Tomorrow, Interrupted?: Risk, Ethics, and Medical Advance in Gene Transfer

In this issue of Molecular Therapy, Deakin et al. ask a provocative question: is the field of gene transfer becoming so averse to risk that important discoveries and advances are being postponed?1Deakin CT Alexander IE Kerridge I Accepting risk in clinical research: is the gene therapy field becoming too risk-averse.Mol Ther. 2009; 17: 1842-1848Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Gene transfer, so the authors argue, has received more than its share of negative publicity from unexpected toxicities. These tragic events may have triggered an overly cautious mindset among investigators. As the authors remind us, however, adverse events have enriched our understanding of gene transfer. To paraphrase the German sociologist Ulrich Beck, the flip side of risk is opportunity.2Willms J Pollack M Conversations With Ulrich Beck. Polity Press, Cambridge, UK2004Google Scholar Although safety and human subject protections are, of course, of paramount importance, curbing our appetite for risk threatens to stymie medical progress and, in many cases, the autonomy of patients who are willing to endure that risk. Deakin et al.1Deakin CT Alexander IE Kerridge I Accepting risk in clinical research: is the gene therapy field becoming too risk-averse.Mol Ther. 2009; 17: 1842-1848Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar are to be congratulated for their thoughtful and timely reflections on risk in translational clinical research. Determination of acceptable risk, as the authors point out, is laden with numerous unresolved social and ethical problems. Without criteria for establishing an appropriate balance of risk, benefit, and scientific value, ethical decision making in clinical trials is likely to rely on privately held intuitions. This makes it difficult for the broader community of stakeholders, such as members of the public, scientific peers, patient advocates, and referring physicians, to trust that decisions are rational and reasonable.3London AJ Does research ethics rest on a mistake? The common good, reasonable risk and social justice.Am J Bioeth. 2005; 5: 37-39Crossref PubMed Scopus (14) Google Scholar It further leaves the ethical design and review of trial protocols vulnerable to heuristics and biases that are well known to lead to suboptimal decision making in other contexts.4Gilovich T Griffen D Kahneman D Heuristics and Biases The Psychology of Intuitive Judgment. Cambridge University Press, Cambridge, UK2002Crossref Google Scholar In the spirit of furthering discussion of acceptable risk, I offer three alternative views on the thesis presented by Deakin et al. that inordinate risk aversion may be hindering patient autonomy and scientific progress. First, although determining whether researchers have indeed retreated from informative and ambitious trial designs will require careful sociological study, I see plenty of evidence to the contrary. The widely celebrated trial of gene therapy for Leber's congenital amaurosis (cited by Deakin and colleagues) provides an example where investigators, rather than complete their safety study in adults, enrolled minors in their second cohort of patients. In cardiology gene transfer and cell transplantation, the use of sham cardiac catheterization in early-phase studies—plus sham stem cell procurement—has become virtually de rigueur. Not very long ago, researchers published results of a phase I gene transfer trial involving Parkinson's disease5Kaplitt MG Feigin A Tang C Fitzsimons HL Mattis P Lawlor PA et al.Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial.Lancet. 2007; 369: 2097-2105Abstract Full Text Full Text PDF PubMed Scopus (849) Google Scholar that several skeptics had, on its initiation, publicly denounced as “crazy.”6Grady D Kolata G Gene therapy used to treat patients with Parkinson's. New York Times, 19 August, 2003Google Scholar Second, Deakin et al. rightly note that patients (and their advocates) are increasingly “seeking to reclaim ownership of risk.”1Deakin CT Alexander IE Kerridge I Accepting risk in clinical research: is the gene therapy field becoming too risk-averse.Mol Ther. 2009; 17: 1842-1848Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Although this may justify greater risk tolerance in trials, it harbors important hazards for scientific advance because patients may be less inclined to support procedures that enhance study value but offer no prospect of therapeutic gain. Consider the University of Pennsylvania ornithine transcarbamylase deficiency gene transfer trial. This study has been widely faulted for enrolling medically stable adults rather than children with acute and life-threatening disease. It is important to remember, however, that the trial involved percutaneous liver biopsies to gather valuable information about transgene expression.7Raper SE Yudkoff M Chirmule N Gao GP Nunes F Haskal ZJ et al.A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency.Hum Gene Ther. 2002; 13: 163-175Crossref PubMed Scopus (317) Google Scholar Such nontherapeutic, nonminimal risk and burden would not have been permissible in pediatric patients845 CFR 46.400–409Google Scholar and is in tension with the therapeutic motivations that generally underlie patient perspectives on trial risk. Similarly, patients with advanced disease who seek trial entry might oppose scientific reviewers who delay protocols by demanding more, and better, supporting evidence. As I have argued elsewhere, however, a sound preclinical evidence base is crucial for achieving the scientific objectives of translational studies because this enables scientists to interpret negative outcomes such as the failure to detect an intended biological effect.9Kimmelman J London AJ Ravina B Ramsay T Bernstein M Fine A et al.Launching invasive, first-in-human trials against Parkinson's disease: ethical considerations.Mov Disord. 2009; PubMed Google Scholar,10J Kimmelman Gene Transfer and the Ethics of First-in-Human Experiments: Lost in Translation Cambridge University Press New YorkGoogle Scholar Finally, the notion that risk aversion generally antagonizes the knowledge value of trials merits a longer view of scientific advance. Patients and clinical investigators might, as Deakin et al. suggest, be willing to accept greater uncertainty and higher risk. However, the decision to administer novel interventions in a clinical trial is not a strictly private matter. Clinical trials make demands on scarce social resources, and adverse outcomes can, in the words of James Wilson, “initiate a chain of events that seriously derail [a] field.”11Wilson JM A history lesson for stem cells.Science. 2009; 324 (e-pub ahead of print 11 August 2009): 727-728Crossref PubMed Scopus (92) Google Scholar In the aftermath of Jesse Gelsinger's death, some investigators reported difficulty in recruiting patients to their own studies.12Weiss R Battle over gene therapy puts hopes on hold. Washington Post, 7 March, 2002Google Scholar Major adverse events can damage investor confidence,13Hoag H Gene therapy rising.Nature. 2005; 435: 530-531Crossref PubMed Scopus (21) Google Scholar deter young scientists from entering a research field, close off promising research avenues, or invite cumbersome oversight mechanisms because of a perceived failure of self-regulation. A cautious and methodical approach to translational trial design is justified not only by a desire to protect the welfare of study volunteers but also by an imperative to safeguard the integrity and health of the broader research enterprise. Deakin et al. warn that “disproportionate risk-aversion...may stifle the development of better patient treatments.”1Deakin CT Alexander IE Kerridge I Accepting risk in clinical research: is the gene therapy field becoming too risk-averse.Mol Ther. 2009; 17: 1842-1848Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Surely there is some truth to this, but defining proportionate risk in fields such as gene transfer requires that investigators consider all that is at stake in running a translational clinical trial.

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