Stable Ethics: Enrolling Non-Treatment-Refractory Volunteers in Novel Gene Transfer Trials

The vast majority of human gene transfer experiments have been tested in patients suffering from advanced, treatment-refractory diseases. Until recently, some jurisdictions actually restricted gene transfer trials to “disorders that are life threatening or cause serious handicap and for which treatment is either unavailable or unsatisfactory.”1Health Departments of the United Kingdom, Gene Therapy Advisory Committee (1995) First Annual Report: November 1993–December. GTAC Secretariat, London1994Google Scholar However, some of the best opportunities for advancing knowledge have involved diseases for which standard, if suboptimal, medical interventions are available. One example is adenosine deaminase–severe combined immunodeficiency disease, which has been tested in subjects whose disease is controlled by enzyme replacement. Another is hemophilia, which has been tested in subjects eligible for factor replacement. Other diseases that have been (or might be in the near future be) targeted in gene transfer protocols, but that can be medically controlled, include α1-antitrypsin deficiency, Gaucher's disease, recent-onset type 1 diabetes mellitus, arthritis, and early-stage Parkinson's disease. For the most part, medically stable volunteer trials in gene transfer have had a good safety record. The exception, of course, is the ill-fated trial at the University of Pennsylvania testing adenoviral vector in volunteers with partial ornithine transcarbamylase (OTC) deficiency. At the outset of that trial and in its aftermath, many critics questioned the decision to enroll stable volunteers. The purpose of this commentary is to propose recommendations for investigators contemplating first-in-human trials of novel interventions that involve medically stable subjects. All major research ethics codes require a favorable balance of risks and benefits.2US Food and Drug Administration. Code of Federal Regulations, 45 CFR 46Google Scholar,3World Medical Association Declaration of Helsinki (2000) <http://www.wma.net/e/policy/b3.htm> Accessed 14 June 2006Google Scholar Conventionally, benefits divide into two categories: those to society (aspirational benefits) and those for the subject (direct benefits).4King NM Defining and describing benefit appropriately in clinical trials.J Law Med Ethics. 2000; 28: 332-343Crossref PubMed Scopus (199) Google Scholar A given protocol can be reconciled to this requirement by two broad strategies. First, investigators can modify their study design by proposing a less ambitious approach (thus reducing risks) or honing the protocol's capacity to test a particular hypothesis (thus heightening the probability that the study will contribute important societal benefits). A second strategy is to select subjects in a manner that improves a given protocol's risk–benefit balance. Many gene transfer trials do this by enrolling subjects with advanced, treatment-refractory illnesses. This “oncology subject selection” strategy reduces risks because there is less opportunity cost for advanced patients enrolling in such studies, and risks of study participation are likely to be comparable with those of receiving off-label, nonstandard curative treatments. Such trials offer small but non-negligible direct benefits as well.5Horstmann E McCabe MS Grochow L Yamamoto S Rubinstein L Budd L et al.Risks and benefits of phase 1 oncology trials, 1991 through 2002.N Engl J Med. 2005; 352: 895-904Crossref PubMed Scopus (378) Google Scholar However, the oncology approach presents several ethical challenges. First, there is extensive evidence that subjects entering such studies overestimate benefits or fail to understand that they are entering research studies and, hence, provide invalid informed consent.6Daugherty CK Banik DM Janish L Ratain MJ Quantitative analysis of ethical issues in phase I trials: a survey interview of 144 advanced cancer patients.IRB. 2000; 22: 6-14Crossref PubMed Scopus (120) Google Scholar,7Daugherty C Ratain MJ Grochowski E Stocking C Kodish E Mick R et al.Perceptions of cancer patients and their physicians involved in phase I trials.J Clin Oncol. 1995; 13: 1062-1072Crossref PubMed Scopus (428) Google Scholar Other commentators worry that these studies interfere with a healthy dying process.8Miller M Phase I cancer trials: a collusion of misunderstanding.Hastings Cent Rep. 2000; 30: 34-43Crossref PubMed Scopus (128) Google Scholar With respect to aspirational benefits, data collected from oncology-type studies are often confounded by the subject's underlying illness and pretreatment. “Healthy-volunteer” studies, which have occasionally involved viral gene transfer,9Marshall E Panel approves gene trial for “normals.”.Science. 1997; 275: 1561Crossref PubMed Scopus (3) Google Scholar present an obverse set of ethical challenges. Here, many consent concerns are allayed, as are many (although not all) validity concerns. The main ethical limitation for healthy-volunteer studies involving novel interventions is the impossibility of direct medical benefit. To paraphrase the ethicist Robert Levine,10Levine RJ Ethics and Regulation of Clinical Research. Yale University Press, New Haven, CT1986Google Scholar such studies offer subjects an infinite ratio of risk to benefit, which is difficult to square with the investigator's fiduciary obligation to act in the best interests of his or her subjects. In many ways, medically stable volunteer studies provide auspicious circumstances: they sometimes (although not in the case of the University of Pennsylvania OTC study, and not in cohorts assigned to receive subtherapeutic doses) provide subjects access to a possibly superior means of treating their disease. Concerns about consent are diminished because subjects are not impelled to participation by medical necessity. Finally, a particularly attractive ethical feature is that, unlike the often indifferent, remunerated “healthy volunteer,” the moral objectives of stable subjects are more likely to align with those of the investigators.11Jonas H Philosophical reflections on experimenting with human subjects.Daedalus. 1969; 98 (2nd edn): 219-247Google Scholar Nevertheless, “stable-subject” studies recapitulate the difficulty of healthy-volunteer studies in that they put at risk a volunteer's stable medical status so as to advance the interests of others. Risks to stable subjects might include those relating to their condition (e.g., induction of an immune response that inactivates protein replacement therapy) or those totally unrelated (e.g., a malignancy). As such, the decision to pursue novel intervention trials in stable and healthy volunteers is fraught with ethical contention. Perhaps one measure of this is that when subjects with advanced renal cell carcinoma are injured in phase I trials, the public takes little notice. The same cannot be said when normal or medically stable volunteers are involved. Determining whether a stable-volunteer trial has a favorable risk–benefit balance will involve at least two steps. The first is assessing the study's risks. The second involves determining whether the benefits of the study justify exposing a medically stable patient population to such risks. The former presents a formidable challenge in novel gene transfer protocols, where difficulties in modeling immune responses, nonlinear dose-toxicity curves, uncertainties about the comparability of reagents across trials, and significant patient variability in response potentially undermine the confidence of risk estimates.12Kimmelman J Recent developments in gene transfer: risk and ethics.BMJ. 2005; 330: 79-82Crossref PubMed Scopus (70) Google Scholar On several occasions, innovative gene transfer strategies have been tested first in stable volunteers. For example, the first hepatic administration of adeno-associated virus vectors,13Manno CS Pierce GF Arruda VR Glader B Ragni M Rasko JJ et al.Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by host immune response.Nat Med. 2006; 12: 342-347Crossref PubMed Scopus (1578) Google Scholar the first attempt to use a highly deleted adenoviral vector to human subjects,14Recombinant DNA Advisory Committee. Minutes of meeting, 25–26 September 2000, pp 19–24 http://www4.od.nih.gov/oba/rac/minutes/Sept00RACMin.pdf (last accessed 24 September 2007)Google Scholar and the first intravenous administration of a retroviral vector15Powell JS Ragni MV White GC Lusher JM Hillman-Wiseman C Moon TE et al.Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion.Blood. 2003; 102: 2038-2045Crossref PubMed Scopus (170) Google Scholar were all performed in studies involving hemophilia. Events such as the detection of vector in the semen of subjects16High KA Clinical gene transfer studies for hemophilia B.Semin Thromb Hemost. 2004; 30: 257-267Crossref PubMed Scopus (65) Google Scholar or a transient rise in serum transanimases and thrombocytopenia17Recombinant DNA Advisory Committee. Minutes of meeting, 6–7 September 2001, pp 18–19 http://www4.od.nih.gov/oba/rac/minutes/rac%20min%20090601.pdf (last accessed 24 September 2007)Google Scholar highlight the challenge of using animal models—and good, large-animal ones at that—to predict the properties of an agent when administered to human beings. What levels of safety and confidence should be expected of trials involving stable volunteers? The questions present a complicated and, as yet, unresolved ethical problem.18London AJ Reasonable risks in clinical research: a critique and a proposal for the Integrative Approach.Stat Med. 2006; 25: 2869-2885Crossref PubMed Scopus (50) Google Scholar,19Weijer CJ Thinking clearly about research risk: implications of the work of Benjamin Freedman.IRB. 1999; 21: 1-5Crossref Scopus (35) Google Scholar Too restrictive an approach frustrates the autonomy of subjects and the fulfillment of their aspirations. Too permissive an approach raises concerns about whether clinicians are adequately safeguarding their subjects from harm. Risk judgments are notoriously value-laden, because persons will always disagree about how to weigh the magnitude of harms for any given risk. Even the technical dimension of risk assessment is permeated with value judgments; researchers often disagree about how to interpret evidence, or how to appraise its significance.20Kimmelman J Valuing risk: the ethical review of clinical trial safety.Kennedy Inst Ethics J. 2004; 14: 369-393Crossref PubMed Scopus (30) Google Scholar Ethicists cannot claim any more authority on these value-laden risk judgments than can clinicians, investigators, or policy makers. Whether the uncertainties and risks of novel intervention, stable-volunteer trials are “reasonable” is probably best decided on the basis of whether parties making this judgment can legitimately vouch for the values and interests of those who are likely to be enrolled in such studies. The standard approach for deciding whether subject selection suits a study's risks and benefits is for investigators to pitch their proposals to institutional review boards (IRBs), the Recombinant DNA Advisory Committee (RAC), and the Food and Drug Administration. However, different parties to the review process are likely to render somewhat varying risk judgments, raising the question of which one best represents the interests of persons who might be invited into the study. The problem is nicely summed up by Alex London: “because it is exceedingly difficult for stakeholders to communicate to others a standard [of reasonable risk–benefit balance] that they can use to make or evaluate assessments of this sort, it is difficult for the broader community to trust that decisions . . . are not the product of some less reasonable and more arbitrary process.”21London AJ Does research ethics rest on a mistake? The common good, reasonable risk and social justice.Am J Bioethics. 2005; 5: 37-39Crossref PubMed Scopus (14) Google Scholar We see evidence of this difficulty and distrust in the range and intensity of recriminations that followed the University of Pennsylvania OTC debacle in 1999. What might be a more ethically robust approach for deciding risk and subject selection? One possibility would be to invite patient-advocacy organizations to contribute to the planning and review of study protocols. Many disorders investigated in translational trials involve well-organized and scientifically sophisticated advocacy organizations. For example, for hemophilia these include the National Hemophilia Foundation, the World Federation of Hemophilia, and other groups. Such organizations offer two opportunities for strengthening the ethical basis of risk decisions. First, advocacy organizations can participate in designing studies by establishing criteria for initiating trials (see, for example, ref. 22National Hemophilia Foundation. (revised November 2002) MASAC Document 137: MASAC Recommendations for Conducting Gene Transfer Clinical Trials in Persons With Bleeding Disorders. <http://www.hemophilia.org/NHFWeb/Resource/StaticPages/menu0/menu5/menu57/masac137.pdf> Accessed 4 January 2007Google Scholar) and helping to decide whether risks and benefits are appropriately balanced (some patient advocacy organizations, such as the Cystic Fibrosis Foundation, operate data safety monitoring boards for certain trials23Goss CH Mayer-Hamblett N Kronmal RA Ramsey BW The cystic fibrosis therapeutics development network (CF-TDN): a paradigm of a clinical trials network for genetic and orphan diseases.Adv Drug Deliv Rev. 2002; 54: 1505-1528Crossref PubMed Scopus (35) Google Scholar). Second, disease advocates can contribute to ethical review of proposed protocols; where translational trials involve contentious levels of risk and uncertainty, IRBs, data safety monitoring boards, or the RAC might invite ad hoc input from disease advocates.24Dresser R When Science Offers Salvation: Patient Advocacy and Research Ethics. Oxford University Press, New York2001Google Scholar This approach has important limitations. For example, groups are often more tolerant of risks than are individual constituents.25Melton GB Levine RJ Koocher GP Community consultation in socially sensitive research.Am Psychol. 1988; 43: 573-581Crossref PubMed Scopus (74) Google Scholar Some patient organizations aim primarily at serving “future” patients and might have a more permissive outlook on trial risks. Indeed, the University of Pennsylvania OTC protocol was endorsed by a major patient-advocacy organization.26Savulescu J Harm, ethics committees and the gene therapy death.J Med Ethics. 2001; 27: 148-150Crossref PubMed Scopus (77) Google Scholar Other groups mainly serve “present” patient needs (e.g., by advocating for services and symptomatic care); these will tend to view trials more cautiously.27Stockdale AD Waiting for the cure: mapping the social relations of human gene therapy research.Sociol Health Illn. 1999; 21: 579-596Crossref Scopus (46) Google Scholar Finally, advocacy organizations often derive a large portion of their budget from pharmaceutical and biotechnology companies and, thus, might have competing interests.28Berenson A In drug-aid foundations, a web of corporate interests. 2006; (New York Times, 8 April)Google Scholar Investigators and IRBs should therefore solicit input from diverse stakeholders within the patient community. Two other policies might further shore up the ethical foundations for novel-agent trials recruiting medically stable volunteers. First, investigators should publicly disseminate preclinical safety and efficacy studies before initiating a human study so that scientific peers, ethicists, and advocates can form an independent judgment about a protocol's risk and benefit claims. Second, subjects might be offered indemnification for research-related injuries. Both are, of course, ethically desirable for any clinical trial. However, they are particularly desirable for these studies because their risks are often contested. As a consequence of the brevity of this commentary, these recommendations leave certain questions unanswered. How should such categories as “medical stability” be demarcated? When is an intervention classified as an incremental modification of a previous one, and when does it become novel? How are investigators and ethics committees to determine which and how many stakeholders to consult? How are conflicts among stakeholders to be resolved? Further inquiry from ethicists, policy makers, and the medical community is clearly warranted. Nevertheless, policies that consult community stakeholders when evaluating risks have been productively applied in realms such as environmental policy and product safety.29National Research Council Understanding Risk: Informing Decisions in a Democratic Society. National Academy Press, Washington, DC1996Google Scholar Moreover, certainly patient advocates have historically contributed in important ways to the design and review of clinical trials.30Epstein S Impure Science: AIDS, Activism, and the Politics of Knowledge. University of California Press, Berkeley1996Google Scholar,31Strauss RP Sengupta S Quinn SC Goeppinger J Spaulding C Kegeles SM et al.The role of community advisory boards: involving communities in the informed consent process.Am J Public Health. 2001; 91: 1938-1943Crossref PubMed Scopus (158) Google Scholar

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