Calculating Risk/Benefit in X-Linked Severe Combined Immune Deficiency Disorder (X-SCID) Gene Therapy Trials: The Task of Ethical Evaluation

Abstract

In response to adverse events in retroviral gene therapy clinical trials conducted in France to correct for X-linked severe combined immune deficiency disorder (X-SCID), an advisory committee of the Food and Drug Administration convened in October 2002, February 2003, and March 2005, to deliberate and provide recommendations for similarly sponsored research in the United States. A similar National Institutes of Health committee met in February 2003. In this article, I review the transcripts and/or minutes of these meetings to evaluate the extent to which the ethical dimension of the research was engaged even as the molecular and clinical evidence was reviewed. I then provide representative ethical arguments to demonstrate the sort of ethical reasoning that should be included as part of the agenda of such committee meetings.

Keywords:

• biomedical ethics
• retroviral gene therapy
• X-SCID

I. INTRODUCTION

In this article I should like to consider one pertinent example of how the skills of the philosopher may contribute to the task of formulating public policy in gene therapy research. I focus on developments within gene therapy trials conducted in France, designed for severe combined immune deficiency disorder (SCID). ¹ Specifically, I take into account discussions (from three meetings, held on October 10, 2002, February 28, 2003, and March 4, 2005) and consequent recommendations from the Biological Response Modifiers Advisory Committee (BRMAC) of the Food & Drug Administration (FDA) with reference to FDA's oversight of similar trials proposed by sponsors in the United States. ²

These three meetings were held in response to adverse events reported in the SCID clinical trials conducted in France, including the officially reported death of a trial participant (reported January 24, 2005). The March 2005 meeting also included a report on the occurrence of myeloid malignancy in a rhesus macaque six years post-transplantation of retrovirally transduced cells and a report on a preclinical study in mice that indicated the gamma-c transgene may contribute to the tumorigenic process (i.e., pathogenesis of retroviral vector-associated leukemia). Thus, these two pre-clinical results raised additional questions about what is to be done with clinical trials involving human participants. I will also refer to the deliberations on the same issues as conducted by the Recombinant DNA Advisory Committee of the National Institutes of Health, engaged at its meeting held on February 10, 2003.

First, however, I invite the reader to consider what is at issue in an ethical reflection such as concerns the case-study review engaged here. I make these preliminary comments in light of the fact that some may argue that ethical reflection such as is presented here is not to be expected in “real-time” deliberations of a committee charged with formulating policy. I disagree with that claim, for reasons to be made clear in due course at the completion of my analysis.

It is generally accepted that ethical reflection on issues in biomedical practice is generally conducted with a view to contributing to research integrity. This is part and parcel of the goal of protecting the public welfare from scientific misconduct, advertent or inadvertent. This is especially so when such research moves from pre-clinical studies involving in vitro techniques or in vivo techniques in animals to clinical trials involving human participants. Ethical reflection can be illuminating of researcher obligations, as in ongoing developments in recombinant-DNA clinical research. This kind of research continues to press at the limits of both scientific and ethical knowledge. That is, such research presents additional complexity to the researcher in identifying her obligations vis-à-vis individuals who are engaged in clinical trials, oftentimes under the ambiguous and not readily separable roles of “human research subject” and “patient.”

Simultaneously, this push at the limits of basic knowledge manifests such a daunting complexity in the basic science that ethical judgment cannot but be quite intricate, in both the scope and structure of adduced argument when attempted. There are, of course, relevant codes of practice providing principled guidance to researchers as they structure their protocols. Ethicists, however, are concerned to articulate judgments that follow from relevant applications of ethical theory, difficult as this may be, even in the case of biomedical research.

Consider, then, that there is value in teaching the theoretical foundations of biomedical ethics, even to advanced researchers who are expected to pursue their craft with integrity. In such teaching, the ethicist has a subordinate pedagogical goal, viz., having students learn and practice elementary logical skill. Thus, one can adduce a basic argument in favor of applying ethical theory in the context of biomedical research. Structured in the logical form of argument known as modus ponens, one may argue in a general sense as follows:

If our actions are guided by a particular theory, then we can explain our actions by demonstrating that the principles of the theory

1. required us to act as we did, or

2. permitted our actions (understanding here that “explanation” includes “justification”).

One would then assert, as the case may be, that the actions at issue are as a matter of fact indeed guided by a particular theoretical frame of ethical reasoning (e.g., utilitarianism, Kantian deontology, Rawlsian justice ethics, natural law/moral theology, etc.). The conclusion that follows is that we can (and presumably do) explain our actions by demonstrating this or that moral principle (the principle of utility, the categorical imperative, the rules of distributive justice, the principle of double effect, etc.), when applied to the case at hand, required or at least permitted the actions in question. (Munson, 2004, p. 741 ff.)

The foregoing argument provides a legitimate place, as well as a method or mode of inquiry, for ethical reflection appropriate to the conduct of biomedical research. Somewhat in contrast to this positive assessment, however, Arthur L. Caplan (2002) asks the question, “Can philosophical analysis really help?” when engaging the topic of gene therapy. Hallvard Lillehammer (2004) asks, “Who needs bioethicists?” These two questions illustrate the state of the discipline of bioethics relative to both the basic research and the clinical research that have called ethicists to the fore to assist in

1. conceptual clarification and

2. justification of decisions taken consistent with standards of practice.

Let us consider these claims briefly en route to our substantive reflection on the ethical dimension of X-SCID gene therapy trials.

Caplan has opined, “[Many] of those who deliver health care are not beset by doubts or ambiguities about the aims, goals, definitions or purposes of their activities.” Caplan is concerned that “the implications of new knowledge in genetics for understanding health, disease and normality are not always center-stage”—“Basic researchers have fewer reasons than clinical researchers to struggle to clarify the conceptual foundations of health …” (2002). Caplan's observations link in consonant way to those of Lillehammer, who takes note of the criticism by some that “the presence of bioethicists is unproductive in practical bioethical debate”—presumably, “bioethicists have no distinctive expertise to offer” (2004). However, Lillehammer goes on to argue that, “bioethics is an area of inquiry in which the standard tools of the philosopher find illuminating applications” (2004). One can infer reasonably that this holds for basic research even as it holds for research that is therapeutic (participants receive benefit themselves) or non-therapeutic (participants receive no benefit themselves, though the results are promising for others). Whether real-time deliberations of a policy committee are “illuminated” by the application of bioethical analysis, I think—at least in the context of the analysis presented here—is more a matter of logistics and less one having to do with the capacity of bioethicists to contribute to the formulation of relevant policy.

Caplan distinguishes between basic genetic research and clinical research, the former group of researchers, so he says, are “simply interested in understanding the composition of the genome, its infrastructure or anatomy”; whereas, in comparison, the latter are normally pursuing therapeutic goals relevant to particular cohorts of individuals having identified genetically transmissible disease (Caplan, 2002). Caplan observes, “The question of how disease is currently assessed in the realm of clinical genetics is not entirely a hypothetical one;” yet, he adds, decades of medical practice suggest that there remain “uncertainty and confusion … about both the criteria that ought be used to define disease and the proper application of concepts of health and disease at the level of genetic difference and abnormality” (2002). Taking Lillehammer to be correct in his estimate of the role of bioethicists, there is yet work to be done at both the level of conceptual clarification and the more applied level of justifying clinical trials. Accordingly, I take up the case of X-SCID gene therapy research to demonstrate how one may achieve such clarification and justification in the process of conducting such clinical trials—even in “real-time” deliberation.

II THE QUESTION AT ISSUE IN THE BRMAC SESSIONS

At issue for the Biological Response Modifiers Advisory Committee (BRMAC) during the October 2002 meeting was the question: “Are there additional data or measures that clinical investigators need to provide before future and present clinical trials in SCID patients should proceed in the United States” (FDA, 2002). At issue for me additionally—as one engaged in ethical reflection—is the question whether the committee's efforts to provide guidance to the research community emanate from reasonable ethical evaluation even as they can be expected properly to engage questions related to the basic science and approved protocols associated with SCID gene therapy trials. Specifically, I consider at this point the committee's focus on assessment of risk and benefit as a way to decide on appropriate regulation of similar trials conducted or proposed in the United States and, hence, subject to FDA oversight. In process I shall also comment on the presence or absence of input from bioethicists during the two meetings, thereby to gauge in this particular case whether the criticism mentioned by Lillehammer (that the presence of bioethicists is unproductive in practical bioethical debate) has any merit.

The 2002 Context of Committee Deliberation: Some Formal Arguments

Several basic formal arguments have been adduced for the purpose of evaluating ethical difficulties in genetic research where assessment of risk and benefit is at issue. The following arguments provide a logical frame according to which one may approach the substantive questions engaged by BRMAC, thus a way to evaluate the context of ethical deliberation to the extent this occurred (as evidenced by the available transcripts of the meetings). The general operating guideline is that “the same standards of safety and the same consideration for the welfare of the patient that are relevant to the use of other forms of therapy should be regarded as relevant to gene therapy” (Munson, 2004, p. 299). Three arguments (the first two are Kantian/Rossian and the third is utilitarian in type) can be structured thus:

Argument No. 1

seeks to respect and preserve the autonomy of the individual who takes on the role of human participant in therapeutic research:

(Conditional proposition): If the person is

1. adequately informed,

2. competent to consent (including here competence in the case of proxy consent), and

3. no alternative therapy is likely to be effective, then it is morally appropriate for the patient to be given the opportunity to benefit from the therapy.

(Affirmation that the conditions obtain in a given case): Person X is

1. adequately informed,

2. competent to consent (including here competence in the case of proxy consent), and

3. no alternative therapy is likely to be effective.

(Conclusion): Therefore, it is morally appropriate for patient X to be given the opportunity to benefit from the therapy. ³

Argument No. 2

seeks to preserve individual autonomy and to assure that the individual's duty to self is not compromised unreasonably:

(Conditional proposition): If the hazards are great or completely unknown, then it is doubtful whether the patient would be justified in risking his or her life.

(Affirmation that the conditions obtain in a given case): The hazards of disease X are great (alternatively, completely unknown).

(Conclusion): Therefore, it is doubtful that patient X would be justified in risking his or her life. ⁴

Argument No. 3

is utilitarian, seeking to assess risk and benefit:

(Conditional proposition 1): If the outcome of gene therapy for person X can be reasonably expected to produce more benefit than harm, then its use might be considered justifiable.

(Conditional proposition 2): If we assume person X is likely to die anyway, that in itself might be enough reason to warrant the use of the therapy.

(Affirmation of antecedents of the conditional propositions): The outcome of gene therapy for person X can be reasonably expected to produce more benefit than harm; and person X is likely to die anyway.

(Predictive result affecting diagnosis and etiological interests): Each case treated is likely to contribute to increased understanding and to benefit others, tending to support the use of gene therapy, even in cases in which it is of doubtful help to the individual.

(Conclusion): The gene therapy for person X is justified. ⁵

With these formal arguments setting forth the logical frame for our intended ethical evaluation, I turn now to deliberations of the committee to identify pertinent information and perspectives communicated at the October 2002 meeting initially, after which I will consider what the February 2003 meeting discloses relative to the same set of questions. I cite speakers directly rather than paraphrase with three purposes in mind:

1. to enable those who appreciate the basic science to review the research results as stated by reporting scientists;

2. to illustrate the emphasis given in committee to the basic science with primary attention to oncogenesis; and

3. to illustrate thereby the lack of explicit attention to ethical issues other than the standard one of informed consent.

As noted earlier, BRMAC convened after FDA received notice of an adverse event in an X-SCID gene therapy trial being conducted in France. One of the trial participants (patient number 4, one month of age at treatment) developed a leukemia-like condition (T-cell clonal expansion) around month 30 during an episode of benign chickenpox (“disseminated varicella-zoster infection which affected the central nervous system”) and presented with hepatosplenomegaly (presenting 50K–80K leukocytes per microliter between months 31 and 35). FDA officials supposed a causal relationship between the retroviral gene transfer and the T-cell clonal expansion. In short, FDA officials hypothesized that the adverse event was likely caused by an insertional mutagenesis of the retroviral vector used in the gene therapy. ⁶ Dr. Alain Fischer, principal investigator in the French trial, reported that when examining cells in the case “they could see that the genetic material of the retrovirus had inserted into a particular gene on the 11^th chromosome that controls the proliferation of cells.” This outcome is consistent with prior information that “retroviruses are capable of activating oncogenes by integrating next or near these genes and activating them transcriptionally so that they are expressed [i.e., expressed mostly as hematopoietic events such as lymphoid, myeloid, or erythroid leukemia—NKS],” hence an adverse event like the T-cell clonal expansion with leukemia-like presentation in patient no. 4 in the French trial.

Indeed, as noted in committee, a 1995 article reported:

“Because clinical experience is so limited, it is not possible to exclude long-term adverse effects of gene therapy such as might arise from mutations when viral sequences randomly integrate at critical sites in the genome of somatic cells. It must be noted that multiple integration events resulting from repeated administration of large doses of retroviruses theoretically pose a risk for leukemic transformation.” (FDA, 2002)

This one case of insertional mutagenesis, though contrasted to a successful trial in nine out of 11 patients at the time the adverse event was reported, suggested that what was understood to be a theoretical possibility was now presenting as a clinical reality.

Thus, in public comment at the meeting, the Council for Responsible Genetics reminded: “Retroviruses are difficult to target effectively, and as a result, they often may not reach the intended DNA location. This becomes a safety hazard … [These] viruses integrated randomly into the genome of the host cell. After the transgene is introduced, inappropriate integration could disrupt important gene and cell functioning, precipitating cancer or other forms of biological damage” (FDA, 2002).

The combined facts of

1. successful gene therapy results in nine out of eleven participants with

2. one adverse event compares to the rate of success and risk associated with the only other mode of treatment available to patients suffering from X-SCID, viz., bone marrow transplantation (BMT), either haploidentical or HLA-identical [HLA = human leukocyte antigen] stem cell transplantation.

In committee deliberations Dr. Kenneth Cornetta opined:

“… what we have to try to do is look at what is the risk associated with gene therapy for this disease versus what are the risks for transplants … We're also faced with looking at fairly limited numbers for SCID with gene therapy, but actually the numbers there are pretty good, too. It's a terrible thing that's happened to that one individual patient, but if this truly is even a ten percent risk for folks going with that disease, it's comparable or maybe even a little better with folks that are being treated with haploidentical transplantation.” (FDA, 2002)

Transplantation has yielded about an 80% rate of success insofar as T‐cell function improves (survival rates for haploidentical transplants is about 90% if the transplant is performed while the patient is a newborn); however, as was reported in committee, there is poor T-cell function in some cases even as “the correction of the B cell immunity … requires intravenous immunoglobulin [IVIG] replacement for the lifetime of these recipients in most cases” (FDA, 2002). It was noted in committee that several factors appear to influence the outcome of BMT—age at presentation, presence of infection at presentation, and type of donor (HLA-identical or haploidentical). The cost of transplantation reportedly ranges from a low of US$50,000 to a high of US$200,000 (excluding the cost of IVIG for patients having poor B-cell function). It is to be noted further that the fatality of SCID is such that, even when BMT is pursued, “for many of these patients the infection that leads to their diagnosis may be something that will be fatal before any therapy can get them good immunity.” Moreover, when quality of life is taken into account, it is noted that despite successful T-cell function resulting from BMT, these are generally “kids who are getting by” given cases with continuing “IVIG dependence, immune disregulation and autoimmunity, recurrent infections, growth retardation, nutritional problems, and lung disease in a subset of these patients” (FDA, 2002).

The foregoing discussion in committee now enables our ethical reflection. We can see that the committee's deliberations are such that they clearly seek to evaluate risk and benefit first and foremost. This they do by comparing the standard treatment for X-SCID—viz., BMT—to the experimental treatment, i.e., retroviral gene therapy. In the case of a child undergoing the standard treatment, the child is understood to be a “patient” first and foremost; in the case of a child undergoing the experimental treatment, however, the child is understood to be first and foremost a “research subject,” even as s/he is a patient to be treated within the frame of the research protocol.

Thus, when one introduces principles of nonmaleficence and beneficence to gauge the obligation of the researcher/physician to the patient/research-subject, there are some interesting deliberative difficulties that ensue. Committee member Dr. David Harlan, e.g., pointed to the obligation of the physician to “do no harm,” as an obligation that is to be guiding even in the context of a gene therapy trial. FDA official Dr. Philip Noguchi, however, redirected this position, arguing:

As a physician, Dr. Harlan is absolutely right. First do no harm. But the clinical trial involves human subjects in which the outcome is not predicted and it cannot be known, and in fact, it is the mechanism by which we as a society and worldwide have determined that where things cannot be known a priori, there is a set of conditions under which experiments are taking place with human subjects who may also happen to be patients.

This is one of the critical internal conflicts that we as physicians and as scientists have in that as physicians we want to do the best and not do any harm, but doing a clinical experiment is to find out what are the risks, what are the potential risks, what are the potential benefits …

And it is really an unfortunate, but a very central issue here. Are we talking about medical treatment? Are we talking about clinical trials?” (FDA, 2002)

Dr. Noguchi's comments conclude with two questions that make it clear there remain significant conceptual difficulties not only for researchers conducting gene therapy trials but also for those who, as members of BRMAC, have policy oversight authority. These conceptual difficulties include:

1. the role of “patient” and “research subject” is not adequately delineated;

2. “standard” treatment and “experimental” treatment are presumably to be conceptually distinguished; and

3. this distinction presumably allows for different application of the principle of nonmaleficence (a greater degree of risk to be permissible in the case of experimental treatment).

In the case of individuals presenting with X-SCID, then, if Dr. Noguchi's reasoning is controlling in the conclusion of policy oversight deliberations, the principle of nonmaleficence does not apply as strictly in retroviral gene therapy trials as it does in the case of the currently available standard treatment of BMT, though clearly there is risk in both types of therapy. Dr. Noguchi's remarks operate on the assumption that retroviral gene therapy is a promising treatment for X-SCID, at least, e.g., given the results from the French trial, notwithstanding the adverse event under discussion.

Dr. Joanne Kurtzberg opined in similar vein:

I would like to put forward to the FDA that do no harm can also—you can be doing harm when you withhold promising treatment, and if you don't test in a responsible way promising treatment, you don't make progress, and if you have a disease that is already doing considerable harm, that should weigh into the equation, and I don't think do no harm by itself carries a compelling argument. (FDA, 2002)

So, what do we learn from our ethical reflection in the above review of committee deliberation? The foregoing comments make it clear that assessment of risk/benefit among those participating in this public meeting will vary in the conclusions adduced because of equivocal conceptions of roles of “patients” versus “research subjects” and questionable applications of the principle of nonmaleficence consequent to the equivocal conceptions of “harm” (“active intervention” on the part of the physician/researcher providing either the standard or the experimental treatment versus the supposedly “passive” position of foregoing the experimental treatment altogether in favor of the standard treatment).

Yet, even statisticians will assess the notion of risk differently. Dr. Anastasios Tsiatis, for example remarked in session, “I'm trying to decide if we really have evidence that the risk for gene therapy right now is worse than the risk of some of the other methods of treatments, like, you know, the bone [marrow] transplantation” (FDA, 2002). He added,

I don't feel like I have the correct numbers in order to make the assessment. For one thing, when one is assessing risk, you don't just look at the number of events over the number of people. Really what's important is how many person-years of exposure has there been on a particular treatment and how many events were seen during those person-years. And certainly there's a lot less of that with the gene therapy than there is with some of the other modalities of treatment, but unless I could actually see those numbers in comparison to each other to make the judgment that it is much worse right now, at least from a statistical point of view, I don't feel I see necessarily that it is much worse risk right now than other methods … (FDA, 2002)

Dr. Tsiatis's approach to risk assessment resonated favorably with the members of the committee, so that the question thereafter in deliberation then turned on estimating the number of person-years in gene therapy that could be determined specifically from the French trial. Accounting for 11 patients with a probable mean follow-up of 1.5 years, the risk in gene therapy is measured to be “one adverse event … in basically 15 patient-years.” Even so, it remained unclear what this measure entails in terms of actual risk to the individual human participant as patient (despite the data presented at the meeting), so that Dr. John Coffin asked, “are there more of these [adverse events]? Are there more sort of smoking guns waiting among these other kids to show up in future years?… We don't know that this is the final story on this particular set of patients, and we won't know that for a great many years really” (FDA, 2002). Dr. Coffin's question links with Dr. Bruce Blazar's concern for “the long term propensity and likelihood that some of the other clones in these patients may become leukemogenic,” even as he (as one performing BMT rather than gene therapy) opined he did not see “a very large difference in the risk between gene therapy and haploidentical bone marrow transplant worldwide” (FDA, 2002). In contrast, Dr. Stuart Orkin reminded of the 1995 report (cited above) and stated, “Because the clinical experience is so limited it's impossible to exclude long term adverse effects and only longitudinal clinical studies will actually show that” (FDA, 2002).

In short, despite their best efforts, we can assert on the basis of the transcripts that members of BRMAC could not satisfactorily state what the risk of retroviral gene therapy is, whether taken by itself or when compared to the risk associated with the standard treatment of BMT. So long as there was adequate informed consent, BRMAC argued that “families be given a choice to have a haploidentical [BMT] or gene therapy.” Clearly, however, one engaged in ethical reflection readily sees that at this point it becomes all the more difficult to address the question of “informed consent:” It is one thing to inform participants in suspended clinical trials of the fact of the adverse event that occurred; it is another to disclose the probability of this event recurring, both of which are presumably important to “adequate” informed consent.

BRMAC surely sought to provide a recommendation that contributed meaningfully to improving researcher compliance with the informed consent criterion of all protocols associated with gene therapy clinical trials, but especially for those involving retroviral vectors. While working to improve the informed consent documents, so that the adverse event was made known to recruited participants, the FDA also sought to enable continued clinical research in trials proposed within the United States. However, it is noteworthy that the FDA identified “three U.S. gene therapy studies that most closely resembled the French trials and stopped enrollment of human subjects in those trials [that involve the use of retroviruses to insert new genes in blood stem cells, irrespective of the disease condition]. They remain[ed] on clinical hold” as of a December 2002 report of a second adverse event in the French trial, even though “FDA's continuing review of adverse event reports from all U.S. studies involving retroviral vectors [had, as of January 14, 2003] found no evidence of leukemia caused by the gene therapy” (FDA, 2003a).

III REFLECTING UPON THE 2003 CONTEXT OF COMMITTEE DELIBERATION

BRMAC convened again in February 2003 in response to a second adverse event, disclosed in the French trial in December 2002. In this event a child participating in the trial developed a leukemia-like condition at 34 months post-treatment. The FDA placed a temporary clinical hold on those gene therapy trials conducted in the United States that were using retroviral vectors in blood stem cells, pending BRMAC's recommendation. The committee proceeded by taking into account what transpired in the October 2002 meeting and asked, “What has changed?” especially related to two questions: “What would happen if a second case [of leukemogenic condition] occurred?” “How would that change the risk/benefit ratio calculations that we made?”

On behalf of FDA, Dr. Noguchi remarked:

We are here to acknowledge that there continues to be extraordinarily difficult diseases and the treatment of them remain hopeful, but are always a problem in terms of balancing risks and benefits. And we are here to affirm that the way to get at this ideal is to do rigorous clinical trials. As we do this, and as we are seeing today, this is not a static evaluation, but it is a continuous balancing of risks and benefits. (FDA, 2003b)

In presenting the data from France, FDA official Dr. Carolyn Wilson informed the committee, “These preliminary data suggested that we were probably looking again at an incident where retroviral vector integration was likely playing a role in the T-cell expansion” (FDA 2003b), the consequence of which was:

1. that sponsors of clinical research using “hematopoietic stem cells as their target for ex vivo transduction” were required to have plans for monitoring clonality before being released from clinical hold;

2. “inactive trials that use hematopoietic stem cells were told that if they ever wanted to resume their trial, that again they would need to meet these conditions;” and

3. all other retroviral vector clinical trials were not put on hold, but it was recommended that “they now would also need to develop plans to monitor for clonality.”

FDA focused initially on

1. the problem of dosing—“the idea that if you reduce the total load of vector integrants that this reduces the risk of integration into a potentially, quote, ‘bad locus’; a locus that might be tumorigenic”—and

2. whether “additional preclinical studies” are needed “to assess the carcinogenic potential of a particular vector backbone-transgene target cell combination.”

These are technical questions concerning the protocols of the gene therapy trials and questions of the relationship between preclinical outcomes as they relate to results obtained in clinical trials. Dr. Wilson then informed BRMAC of the NIH Recombinant DNA Advisory Committee opinion that, “gene transfer was a cause of both leukemias and the occurrence of leukemia in this protocol is not a random event and constitutes an inherent risk in this study.” The NIH committee consequently recommended as guideline, “Pending further data or extenuating circumstances, retroviral gene transfer studies for X-linked SCID should be limited to patients who have failed identical or haploidentical stem cell transplantation” (FDA, 2003b). It is noteworthy that this recommendation is starkly in contrast to the French trial, which initiated gene therapy de novo, i.e., in individuals who did not first attempt the standard treatment of BMT.

What is immediately clear in the context of ethical reflection is that FDA's questions after disclosure of the second adverse event remained at the level of the science performed, not directly with questions as to how the ethical evaluation should proceed. As stated in committee, “So the specific question then we have, is this

1. [having a revised informed consent document and

2. plans for monitoring of peripheral blood cells for the clonality of vector integration—NKS] sufficient, or should additional conditions be placed on these trials.

We ask you to consider whether dose should be altered, whether we need to include additional pre-clinical studies, whether we need to look at the particular target cells, or have alterations in the vector design.” ⁷

In her report to the committee, Dr. Marina Cavazzana-Calvo from the French clinical trial provided updated information on follow-up of trial participants, noting that patient 4 (the child who initially suffered the adverse event) experienced “insertional mutagenesis with the aberrant LMO-2 expression,” though there was continuing work to rule out other factors (“such as aberrant clonal gamma-c signaling, the role of varicella-zoster infection, and genetic associativity to the cancer”). Patient 4 also had “no immunological reconstitution” following the adverse event and the initiation of chemotherapy, though the French team believes “that theoretically the persistence of gamma-c positive cells in bone marrow can be expected to restore or it could restore an immunological system.” Important to the effort to evaluate risk and to delineate the status of trial participant number 4 as “patient” or “research subject,” Dr. Cavazzana-Calvo conceded, “Naturally everybody prefers not to run any risk for the clinical status of this patient. And on the basis of the consideration that the appearance of this lympho proliferation with the characteristics of a high-risk one, we recommended to be as cautious as possible and to perform the bone marrow transplantation.” The therapeutic task for this patient at month 40, Dr. Cavazzana-Calvo reported, was “to treat the residual leukemic cells eventually persisting in bone marrow,” obtain complete remission, and then move to BMT.

In the second case of adverse event, Dr. Cavazzana-Calvo reported the patient presented “at month 34 with splenomegaly, an enlarged mediastinum, and a huge number of white blood cells, 80 percent of blast.” This patient was placed under chemotherapy, showing himself “much more sensitive [responsive] to chemotherapy than the first one;” even so, the French team was not prepared to conclude the chemotherapy had led to complete remission.

Since the assessment of benefit and risk between the standard BMT treatment and the experimental gene therapy treatment is important for the FDA/BRMAC's charge to provide some recommendation, in closing remarks Dr. Cavazanna-Calvo provided a pertinent comparison: When comparing immunological reconstitution in the two methods, it takes about “twelve months to obtain a protective number of the CD3 cells” from BMT “versus three months for the gene therapy-treated patient.” She also conceded that “the quality of the immunofunction” could be evaluated only after long-term follow up.

BRMAC was specifically concerned to assess risk/benefit in X-SCID type trials, with a sense for what this implies for other gene therapy trials such as for ADA-SCID. In his presentation before the committee, Dr. Claudio Bordignon disclosed favorable outcomes without adverse events, reporting that the available data on hematopoietic stem cell gene therapy for ADA-deficient SCID did not show an expansion of dangerous clonal integration, even when monitored over time. As for immunological reconstitution, Dr. Bordignon reported that they obtained “multilineage stable engraftment, and restoration of lymphocyte count, correction of humoral and cellular effect, correction of ADA activity and metabolic defects, clearly superior to mismatched transplantation, comparable, or at least comparable to matched transplant” (FDA, 2003b). Thus, these results support continuation of these trials at least with need to identify critical differences in protocol for the X-SCID trials.

In comments on European gene therapy studies related to X-SCID, Dr. Adrian Thrasher reported a 30% survival rate across Europe “for mismatched transplanting ADA SCID.” Since “preferative chemotherapy” is used “to achieve efficient or improve the B cell engraftment and T-cell engraftment,” Dr. Thrasher stressed the importance of accounting for the longer-term negative effects of chemotherapy in considering risk and benefit. When chemotherapy is employed in infancy, “there are clear effects documented on growth, fertility, possible developments of secondary malignancies later in life, and also neuropsychological effects, which may in-part at least be related to the use of chemotherapy” (FDA, 2003b).

Only after public comment had concluded was the committee reminded directly of the ethical context of their deliberations. What is clear from the ensuing discussion, however, is that BRMAC was first and foremost concerned with “the science” of gene therapy, and, at least in the context of real-time deliberation of committee, tended to reduce matters of ethics to a single question, viz., what documents of informed consent should report about adverse effects associated with gene therapy. Committee member Abbey Meyers, noting this restricted discussion, raised the question whether there should be a return to testing in animals rather than continuing the human trials. Stating explicitly that the principal concern of the scientists was “a potentially extremely important insight into oncogenesis,” committee chair Dr. Salomon conceived the ethical problem in a rather restricted sense:

But at the same time we acknowledged in October how important it was to keep the ethical issues, which … represents two sides of a coin … [On] one hand you have patients who are grievously ill or dying or have almost basically zero hope of being alive in two years. And you have patients who—or you have a community or a public that has other interests … should this stop now and not go forward into the clinical trials, and go back into the lab … One way we deal with it is in informed consent … But we are going to leave some time to try and maybe end on some of the ethical issues.” (FDA, 2003b) ⁸

The problem here, of course, is that the attention to oncogenesis dominated the discussion to the point of excluding a sustained engagement of the relevant ethical questions.

Pointing to a relevant factor in the assessment of harm, Dr. Kurtzberg reminded that SCID affects babies, physicians not having “the luxury” of waiting until these children are older, and that any recommendation to postpone could itself “cause harm,” thereby raising a further ethical question on the merits of treatment during infancy. On Kurtzberg's view, “Treating younger children is an obligation because of the diagnosis, not because of the safety of the situation,” meaning that harm to the patient is minimized when s/he is treated as an infant despite the safety (adverse event) issue (FDA, 2003b). The ethical point is not a trivial one, as Dr. Murray, the representative bioethicist on BRMAC, understood in pointing to the dilemma faced of “striking the right balance” between benefit to those subjected to the risk of clinical trial without certain benefit and the benefit that would likely accrue to other patients later consequent to those trials” (FDA, 2003b). But, of course, here, in the voice of the bioethicist on committee, we have the ethical questions once again limited to the requirement of informed consent, with an implicit argument in favor of proceeding with gene therapy trials. The argument given is that progress in the treatment of genetically transmissible diseases such as X-SCID is a value we ought to support given the desperate demand for cure; no progress in treatment would be made in the absence of human/clinical trials as opposed to laboratory studies; therefore, human gene therapy trials should continue—so long as the prospect of harm (e.g., leukemogenesis) is made abundantly clear to a human participant in any such clinical trial.

The argument, on the face of it, sounds convincing. But, in addition to a false second premise (false given that animal gene therapy studies—especially large animal research—often do and may provide the relevant predictive data ⁹ ), the argument does not fully capture the problem of risk in X-SCID gene therapy trials adequately. This latter point is made evident by Dr. Coffin's observations, which are worth citing in full to show why the above argument is to be rejected in the absence of further reasoning:

In the last discussion we had a fairly long discourse on denominators. When you have one out of nine that the real denominator could be a thousand or a million, and it could be a fluke; when you have two out of nine, the real denominator is nine.

And that is a hundred-fold, thousand-fold, change in one's thinking in a way. Because I think we can have some confidence that if this protocol were to be repeated exactly this way in another similar group of patients, we would be looking at exactly the same thing going forward.

And so I have a lot of trouble seeing — I'm wrestling with that. Before, I was quite enthusiastic about continuing these studies because of the likelihood that it really was a flukish experience.

But now I think we really have to come to grips with what we need to do and what steps need to be taken to try to prevent this from happening in the future.

You know, we are not going to send the space shuttles back up until we figure out what went on with the Columbia, and I don't — I think we would be derelict in our duty if we didn't make a real effort to come to grips with some technical way to deal with this, rather than just saying we should keep going along as we are. I don't think we can afford to do that at this point, with these kinds of studies at least. I mean, there are other kinds of studies we can consider.” (FDA, 2003b)

Dr. Coffin's remarks speak for themselves on the question raised by the bioethicist, Dr. Kurtzberg. It is important, then, that as the deliberation proceeded the committee yielded in its reasoning to the fact that the risk in the X-SCID gene therapy (“using the retroviral vector with the gamma-chain transgene and X-SCIDs with the JAK-3 deficiency, and the IL-7”) was simply not at an acceptably known level to allow such trials to proceed in the United States. At issue thereafter was the question, as Dr. Harlan put it, of whether “we should let informed consent be the arbiter or regulatory guidelines be the arbiter” (FDA, 2003b). This question is important insofar as patient/research-subject expectations are more trusting in the case of informed consent—“If it [gene therapy] is allowed, there is an implicit statement that doctors wouldn't even let me do this if they really thought that it was dangerous, or they didn't have some pretty good idea [about the danger associated with the therapy].” In other words, gene therapy of the sort performed in the French trial ought not be “first-line” of defense therapy so long as there is an alternative (e.g., BMT).

IV ENGAGING THE ETHICAL DIMENSION: THE THEORETICAL FRAME

It is clear from review of the transcript of deliberations of BRMAC's October 2002 and February 2003 meetings that engagement of the ethical dimension of X-SCID gene therapy research was limited to

1. some effort to gauge risk of adverse events, specifically leukemogenesis,

2. revision of informed consent documents so as to represent explicitly to recruited participants the fact of leukemogenesis, and

3. some general concept of avoiding harm consistent with the principle of nonmaleficence.

In both sessions there was a bioethicist present, but it was only in the February 2003 meeting that the affiliated bioethicist contributed comment, and even then this comment was limited in content and provided little ethical reflection so as to help shape the committee's eventual recommendation. Thus, I suggest that the criticism engaged by Lillehammer, noted at the outset of this paper, has some merit in the context of BRMAC deliberations on a substantive matter—that is to say, the presence of bioethicists at the BRMAC meetings was unproductive in the practical bioethical debate of those sessions. The ethical dimension of those deliberations remains to be engaged productively, consistent with the formal arguments posed at the beginning of this essay. I turn to those arguments now with a view to their application to the BRMAC deliberations. In doing so, my point is to show how bioethical reflection could contribute to real-time committee deliberation, provided those concerned with the science of the matter are prepared to assign the requisite time to that kind of discussion formally, rather than merely to privilege the scientific questions and relegate the ethical questions to subordinate status to be engaged at the close of discussions “if there is sufficient time left.”

First, we have the Kantian/Rossian formal argument, which I apply now specifically to the X-SCID trial. The initial conditional premise now structured is to be stated thus: If a recruited participant in a proposed X-SCID gene therapy trial is

1. adequately informed,

2. competent to consent (including here competence in the case of proxy consent, e.g., from parents/guardians of infants or children suffering from SCID), and

3. no alternative therapy to gene therapy is likely to be effective in the given case of that particular patient, then it is morally appropriate for the recruited participant to be given the opportunity to benefit from the gene therapy.

This conditional proposition places the researcher in the position of fulfilling several obligations. Let us consider each in turn.

1. At issue here is the question whether the recruited participant—actually the child's parents/guardians in the case of X-SCID gene therapy research—is being adequately informed. What does this entail in the actual practice of the clinical trial?

   In the 2002 BRMAC meeting, Dr. Blazar summarized that, in his view and practice, information in this kind of research entails “a long process of education” with “tapes sent” and

   “nurse coordinators that meet independently of the physicians to make sure there is as much ability to transmit information without having the direct care involved … [Thereafter] we have two sets of conferences, a conference on the out patient, a conference on the in patient, and the forms are typically ten to 12 pages long, and go through each of them in extraordinary detail to the point where people really don't want us to have gone into those kind of statistics, but we do anyway … [And] it's not done emergently. It's done several weeks before the patient might be transplanted.”

   This description of process reasonably satisfies the criterion of the recruited participant/parent/guardian being adequately informed; so that, as long as a process like this is implemented as part of the protocol proposed by a sponsor of a gene therapy trial in the USA, it can be safely said that the criterion is met within reason.

   In the case of X-SCID gene therapy trials, this information must be disclosive of the anticipated risk to the participant. BRMAC made it clear in the October 2002 recommendation that informed consent documents had to be explicit about the probable causal connection between the gene therapy and the adverse event of leukemogenesis. On the other hand, it is also clear from the February 2003 meeting that the data were in fact inadequate to get an adequate measure of the actual risk of leukemogenesis so as to provide some guidance to sponsors of similar trials proposed in the United States.

   This was Dr. Coffin's point about not knowing what “the real denominator” is, even though he opined, on the basis of a second adverse event in the French trial, “we can have some confidence that if this protocol were to be repeated exactly this way in another similar group of patients, we would be looking at exactly the same thing going forward” (FDA, 2003b). In short, Dr. Coffin's observation tells us that the recruited participant/parent/guardian must understand that the child undergoing retroviral gene therapy

   1. may end up having a leukemia-like disease (or some other long-term adverse effect, given that only longitudinal clinical studies would provide this information), even as

   2. the therapy is designed to achieve immunological reconstitution in that child; and

   3. it is clear that the child would not have leukemia except for being a recipient of the gene therapy.

   Adequate information about risk would also have to communicate to the participant/parent/guardian the likely treatment process for the patient in the event of an adverse effect like leukemogenesis. That is, in such an event the treatment would entail chemotherapy (with its already known side effects given clinical practices in pediatric oncology—viz., effects on growth, fertility, secondary malignancies later in life, neuropsychological effects), provided normally to the point of achieving remission of the leukemia-like disease, then treatment with haploidentical BMT in the hope of achieving some immunological reconstitution and active immune function.

   Adequate information about risk must also include some comparative assessment of the risk to the participant in the proposed clinical trial from the experimental treatment in contrast to the risk associated with the standard treatment, viz., BMT. A child having a definitive diagnosis of X-SCID is, as a patient, normally to be offered the standard treatment of BMT, either HLA-identical or haploidentical stem cell transplantation. BRMAC's discussion of the data included some effort to gauge this comparative risk. Thus, the recruited participant/parent/guardian would have to be informed that:

   1. transplantation yields about a 75%–80% rate of success for T-cell function (in US centers of treatment such as at Duke University facilities, though rates worldwide are lower, at 30%–50%);

   2. low correction of B-cell function would entail IVIG replacement for the lifetime of the patient;

   3. the cost of transplantation ranges from a low of $50,000 to $200,000, excluding cost of IVIG post-transplant;

   4. quality of life for a surviving BMT recipient will be manifest by the continuing IVIG dependence, recurrent infections, growth retardation, nutritional problems, and lung disease in some X-SCID BMT recipients;

   5. achievement of a protective number of CD3 cells from BMT takes about 12 months in contrast to 3 months for the gene therapy treatment;

   6. the time frame, whether 3 months or 12 months, for the protective number of CD3 cells does not translate automatically to actual immune function, so that

   7. the infection that led to the definitive diagnosis of SCID may itself be fatal before either the BMT or the gene therapy achieves immunological reconstitution and actual immune function.

   I conclude that only if the recruited participant/parent/guardian understands all of the foregoing is there “adequate” information provided and a reasonable basis for “informed” consent demonstrated in the given clinical trial.

2. The second criterion concerns competence on the part of the recruited participant/parent/guardian to consent to participate in the clinical trial as a research subject.

   Clearly, competence is a function of the individual's manifest common sense, basic formal education, and the process employed within the proposed trial itself to satisfy criterion (a) above on the task of providing adequate information as to anticipated risk and benefit. However, competence is also a function of the parent/guardian's degree of trust in the researcher/clinician's approach to the decision at hand. As Dr. Harlan observed, in the case of SCID patients in particular, where parents face a desperate situation of finding treatment within the first year of life of the newborn (without which treatment death of the child is imminent), parents/guardians are likely to think “that doctors wouldn't even let me do this if they really thought that it was dangerous… .” This implicit faith or trust in the clinician as clinician must be taken into account such that researchers determine that the parent/guardian is competent to distinguish between

   1. the interest of the clinician to be nonmaleficent and beneficent to the patient being provided reasonable treatment, consistent with standards of practice, and

   2. the interest of the researcher to evaluate both risk and benefit in a human research subject being provided an experimental treatment that is by definition outside of the extant “standard” of practice.

   Recall Dr. Noguchi's remarks in response to Dr. Harlan's reminder of the obligation of physicians to “do no harm.” Dr. Noguchi claimed that a clinical trial is conducted such that “the outcome is not predicted and it cannot be known.” On the face of it, I submit, the claim is false. A clinical trial, including retroviral gene therapy, proceeds in virtue of its experimental protocol on the basis of a hypothesis as to various intended effects of the recombinant-DNA procedures employed; and, presumably, the trial seeks to falsify the hypothesis and/or obtain data supporting the hypothesis as to the predicted outcome of the experimental therapy in the particular subject (but also in the trial cohort). Thus, while the outcome cannot be known with certainty in light of the ineradicable chance of adverse events, the protocol and norms of clinical practice relevant to the clinical trial do inform as to predicted outcome to some reasonable degree of probability.

   In this sense, then, I submit that the dichotomy Dr. Noguchi presented is itself a false dichotomy (“Are we talking about medical treatment? Are we talking about clinical trials?”). The fact is that when retroviral gene therapy is introduced de novo (as in the French trial) or as an alternative to BMT, such therapy is indeed medical treatment, experimental yet treatment nonetheless. The recruited participant is first and foremost a patient and only secondarily a research subject. It is the desperate status of the X-SCID child that leads the parent/guardian and referring physician to attempt the experimental treatment, presumably in light of what is already known by comparison about the risks and benefits associated with the standard BMT treatment. Accordingly, I conclude that the principle of nonmaleficence cannot but remain a relevant operative guideline in retroviral gene therapy trials for X-SCID in sorting out the obligation the clinician has to the patient and the obligation the researcher has to the research subject as patient.

   Only to the extent the foregoing items are engaged can one say that the researchers have properly determined the competence of the participant in providing relevant consent.

3. The third criterion poses the issue of effective therapy alternative to the proposed gene therapy.

   Here, obviously, the question of efficacy of treatment depends on being clear about the particular patient's medical history, taking into account age at presentation, presence or absence of infections prior to recruitment to the clinical trial, whether the standard BMT treatment has been attempted at all or attempted and failed, etc. The way this criterion is formulated, I submit it is clear that de novo application of gene therapy is not acceptable (as occurred in the French trial), but rather that the patient ought to be considered for the standard BMT treatment first and considered for the experimental treatment only in the case in which the standard treatment fails. In the case of X-SCID, the risk and benefit of the standard BMT treatment is already adequately documented such that a clinician is able to evaluate in the particular case the likely efficacy of BMT anterior to any consideration of an experimental treatment such as retroviral gene therapy.

In short, on the line of reasoning above on items (a), (b), and (c), I claim that retroviral gene therapy trials proposed by sponsors in the USA would have to demonstrate compliance with the above criteria if such clinical trials are to authorized anew or released from clinical hold by FDA. Only with this compliance demonstrated could it be concluded that retroviral gene therapy trials are morally appropriate for those individuals recruited as participants.

I turn next to the formal Argument No. 2 in its application to X-SCID gene therapy. Here the conditional proposition is now stated such that: If the hazards of the retroviral gene therapy are great or completely unknown, then it is doubtful whether the parent/guardian would be justified in risking the life of the child qua patient. The task at hand for the researchers (and, for the BRMAC members, as a matter of policy oversight) is to answer the empirical question: Are the hazards of the retroviral gene therapy either “great” or “completely unknown?” As the reader will realize, this question presupposes settlement on a prior question as to what methods are employed to garner information about hazards. This latter question is answered first with reference to the evidence available from pre-clinical studies, either in vitro or in vivo in animals, then with reference to any clinical trials conducted worldwide but not subject to FDA oversight. Both types of empirical evidence are available. The fact of two adverse events in the French trial is, of course, already in evidence, the hazards of which have already been considered. This leaves other gene therapy trials using retroviral vectors either in other forms of SCID (e.g., ADA-SCID) as well as the preclinical evidence. Let us consider some of the pre-clinical evidence first insofar as it contributes to settling the empirical question that is essential to adducing a conclusion in Argument No. 2 above.

In her presentation before BRMAC at the February 2003 meeting, Dr. Cavazzana-Calvo summarized the pre-clinical basis for approval of the French trial. The French scientists involved in this research and two other research groups worldwide “demonstrated … that the B-lymphocyte transformed by EBV [Epstein-Barr virus], derived from the patient and the gamma-c negative, can be efficiently transduced” by the retrovirus vector used in the French trial. This team also demonstrated “almost in vitro that the CD34 positive cells gamma-c negative, obtained from the patient at the time of general anesthesia through the central line, can be efficiently transduced in vitro and can restore, almost in vitro, NK and T-cell differentiation.”

A parallel “knockout mouse model” demonstrated “no toxicity.” In this study, “the survival curve of treated animals in comparison with non-treated animals” was such that “Non-treated animals in the standard animal facilities died within 15 weeks,” whereas “treated animals” were observed for “primary transplantation up to 47 weeks and the animals show[ed] no toxic effect” (FDA, 2003b). Transplantation of cells from “the primary transplantation of eight-weeks-old aged animals” into “secondary mice” demonstrated “the efficacy of the transduction of the stem cells,” with “ correction of animal disease with no toxic effect” (FDA, 2003b). Thus, the pre-clinical results showed reasonable promise for French authorities to approve the clinical trial. The absence of toxic effects in these pre-clinical studies allowed one to conclude that, ceteris paribus, there was a low probability of toxicity as a hazard for human participants in an analogously designed clinical trial. There were apparently no adverse events detected in the animals observed up to 47 weeks, thus leading one to conclude that there was a low probability of an adverse event (such as insertional mutagenesis) occurring in human trials. (Dr. Cavazzana-Calvo also reported that there are transgenic mice for gamma-c under a CD2 promoter, important because “the mice did not develop any leukemia.”)

The report by Dr. Claudio Bordignon at the February 2003 meeting also included data from pre-clinical studies, this overall research effort concerned with ADA-SCID. Pre-clinical data on animal models in this group were published in 1990. Other pre-clinical studies that included follow-up observation “with several secondary and tertiary transplant recipients” over weeks led to a claim of “all the animals appear[ing to] have a normal hematopoiesis” with “cumulative data on over 300 animals transplanted with hematopoietic stem cell, and transduced with delta-LNFGR-coding vector” revealing “no adverse event, with normal engraftment, persistence of differentiation of transduced cells, secondary and tertiary successful transplants” (FDA, 2003b). Dr. Bordignon reported that, “risk of oncogenic transgenic transformation by transduction with this vector system is less than 1 in 10 to the 9^th events” (FDA, 2003b). Thus, the pre-clinical data suggest no great hazard for the type of gene therapy proposed for ADA-SCID human trials. For their clinical trial Dr. Bordignon reported all patients “doing clinically well with normal growth and development. Gene therapy with CD34 cells, combined with mild myeloblation, is safe and efficacious as a single therapy” (FDA, 2003b). Hence, there has been good reason to expect reasonably positive results from retroviral gene therapy for both X-SCID and ADA-SCID clinical trials.

The foregoing review leads me to conclude on the empirical question raised above (whether the hazards associated with X-SCID gene therapy are great or unknown) that pre-clinical studies revealed no great hazard. Accordingly, a parent/guardian having this information as part of the process of informed consent would have good reason, thus reasonable justification, to risk the life of the child in the proposed experimental therapy such as has been delivered in the French clinical trial.

Before turning to the formal Argument No. 3 presented at the outset, I turn briefly to note developments from meetings of the NIH Recombinant DNA Advisory Committee in February 2003 and of BRMAC in March 2005.

V THE NIH RAC SESSION

Meeting on February 10, 2003, the NIH Recombinant DNA Advisory Committee considered the 2002 and 2003 events associated with the French trial (NIH/RAC, 2003). Reviewing the purpose and objectives of the meeting, committee chair Dr. Theodore Friedman commented, there was “an urgent need to determine the mechanisms responsible for the leukemia, to improve the technology, and to devise more effective and safe approaches to future studies” (NIH/RAC, 2003). It was noted in the presentation of data from the French trial that the two children were “atypical” in their clinical presentation, though “the immunophenotype” was not atypical. After other technical data were reviewed, the committee engaged various “points to consider,” among these being one question on risk and one question on informed consent, which the committee formulated thus: “How should the assessment of the balance of potential benefits and risks in these protocols [i.e., for ongoing SCID studies and for ongoing other gene transfer studies using retrovirus vectors—NKS] be modified in light of our understanding of these two cases?” “What new information needs to be communicated to participants in ongoing protocols, prospective participants in new protocols, and participants who participated in trials closed to further enrollment and even beyond the protocol defined follow-up period?”

During discussion several of those present engaged the question of acceptable risk, the various positions manifesting clear differences of opinion about the purpose of phase I clinical trials even as there was ambiguity about the status of human research subjects as patients. Dr. Bernard Lo (professor of medicine and director of the program in medical ethics at the University of California San Francisco) pointed to the problem of evaluating “the risk in different types of retroviral vector protocols” (NIH/RAC, 2003, p. 13). Such protocols vary in risk relative to each other for research participants, presumed to be acceptable in the case of those who have no therapeutic option, including BMT. Committee member Terry Kwan remarked that any such trial had to have some promise of “a reasonable expectation” of benefit, “if not directly to the participant, then to future participants or to advance the field” (NIH/RAC, 2003, p. 14).

This opinion contrasts in part with that of Dr. Richard P. Junghans, who argued, “benefit to the participant is not a consideration in Phase I clinical trials. The motivation for participants must be that they are contributing to research that likely will not help them, but may help many patients in the future. Phase I trials cannot be given the burden of justifying the treatment of individual patients” (italics added). Dr. Dale Hammerschmidt (Director of Education in Human Subjects' Protection at the University of Minnesota) likewise sees risk acceptable “for altruistic reasons” so long as “researchers believe that the risk is not unreasonable for an individual to bear,” in which case “a clinical trial may be acceptable” (NIH/RAC, 2003). These points of view, emphasizing research results that allow risk without immediate or likely benefit to the human subject of the clinical trial, look to future benefit as the relevant ethical criterion for deciding the acceptability of such research.

In contrast, Dr. Ricardo Sorensen (professor and chair of pediatrics at Louisiana State University Health Sciences Center) opined in no uncertain terms, “gene transfer can no longer be justified for the treatment of SCID until more is known,” e.g., doing more in vitro experiments “to increase knowledge about insertion sites and secondary events” (NIH/RAC, 2003). Dr. Sorensen's statement is especially weighty given his perspective issuing from the practice of pediatric medicine and having the interest of the pediatric patient in mind rather than the particular disease process such as oncogenesis as such. It is this distinction—between the scientific concern for the disease process of oncogenesis and the therapeutic concern for patient benefit—that is pertinent to

1. Dr. David Harlan's (chief of transplantation and autoimmunity branch, NIH/NIDDKD) recommendation, “that patients with X-linked SCID should not be referred to this kind of clinical trial unless they already had a stem-cell transplant or that would not be available,” and

2. Dr. Baruch Brody's (director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine) proposal, “that pediatric regulations include specific language that states that inclusion in such clinical trials should be allowed only if there is no alternative therapy with a more favorable risk-benefit ratio” (NIH/RAC, 2003).

In short, proper assessment of risk/benefit is not merely about understanding oncogenesis with a view to altruistic benefit to future generations; the ethical assessment must keep attention to the human participant who is first and foremost a patient in need of therapy, whether standard treatment or experimental such as that of gene therapy.

The committee concluded its deliberations with a unanimous recommendation: “Pending further data or extenuating circumstances, reviewed on a case-by-case basis, retroviral gene transfer studies for X-linked SCID should be limited to patients who have failed identical or haploidentical stem-cell transplantation or for whom no suitable stem cell donor can be identified” (NIH/RAC, 2003). This recommendation was approved by the NIH director and adopted as NIH policy.

VI THE MARCH 2005 CTGTAC (BRMAC) SESSION

The March 2005 meeting of the committee (BRMAC renamed as the Cellular, Tissue and Gene Therapy Advisory Committee) concerned the death of one of the children who suffered the leukemogenic event (death due to relapse of leukemia following BMT), a third child developing the leukemia-like condition (“uncontrolled T lymphocyte proliferation,” detected at 32 months post-transplantation), as well as two reports of tumorigenesis in preclinical studies. ¹⁰ The latter included the death of a rhesus macaque six years following transplantation of retrovirally-transduced (CD34 +) cells, as well as a report on retroviral vector-mediated insertional mutagenesis in mice. “[The] monkey is reported to have had widespread myeloid sarcoma, with myloperoxidase positive tumor cells infiltrating many organs (liver, kidney, skin, choroids plexus), despite the absence of blastic cells in the peripheral blood” (Kelly, 2003).

In the case of the mice models, it was reported that, “results from a preclinical study … indicate that the gamma-c transgene may play a cooperative role in tumorigenic process” (FDA, 2005). Statistical analyses were “suggestive of a ‘co-selection,’ rather than a random event,” with “previous studies indicating that the identification of ‘co-selected’ genes often correlates with a cooperative effect in inducing leukemia.” It was observed “that the mouse tumor has activation of LMO2 gene transcription in the absence of any obvious dysregulation of ll2rg is analogous to what had been observed in the first two patients where LMO2 was transcriptionally activated without evidence of dysregulation of cell activation pathways due to gamma-c expression” (Dave, Jenkins, & Copeland, 2004, p. 303).

Despite these pre-clinical data and the third leukemogenic event in the French trial, committee chair Dr. Mahendra Rao opined, “The additional data hasn't suggested that there's a heightened risk …” ( Baltimore Sun, 2005), even as the committee recommended restriction of gene therapy in cases of X-SCID “to those who have no alternative” ( New York Times, 2005). I submit that, clearly, the latter recommendation places additional restriction on retroviral gene therapy for X-SCID precisely because there is heightened risk, given both the third leukemogenic event in the French trial and the preclinical evidence from the rhesus macaque and the mice models. That evidence, I submit further, changes the estimate of risk substantially so as to make it morally probative for decisions about similarly proposed trials in the United States, even if the assessment of risk is narrowly interpreted within the context of the protocol followed in the French trial.

VII ARGUMENT NO. 3

We can turn now to the formal Argument No. 3, now structured with reference to the gene therapy trial, and which links in form to the CTGTAC (BRMAC) and NIH/RAC efforts to assess risk and benefit in retroviral gene therapy. Once again, in the context of X-SCID gene therapy trials, the argument premises:

1. If the outcome of retroviral gene therapy for a given patient suffering from X-SCID can be reasonably expected to produce more benefit than harm, then the retroviral gene therapy might be considered justifiable.

2. If we assume a given patient suffering from X-SCID is likely to die anyway (within the first year of life, as is generally the case for X-SCID infants), that in itself might be enough to warrant the use of retroviral gene therapy.

3. Each case of X-SCID treated with retroviral gene therapy is likely to contribute to increased understanding (etiology, diagnosis, treatment, prognosis) and to benefit others suffering from X-SCID, tending to support the use of retroviral gene therapy, even in cases in which it is of doubtful help to the individual.

Premise (1), of course, depends on sorting out the empirical data as to whether retroviral gene therapy such as undertaken in the French trial reasonably predicted an outcome of more benefit than harm; and premise (2) depends on identifying the known infant morality rate for X-SCID patients generally (and thus for recruited participants to the phase I clinical trials).

My review of the transcripts of the CTGTAC and NIH/RAC meetings leads me to believe that prior to the adverse events in the French trial there was sufficient reason to predict (from pre-clinical studies) more benefit (immunological reconstitution, survival beyond the first year) than harm (toxicity, tumorigenesis, leukemogenesis) from retroviral gene therapy, such that use of such therapy in a clinical trial was at the time justifiable. Thus, the first premise of argument no. 3 is reasonably to be accepted. Premise (2) fails, however, given that while we can assume X-SCID infants are likely to die anyway within the first year of life, the option of the standard HLA-identical or haploidentical BMT treatment interposes to require that the standard treatment be provided before the experimental treatment be undertaken, with the gene therapy option to be pursued only in the case of a failed BMT. This was not the case in the French trial. As for premise (3), surely it is to be granted that infants recruited as participants in X-SCID retroviral gene therapy trials would likely contribute to increased understanding and benefit others; however, arguments I have presented above concerning informed consent remain pertinent such that those elements identified must be surmounted by any proposed protocol before any “altruistic” motive of participation is to be warranted and thus said to justify the proxy consent provided by parents/guardians of X-SCID infants. Indeed, I submit that CTGTAC (BRMAC) and NIH/RAC committee deliberations make it clear that altruistic motivations for consent are not sufficient reason for participation in such trials given the option of the standard treatment and given the need to assess the risk more carefully consequent to leukemogenic events. Hence, Argument No. 3 is not compelling. Said otherwise, the utilitarian argument in favor of X-SCID retroviral gene therapy fails to compel one's assent on the basis of the premises adduced.

VIII CONCLUSION

In the foregoing presentation of argument, I have attempted to demonstrate the sort of contribution a philosopher/bioethicist might offer in practical bioethical debate concerning a current experimental therapeutic option. As my review of the CTGTAC (BRMAC) and NIH/RAC meeting transcripts and minutes shows, committee members attended far more to the particulars of the science than they did to the evaluation of the ethical issues. The latter even then was restricted to improvement of informed consent documents and trying to gauge the degree of risk insofar as adverse events in the French trial heightened this concern. The NIH/RAC discussion was notable for the fact that there was more vocal presence of bioethicists who contributed to the proposed recommendation of the panel, in contrast to the CTGTAC (BRMAC) meetings at which apparently only one bioethicist was present and, in each meeting, provided limited comment (no transcribed comment in the 2002 meeting).

It may be argued on behalf of the committee's performance, as represented in transcript, that:

1. the “real-time” deliberation of a policy review committee is different in kind from the sort of ethical reflection carried out here in hindsight;

2. precisely this difference has to be taken into account in any judicious evaluation of the work of such a committee; and

3. when this difference is taken into account, the CTGTAC (BRMAC) cannot in all fairness be faulted for the degree to which the points of ethical deliberation reviewed here were not explicitly engaged or otherwise subordinated to questions of basic science and clinical evidence in the French gene therapy trial.

I, for one, readily grant the first and second premises of the foregoing argument. Statement (3), however, does not follow. I submit that the philosophical evaluation presented herein is itself a demonstration of the kind of bioethical evaluation that could have been provided at the CTGTAC (BRMAC) and NIH/RAC meetings.

The point turns on a question of committee procedure. There is ample reason to recommend FDA/CTGTAC (BRMAC) consider revising its procedure and agenda, so that

1. there is more balanced representation of bioethicists on the committee with explicit effort made to engage and solicit such specialist commentary throughout the course of the day's deliberations, as well as

2. dedicated engagement of the ethical issues as a central (rather than ancillary) part of the penultimate discussions of the committee en route to final recommendation.

For example, while there may be ready obstacles to getting the logistics straight, CTGTAC meetings could be held over two-working days, structured such that the first day is devoted to reviewing the relevant empirical data (pre-clinical and clinical) much as occurs now, with the second day assigned to engagement of the pertinent ethical issues. Transcripts of the previous day's meeting can be made available to all committee members, providing the relevant information pertinent to ethical reflection such as has been carried out in this article.

If the ethical reflection carried out here is even provisionally a sign of the sort of deliberative contribution a bioethicist may make to a policy recommendation, with CTGTAC bioethicists prepared to contribute in like manner in the work of the committee, there is good reason to think that such bioethical evaluation would contribute substantively to

1. the quality of the committee's final recommendation and

2. public confidence in FDA oversight of retroviral gene therapy sponsored in the United States as a potentially corrective treatment for X-SCID.

Recall that, at the outset of this article, I set forth the guiding orientation of ethical reflection applied to biomedical research: If our actions are guided by a particular theory, then we can explain our actions by demonstrating that the principles of the theory

1. required us to act as we did, or

2. permitted our actions (understanding here that “explanation” includes “justification”).

I emphasize here the word “demonstrating,” since the act of demonstration connotes explicit rational deliberation, relevant argument structure, and choice relative to conclusions adduced. My review of the CTGTAC meetings disclosed no explicit appeal to the authority of ethical theory in sorting out the evidence en route to a policy recommendation, hence no evidence that ultimately the committee's recommendation, as the action taken by the group, was guided by a pertinent theoretical framework. While there was some reference to ethical principles (e.g., the principle of nonmaleficence), there was no systematic endeavor to assure that principles of a theory (utilitarian, deontological, etc.) required or at least permitted the recommendations issued by the committee in its policy oversight of gene therapy trials to be conducted in the United States. Yet, such a “demonstration,” albeit incomplete in the structure and content of extended argument, would significantly add to the public warrant of the committee's recommendation, especially given that such recommendations are issued with a view to assuring research integrity in the conduct of clinical trials. This case-study has been undertaken with a view to illuminating one way in which assurances to the public can be enhanced.

ACKNOWLEDGMENTS

I hereby acknowledge my gratitude to anonymous reviewers for the journal, who contributed generous constructive comments with very helpful recommendations for revision. I have worked to revise the present article with those recommendations at hand, though clearly I alone am responsible for errors of substance and style that remain.

Notes

1. SCID—severe combined immune deficiency disorder—sometimes called “bubble boy disease,” is a genetic disorder caused by a defect on the X chromosome. Stated technically: “XSCID is a distinct immunodeficiency characterized by failure of both humoral (antibody or B cell) and cellular (T cell) components of the immune system. Affected patients develop failure to thrive and chronic and recurrent infections by 6 to 9 months of age. In the past, infants with XSCID did not survive, but now bone marrow transplantation can restore immune function and rescue the great majority of patients. XSCID is caused by mutations in IL2RG, a gene encoding the gamma chain of the interleukin-2 receptor, also called the common gamma chain. Because IL2RG is located on the X chromosome, XSCID disease is seen only in boys, although girls can carry a copy of the gene on one of their two X chromosomes and can pass it on to their children. Identification of IL2RG as the XSCID gene allows for precise diagnosis by finding a specific harmful change, or mutation, in the gene in each affected family. When the mutation is known, it is possible to test female family members for carrier status and to perform fetal diagnosis during pregnancy.” The latter is from Jennifer M. Puck and Ronald M. Green, “X-Linked Severe Combined Immunodeficiency (XSCID) Family Workshop Report,” Conference on X-Linked Severe Combined Immunodeficiency (XSCID), April 18 – 19, 1997, Bethesda, Maryland, Office of Rare Diseases, National Institutes of Health. It is also to be noted, according to Dr. Puck, that, “No one knows what the incidence of SCID is. We presume that it's on the order of one in 50,000 to one in 100,000 births, but we also recognize it's under-diagnosed because babies die of infections before being recognized.”

2. The committee has since been renamed the Cellular, Tissue and Gene Therapy Advisory Committee.

3. Slightly modified from text, with argument structure provided by me.

4. Slightly modified from text, with argument structure provided by me.

5. Slightly modified from text, with argument structure provided by me.

6. Those involved in the trial considered other possibilities for the aberration, e.g., genetic predisposition, “a pedigree for medulloblastoma in the family of this patient with one sibling, as well as one distant relative on having this disease.” The age of this particular patient—one month of age at treatment—could also have been a factor causally in predisposing for an adverse event.

7. Dr. Marina Cavazzana-Calvo reported in the February 2003 meeting of BRMAC that the two children having the adverse event had received between 40–44 million CD34 cells per kilo, patient 4 receiving 8 million gamma-c transduced cells (CD34 negative) and patient 5 receiving 20 million gamma-c transduced (CD34 negative) cells; the French team was more concerned with “efficacy” than with “toxicity” at the time.

8. Near the end of the day's deliberations, Dr. Salomon offered his position on recommendation to be, “I am not comfortable at this point going forward with these cases anymore, using gene therapy. I am okay with doing it if you can convince me that there is no alternative therapy. I am okay with that caveat.” Comparing the known risk in BMT to risk in gene therapy, Dr. Salomon added: “At this point, I don't know anymore what the risk of gene therapy is in these kids. I really don't know today.” Dr. Salomon stated at a point later in the discussion: “Now, in this particular case, I am saying that we need about two more years before I can say how safe this therapy is. And until then, regardless of its incredible benefit which I acknowledge to everyone, I am not comfortable supporting it any longer, unless there is no alternative.”

9. Obviously, given the mortality that occurs in the first year of life with SCID, there are those who will argue that one cannot afford extended time commitments to preclinical studies. Dr. Jeffrey French commented at the meeting, “I have not seen anything today thus far that really shows that those studies in mice that tried to address safety were done to the extent where you could come to a conclusion about the actual safety.” Clearly, if preclinical phases of SCID gene therapy research are not carried to that level of data potential, gene therapy trials involving human participants are rendered all the more questionable, especially when adverse events such as leukemogenesis occur very probably as a direct cause of the therapy. This is so even when accounting for the fact, also reported by Dr. French, that one can spend six years and $50 million to work out applicable animal models “to try to determine a pre-clinical safety assessment.” This point relates to Dr. Kurtzberg's statement that, “If this was an oncology study, you would say we have met a stopping rule. We need to sit down and figure out if we can make this safer and have a hypothesis about how to do that and then reopen the study with whatever that change may need to be.” The point is that there is sufficient reason to halt the gene therapy given the availability of the standard (specifically, haploidentical) BMT treatment.

10. Food and Drug Administration, CTGTAC, March 4, 2005. The transcript of the session was not available for consultation at the time this article was written.

Food and Drug Administration, Center for Biologics Evaluation and Research, Biological Response Modifiers Advisory Committee (BRMAC), 33^rd Meeting, Thursday, Transcript. (2002, October 10)

Food and Drug Administration, Press Office, FDA Talk Paper. (2003a). FDA Places Temporary Halt on Gene Therapy Trials Using Retroviral Vectors in Blood Stem Cells, T03–04. (2003, January 14)

Food and Drug Administration, Center for Biologics Evaluation and Research, Biological Response Modifiers Advisory Committee. (2003b). 34^th Meeting, Friday, Transcript. (2003, February 28)

Food and Drug Administration, Cell Tissue, Gene Therapy, Advisory Committee, Meeting No. 38, Update on Retroviral Vector-Mediated Tumorigenesis in Gene Transfer Clinical Trials. (2005, March 4)

U.S. Department of Health and Human Services, Public Health Service, National Institutes for Health, Recombinant DNA Advisory Committee (RAC), February 10, 2003 Meeting Minutes. (2003, February 10)