, increasing doses of T lymphocytes in a donor hematopoietic stem cell graft can increase the recipient's risk of developing undesirable graft-versus-host disease (GVHD) but simultaneously decrease the risk of leukemic relapse by augmenting the graft-versus-leukemia reaction. Determining the optimal dose of T cells in hematopoietic stem cell transplants thus depends on a major complication and a welcome side effect.4Gooley TA Martin PJ Fisher LD Pettinger M Simulation as a design tool for phase I/II clinical trials: an example from bone marrow transplantation.Control Clin Trials. 1994; 15: 450-462Abstract Full Text PDF PubMed Scopus (79) Google Scholar The successive phase I/II trial may not be the most efficient way to identify a safe (and efficacious) dose for these new biopharmaceuticals. For interventions using stem cells there is additional complexity; the stem cells could proliferate, or differentiate into distinct populations with diverse positive or negative functions, or mutate and become tumorigenic, making it difficult to establish a safe dose. Moreover, for stem cell interventions standardization is complicated by the variability of cell lines and the variability introduced by the different clinicians performing the transplantation. It is therefore not surprising that some professionals in the stem cell field have reservations about the suitability of the phasing research “paradigm” for first-in-human (FIH) pluripotent stem cell (PSC) interventions.5Habets MGJL van Delden JJM Bredenoord AL Studying the lay of the land: views and experiences of professionals in the translational pluripotent stem cell field.Regen. Med. 2016; 11: 63-71Crossref PubMed Scopus (7) Google Scholar Indeed, the exclusive focus on safety in phase I has been a point of contention, both among professionals and in the academic literature.5Habets MGJL van Delden JJM Bredenoord AL Studying the lay of the land: views and experiences of professionals in the translational pluripotent stem cell field.Regen. Med. 2016; 11: 63-71Crossref PubMed Scopus (7) Google Scholar6Hess P Intracranial stem cell-based transplantation: reconsidering the ethics of phase 1 clinical trials in light of irreversible interventions in the brain.AJOB Neurosci. 2012; 3: 3-13Crossref Scopus (17) Google Scholar7Miller FG Joffe S Benefit in phase 1 oncology trials: therapeutic misconception or reasonable treatment option?.Clin Trials. 2008; 5: 617-623Crossref PubMed Scopus (67) Google Scholar8Ross L Phase I research and the meaning of direct benefit.J Pediatr. 2006; 149: S20-S24Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar9Gilbert F Harris AR Kapsa RMI Controlling brain cells with light: ethical considerations for optogenetic clinical trials.AJOB Neurosci. 2014; 5: 3-11Crossref Scopus (40) Google Scholar10Hey SP Kimmelman J The risk-escalation model: a principled design strategy for early-phase trials.Kennedy Inst Ethics J. 2014; 24: 121-139Crossref PubMed Scopus (18) Google Scholar Surprisingly, in the new regulatory system in Japan, the determination of efficacy has shifted from premarket clinical trials to a postmarket mechanism.11Sipp D Conditional approval: Japan lowers the bar for regenerative medicine products.Cell Stem Cell. 2015; 16: 353-356Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar By contrast, in this paper we argue that efficacy testing should be moved forward from phases II and III to FIH studies as well. Under certain conditions, PSC-based interventional FIH studies should have compatible safety and efficacy end points. Compatible efficacy and safety end points allow participants to gain a possible direct benefit. FIH studies are ethically the most challenging of all phases because finding a balance between the anticipated risks and anticipated benefits is difficult; indeed, risks cannot be reliably evaluated. Moreover, for new biopharmaceuticals, more uncertainty may exist owing to a lack of experience with interventions that are similar in mode of action. The typical irreversibility of interventions is an added complication. Participants may thus be exposed to high risks and burdens. Direct benefits (therapeutic benefits to research participants received via the intervention tested) are not expected, as the aim is to find the MTD. To justify initiating an FIH study, direct benefits cannot be weighed. However, in certain cases the study can be designed in such a way that there is at least a possibility that participants will gain a therapeutic benefit. The main argument in favor of designing an FIH trial to test efficacy is the potential for a participant to gain a direct benefit and thus balance the exposure to possible severe harms and heavy burdens.6Hess P Intracranial stem cell-based transplantation: reconsidering the ethics of phase 1 clinical trials in light of irreversible interventions in the brain.AJOB Neurosci. 2012; 3: 3-13Crossref Scopus (17) Google Scholar Although it is true that FIH studies are not designed to offer a prospect of direct benefit,8Ross L Phase I research and the meaning of direct benefit.J Pediatr. 2006; 149: S20-S24Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar and there is little empirical evidence of direct benefits in FIH studies, this very low probability of the chance to benefit is merely one dimension of direct benefits.7Miller FG Joffe S Benefit in phase 1 oncology trials: therapeutic misconception or reasonable treatment option?.Clin Trials. 2008; 5: 617-623Crossref PubMed Scopus (67) Google Scholar Other dimensions are the nature and the magnitude of the anticipated benefit.12King NM Defining and describing benefit appropriately in clinical trials.J Law Med Ethics. 2000; 28: 332-343Crossref PubMed Scopus (199) Google Scholar Particularly for interventions for currently untreatable diseases that have a high morbidity or mortality, it may be desirable to design studies to offer at least a minimal chance of direct benefit. This can be done by using what is expected to be a therapeutic dose instead of starting with subtherapeutic levels, and by enrolling patients within a therapeutic window rather than refractory patients. According to Hess, intending to provide clinical benefit to subjects in early-phase stem cell–based interventions in the brain is an ethical duty; she argues that the sole aim of generating scientific knowledge can never justify submitting participants (children) to the burdens of an invasive brain procedure.6Hess P Intracranial stem cell-based transplantation: reconsidering the ethics of phase 1 clinical trials in light of irreversible interventions in the brain.AJOB Neurosci. 2012; 3: 3-13Crossref Scopus (17) Google Scholar Gilbert and colleagues similarly note that modification of phase I end points to include efficacy as a target could promote acceptance of invasive and irreversible risks in optogenetic trials.9Gilbert F Harris AR Kapsa RMI Controlling brain cells with light: ethical considerations for optogenetic clinical trials.AJOB Neurosci. 2014; 5: 3-11Crossref Scopus (40) Google Scholar Although adding efficacy end points will be necessary if we would like participants to have a minimum possibility of gaining some therapeutic benefit, it should be clear that the likelihood that participants would benefit, as well as the likelihood that FIH trials will generate data regarding efficacy, is extremely small. Indeed, only about 8–10% of interventions tested in FIH studies lead to market authorization,13Hay M Thomas DW Craighead JL Economides C Rosenthal J Clinical development success rates for investigational drugs.Nat Biotechnol. 2014; 32: 40-51Crossref PubMed Scopus (1491) Google Scholar14US Food and Drug Administration Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products.http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htmDate: 2004Google Scholar and the rate for novel interventions is lower.15Kimmelman J Gene Transfer and the Ethics of First-in-Human Research: Lost in Translation. Cambridge University Press, Cambridge, UK2010Google Scholar A major problem with designing trials to test safety and efficacy is an increased risk of therapeutic misconception, i.e., a lack of understanding that the main purpose of research is to produce generalizable knowledge.16Henderson GE Churchill LR Davis AM Easter MM Grady C Joffe S et al.Clinical trials and medical care: defining the therapeutic misconception.PLoS Med. 2007; 4: e324Crossref PubMed Scopus (306) Google Scholar This has been a major aspect of discussion of the first FIH embryonic stem cell (hESC) trial by Geron.17Solbakk JH Zoloth L The tragedy of translation: the case of ‘first use’ in human embryonic stem cell research.Cell Stem Cell. 2011; 8: 479-481Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar18Wirth E Lebkowski JS Lebacqz K Response to Frederic Bretzner et al.Target populations for first-in-human embryonic stem cell research in spinal cord injury.Cell Stem Cell. 2011; 8: 476-478Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar19Bretzner F Gilbert F Baylis F Brownstone RM Target populations for first-in-human embryonic stem cell research in spinal cord injury.Cell Stem Cell. 2011; 8: 468-475Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Subacute complete spinal cord injury (SCI) patients without neurological function below their torso were injected with hESC-derived oligodendrocyte progenitor cells. These patients had an open therapeutic window, meaning that there was a possibility that they would be affected by the cells, in contrast to chronic patients in whom spinal cord damage has caused scarring and the injected cells would probably not have any effect. However, the patients had to decide within two weeks of their trauma whether to enroll in the trial. They were therefore likely to be emotionally unstable, and they had no knowledge of what life is like with a spinal cord injury. Criticism was expressed because the therapeutic misconception is higher for these patients than for chronic complete-SCI patients.19Bretzner F Gilbert F Baylis F Brownstone RM Target populations for first-in-human embryonic stem cell research in spinal cord injury.Cell Stem Cell. 2011; 8: 468-475Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Here, a trade-off existed between the optimal trial design for obtaining valid informed consent, and the optimal trial design to provide a possible benefit to participants. Careful consideration is necessary when establishing the goal of FIH studies and choosing a subject population.16Henderson GE Churchill LR Davis AM Easter MM Grady C Joffe S et al.Clinical trials and medical care: defining the therapeutic misconception.PLoS Med. 2007; 4: e324Crossref PubMed Scopus (306) Google Scholar20Dresser R First-in-human trial participants: not a vulnerable population, but vulnerable nonetheless.J Law Med Ethics. 2009; 37: 38-50Crossref PubMed Scopus Google J enrolling in novel 2007; 15: Full Text Full Text PDF PubMed Scopus Google A J clinical trials a of the of the trial on the and ethics of J 2007; PubMed Scopus (31) Google Scholar In choosing patients also affected the as enrolling in the trial may have which is no for chronic patients. A trade-off between the optimal trial design for efficacy testing and the optimal design to risks was thus with the trial. on this trade-off stem cell that promising interventions be at the phase I even they be van Delden Bredenoord AL Studying the lay of the land: views and experiences of professionals in the translational pluripotent stem cell Med. 2016; 11: 63-71Crossref PubMed Google Scholar participants are in phase I trials, are to testing because marketing the could lead to Moreover, negative trial will stock making it more difficult to an drug development may thus be efficacy has even been Indeed, the of the three phases in 1963, pharmaceutical anticipated approval of C Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Prince-ton University Press, Princeton, NJ2014Google Scholar approval was development was of the heavy on not only we to a potentially but some professionals it may lead to a lack of designing of research and a to evidence of MGJL van Delden JJM Bredenoord AL Studying the lay of the land: views and experiences of professionals in the translational pluripotent stem cell field.Regen. Med. 2016; 11: 63-71Crossref PubMed Scopus (7) Google Scholar Moreover, an point that should not be is the potential to the risks and side and the a is in development or has been This is for For example, the the of hematopoietic stem cell MM A of human bone marrow PubMed Scopus Google Scholar has improved because of in the understanding of and diseases with the of and F P T J F et hematopoietic stem cell transplantation: a three 2014; Full Text Full Text PDF PubMed Scopus Google Scholar be expected with or these on the of a of phase I an treatment that can be and made The of efficacy and A in by the FDA and the Medical on and that efficacy of a drug could not be from can be only in of the of the and of Medical Scholar The first is that the dose of or both risks and efficacy. safety is a on the therapeutic of a drug well as the of the of the and the and of the the side and can be as or hematopoietic stem cell is a with severe side that can be for the of safety is for a disease such as the of efficacy and a trade-off can exist between the optimal trial design for efficacy testing and the optimal design to For example, in a phase I study in patients with stem cells were injected within the spinal NM K T M et of stem cells in patients with of a phase I trial in 2012; PubMed Scopus Google Scholar the trial had been designed to provide potential direct cells should have been injected at the of the However, if would it would be more severe with an at the The was made to safety for the and therefore the were to the M T J The complex ethics of first in human stem cell clinical trials.AJOB Neurosci. 2012; 3: Scopus (7) Google Scholar Although we would argue for the additional aim of efficacy testing in phase I studies, we with the The should be made on a problem testing efficacy in phase I trials is the to establish efficacy, meaning that more participants will be exposed to R First-in-human trial participants: not a vulnerable population, but vulnerable nonetheless.J Law Med Ethics. 2009; 37: 38-50Crossref PubMed Scopus Google Scholar that evidence for efficacy not be in phase I with a minimal of participants. However, phase I trials not provide any evidence for safety Indeed, only risks will be in phase I trials because of the of participants. Although risks and benefits are in early-phase trials, safety and efficacy are not the of phase III trials, or even market J R The FDA Critical Path and on new drug Med. 2008; PubMed Scopus Google Scholar efficacy safety can be with a of it is only possible to therefore not argue for an increase in the of participants in FIH studies, only for a focus on compatible safety and efficacy end points. that the for testing some efficacy end points in to for new and invasive such as pluripotent stem cells. This the chance of interventions and will provide participants the potential to benefit. Moreover, can aim to the risks and side drug for can be in the on clinical of complex Gilbert et have that efficacy forward to phase I may increase the of trials and thereby the In safety and efficacy end points for optogenetic trials may for safety in phase I should phase II trials F Harris AR Kapsa RMI Controlling brain cells with light: ethical considerations for optogenetic clinical trials.AJOB Neurosci. 2014; 5: 3-11Crossref Scopus (40) Google Scholar and Kimmelman have what they a risk-escalation of early-phase trials, a between benefits to research participants and maximum of in early-phase SP Kimmelman J The risk-escalation model: a principled design strategy for early-phase trials.Kennedy Inst Ethics J. 2014; 24: 121-139Crossref PubMed Scopus (18) Google Scholar minimal However, there are in efficacy to be tested simultaneously with safety in phase I trials. we provide some and for efficacy testing in phase and for efficacy as additional of phase testing efficacy in FIH studies should never be to the of trials. Although in certain we that phase I trials should be designed to allow participants to benefit, it should be as research. This is also because the therapeutic misconception should be when efficacy will be in FIH should the that FIH studies are to for trials. a benefit to the participant is not the aim of research. To it may be to have of the research the informed the of the safety of the participants should the main focus of The and regulatory should the between safety and efficacy because for to to have in the medical research for novel only data of efficacy are of clinical in as there is no Kimmelman and have a process for to to efficacy. In a first all evidence should be and in the light of potential to In a the should be by similar by similar have in the translational J for trials using a Med Ethics. 2016; PubMed Scopus Google Scholar if efficacy is tested in FIH studies, it should be which aspect of efficacy is such as of cells, clinical such as ethics not have a or a for these benefits in human LR GE Davis AM E et benefits in clinical in benefit can be Ethics PubMed Scopus Google Scholar and as well as discussions with are and with to benefit, making this a GE Davis AM Easter MM et views and in phase Full Text Full Text PDF PubMed Scopus Google Scholar to test both safety and efficacy it is that and clinical which trial design should be can be from in which a has taken place phase I and phase II in to drug C phase I/II adaptive design for oncology trials of 2014; PubMed Scopus Google Scholar Similarly, in a has been in the clinical development A K M A et clinical development for and 2007; PubMed Scopus Google Scholar The Clinical with from the pharmaceutical and and the a new clinical development for and The field can from both the process of and the discussion of this A clinical development has been that of a drug development a trial and an efficacy A K M A et clinical development for and 2007; PubMed Scopus Google Scholar The trial dose and and that for FIH studies it is also very to of This a understanding of the and FIH studies should the of the in of efficacy. the intervention cell with the clinical should be For example, for in a spinal studies should the in the spinal cord in via studies or studies of cells. it would be more if all the were and this may the of patients to some evidence of efficacy in an FIH This is even more when studies are in patients with diseases because randomized controlled trials are often not owing to a of patients. if cannot be by a it may at least provide the starting point for it J Gene Transfer and the Ethics of First-in-Human Research: Lost in Translation. Cambridge University Press, Cambridge, UK2010Google Scholar This can be for additional studies and early-phase trials as well as phase II J Gene Transfer and the Ethics of First-in-Human Research: Lost in Translation. Cambridge University Press, Cambridge, UK2010Google Scholar The phasing of research is in the medical research field and is However, changes are as is by the of trial such as and trials, in Although risk should the aim of FIH studies, for stem cell interventions it ethically desirable for participants to have at least a chance to benefit. Moreover, promising interventions may be in FIH studies and not their efficacy can be Indeed, the safety of interventions is on the of risks and efficacy.

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