Introduction

Clinical trials are crucial to the translation of biomedical research to better treatment alternatives for patients. In the gene therapy field, however, disproportionate media attention given to serious adverse events (SAEs) in early-phase trials has the potential to stifle therapeutic progress. Commentators from within and outside gene therapy have called for greater ethical guidance for the informed consent process.^1,2,3 Indeed, the recent American Society of Gene and Cell Therapy Position Statement on Informed Consent encourages American Society of Gene and Cell Therapy members to "consider current information on the content and conduct of the consent process."⁴ This requires investigation into the nature of risk, which poses challenges for both the informed consent process and the conduct of clinical research more generally. It is therefore timely to stimulate discussion within the gene therapy field about risk in clinical research and to ask whether the gene therapy field is becoming too risk-averse in response to SAEs that have occurred.

Risk underscores many aspects of clinical research. It is an issue in clinical research at the stage of study design, when matters such as the strength of preclinical data and the category of research subjects are considered, as well as during the trial as the possibility of adverse events. What makes risk so difficult and complex is that it can be understood, perceived, communicated, and assessed differently. Questions of risk are impossible to avoid, as research is a moral enterprise, as well as a scientific one, and aims to establish new knowledge while precluding causing unnecessary harm. Failure to engage with the complexity of risk or to question the degree to which it is avoidable is ethically problematic because it may lead to both unnecessary harm to research subjects and unjustifiable limits on research. What is required, therefore, is critical, transparent, and inclusive discourse about risk in clinical research.

All clinical research involves a degree of risk. This risk may be acceptable as long as appropriate preclinical safety studies have been conducted and sufficient effort is made to ensure that the informed consent process is rigorous, with particular attention given to the communication of risks to prospective subjects. After all, well-designed clinical studies are the best available means of addressing uncertain gene therapy risks in human patients. A major challenge during risk assessment, then, is to strike the most appropriate balance between accepting and averting risks. Key questions about the acceptability of risk in clinical trials include who makes decisions about risk, whether the possible benefits justify the level of risk, what values underlie these decisions, how these decisions are scrutinized, and what kinds of questions should be asked to both protect research subjects and allow research to progress.

Additional layers of scrutiny and transparency are imposed by the public nature of decision-making about risk in gene therapy trials via, for example, the Recombinant DNA Advisory Committee.⁵ This heightened attention presents an opportunity for gene therapy researchers to be proactive and have a voice in dialogue about the acceptability of risk in clinical research. Increasing the focus of gene therapy on risk, judgments about risk acceptability, and the implications of risk for informed consent will lead toward better protection of patient safety in trials, as well as communicating the commitment of the field to the ethical conduct of clinical research.

Risk, Fear, and Adverse Events in Gene Therapy Clinical Trials

Much controversy surrounded the deaths of Jesse Gelsinger and Jolee Mohr in gene therapy trials for ornithine transcarbamylase (OTC) deficiency and rheumatoid arthritis, respectively, with some commentators suggesting that these events raised fundamental questions about the nature of informed consent and even exemplified some of the failings of clinical research.^6,7 As discussed below, controversy in gene therapy trials appears more likely to attract media attention than trials in other disciplines. The media heightens public fears and influences public perceptions of risk, and so plays a significant role in the social amplification of risk.^8,9 In turn, media hype about gene therapy is undoubtedly generated by public fears about gene technology, modifying nature, and ethical concerns regarding gene therapy as an application of human genetic engineering.¹⁰ Media hype and public fear are further exacerbated when trials involve children, and this may have also rendered the gene therapy field particularly sensitive to risks in clinical research.

There is evidence that the public is more likely to support medical applications of biotechnology than, for example, agricultural applications.^11,12 Although this does not eliminate the possibility of public fears of gene technology in humans, it does suggest an opportunity to address public fears. Public outreach strategies of the gene therapy societies, such as the educational information on the American Society of Gene and Cell Therapy website, could be extended to address these fears by emphasizing the ultimate fundamentally therapeutic goals of gene therapy, and explaining why it is strategic to modify DNA of somatic cells in the treatment of inherited diseases and why this is ethical, especially when effective long-term treatments are limited.

Patient deaths and SAEs in clinical trials are by no means uncommon or peculiar to gene therapy trials. Yet, Jesse Gelsinger's death in 1999 was highly publicized in the lay and professional media, including 22 articles in The New York Times.¹³ In that same year, 153,964 SAEs in clinical trials, including 17,399 patient deaths, were reported to the Center for Drug Evaluation and Research of the US Food and Drug Administration.¹⁴ Few of these people's names would be known by the lay public, researchers, or critics of research. There is a danger that in response to this type of disproportionate media attention, gene therapy may become too averse to taking risks in clinical research. This could mean a greater lag in the commencement of trials, the initiation of fewer trials, and greater scrutiny of gene therapy trials by regulatory authorities.

The development of leukemia in 5, and the resultant death of 1, out of 20 infants in two separate and otherwise highly successful trials of gene therapy for X-linked severe combined immunodeficiency (SCID-X1), have presented challenges of a different nature for the gene therapy field. These SAEs were caused by insertional mutagenesis, a risk that was foreseen but significantly underestimated based on preclinical animal data. Consequently, a major focus for research involving integrating vectors has shifted toward improving vector design and understanding of genotoxicity, by characterizing insertion site preferences and clonal dynamics and survival. Ultimately, the best of these improved vectors will have to be assessed for safety and efficacy in the clinic. By bringing attention to the uncertainty of genotoxicity, the SAEs in the SCID-X1 trials pointedly raised issues about risk and uncertainty in gene therapy research, while at the same time illustrating the very need for clinical trials.

The problems of risk and uncertainty in clinical trials are not encountered by gene therapy alone. Genotoxicity has a high profile in gene therapy but is also associated with other interventions, including chemotherapy and radiation. Teratoma formation is a high-profile risk in stem cell research, and the International Society for Stem Cell Research has recently developed Guidelines for the Clinical Translation of Stem Cells, which purport in part to address concerns about risk.¹⁵ In its report >25 years ago, the US President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research viewed gene therapy as "analogous to other forms of novel therapy and can be judged by general ethical standards and procedures".¹⁶ Although some commentators have argued that gene therapy is a case for exceptionalism and should be treated differently to other areas of practice and research,^5,17 it is perhaps better viewed as a good example of a novel field, providing an opportunity to focus more generally on risk in clinical research.

What is Risk?

Any discussion about risk in clinical research requires an understanding of what risk is and how knowledge about risk is constructed. Risk is closely tied to uncertainty and unknown outcomes, and carries notions of harm occurring to something of human value.¹⁸ It can be defined as the probability that a particular adverse event will occur within a defined period of time,^19,20 where that probability is a function of hazard and exposure.²¹ Despite the appeal of definitions suggesting that risk is an objectively measurable phenomenon, it is also clear that risk encompasses subjective elements.²² Thus, risk can be viewed as both a positive and a negative force,²³ with lay persons especially identifying risk as negative and associated with fear, uncertainty, and loss of control.²⁴

Although risk is ubiquitous, its subjective nature renders the meaning of risk far from certain. Different understandings of risk have been developed in many disciplines, including statistics, psychology, economics, philosophy, law, and the social sciences. Thus, statistics emphasizes calculable aspects of risk such as probability and modeling; psychology emphasizes subjective aspects of risk as a behavioral and cognitive phenomenon; philosophy considers the validity of knowledge about risk and moral acceptability of risk; and sociology studies risk as a societal phenomenon associated with fear and trust.²⁵ Accordingly, many stakeholders have an interest in defining and analyzing risk, and their approaches can differ and may conflict.

Different stakeholders also have different perceptions about risk. A number of sociodemographic factors affect risk perception, including age, sex, culture, and education; and within these groups there are degrees of heterogeneity.^26,27,28,29 It is also well-established that the same risk is perceived differently by lay people and experts in that field.^30,31 For example, lay people rank nuclear technology risks as more severe in magnitude than experts do.³¹ Furthermore, people display a cognitive bias, whereby they tend to perceive their own risk of harm as below average,³² suggesting research subjects are likely to underestimate their own risk of harm.

In gene therapy and other fields of biomedical research, knowledge about risk, understood in its objective and probabilistic sense, is constructed through preclinical studies and empirical knowledge. For example, the SAEs in the SCID-X1 trials triggered much work toward developing assays to measure the probability of genotoxicity and to enable benchmarking of safety improvements against clinically tested vectors. These assays do not purport to provide a direct quantification of the risk of insertional mutagenesis occurring in a human subject, but will assist researchers, institutional ethics committees (IECs), and regulatory authorities with the ultimate goal of defining an acceptable level of risk for further trials to measure genotoxicity risks in humans.

Understanding and managing risks, such as genotoxicity, requires knowledge about the type, extent, and probability of that risk. Although empirical studies help elucidate risk knowledge, it must be appreciated that the weight attached to these criteria when decisions about risk are made is not a matter of science and is laden with values that are personal, cultural, and moral. Decisions about risk consequently draw upon subjective elements of risk and not just probability statistics. Accordingly, judgments about risk, such as defining and managing acceptable risk levels, are normative rather than scientific. That is, they involve interpretation of facts based on values and norms. What, then, are the values that underlie judgments about acceptable levels of risk during study design, and who makes these kinds of decisions?

Defining Acceptable Risk Levels During Study Design

Many people would agree that a degree of risk is an acceptable, and indeed, a desirable aspect of life. A degree of risk is inherently involved in all clinical procedures and research, so it follows that some degree of risk must be accepted in clinical research. The challenge lies in achieving agreement on an acceptable level. At the same time, risk is a corollary of many activities that have beneficial outcomes.²² For example, the strategy behind the success of SCID-X1 gene therapy, the use of integrating vectors to transduce hematopoietic progenitors that subsequently undergo massive replicative expansion in vivo, also carries the risk of insertional mutagenesis. Although direct patient benefit is not the purpose of early-phase research, clinical trials offering zero chance of societal benefit would never be initiated. This raises the questions of what degree of risk is acceptable in clinical research, what level of benefit justifies that risk, how these judgments are made, and who makes them.

Judgments about acceptable levels of risk are made during study design, and include when it is appropriate to commence a study, based on preclinical in vitro and in vivo testing. These kinds of judgments involve epistemological questions about the extent of legitimate extrapolation of preclinical data to humans. Animal models of human disease are currently the best available means of testing new therapies, but are imperfect. Discordance between outcomes in animal experiments and human trials is well-documented,^33,34 and it has been suggested that systematic review and meta-analysis of animal data could improve the quality of preclinical data.³⁵ The underestimation of genotoxicity risks before the SAEs in the SCID-X1 trials highlighted the shortcomings of prior animal data, and retrospective critical evaluation emphasized the inadequate long-term follow-up of those animals.³⁶ Further examples include the failure of mouse studies to predict immune responses to adeno-associated virus that have occurred in therapeutically promising gene therapy trials for hemophilia B and lipoprotein lipase deficiency.^37,38

The decisions of researchers to take research to the clinic and of regulatory authorities to approve clinical research are based on statistical significances observed in preclinical data. However, the limitations of animal data, particularly the well-recognized problems with interspecies extrapolation,³⁹ imply that a degree of uncertainty is inescapable during risk assessment. The Declaration of Helsinki acknowledges this uncertainty in requiring risk assessment to be based on "predictable risks and burdens".⁴⁰ Yet how can researchers and regulatory authorities make judgments about acceptable levels of risk when risks are uncertain? Clearly when researchers and regulatory authorities make decisions about commencing clinical studies, their judgments about acceptable levels of risk carry a strong normative component. The values underpinning these normative judgments warrant critical evaluation.

Acceptable Risks: Who Decides?

A further question regarding risk acceptability concerns who is, and who should be, ultimately responsible for defining the acceptable level of risk. In research, this decision is shared by several parties with different roles: the researcher, who decides when to commence a clinical trial; the IEC, which decides whether to grant ethics approval; and the research subject, who decides whether to consent to participation. By contrast, in a clinical setting, it is the patient who largely determines which level of risk is acceptable by consenting to their choice from a number of treatment options, with varying degrees of risk and possible benefit. The patient's clinician also makes a judgment about risk acceptability when deciding which treatment options to present. These kinds of decisions occur routinely in the clinic and are rarely scrutinized, save for the few exceptional cases in which consent is determined by a guardianship tribunal or in which mediation or litigation occurs.

Furthermore, given there are many stakeholders in clinical research, each with different perceptions of risk, there is a deep question of "whose risk is it anyway?" Researchers, regulators, and the public legitimately have deep concerns about risk in clinical research, however, these concerns should not excessively restrict research or eclipse the interests of patients. Patients are increasingly seeking to reclaim ownership of risk and to have a voice in decisions about the risk levels they are exposed to. Patient advocacy was successful in the 1990s, when human immunodeficiency virus/AIDS advocates successfully lobbied US regulatory authorities for seriously ill patients to have greater access to therapies that were yet to be approved.^41,42 Engaging with the patient community would assist gene therapy researchers judging risk acceptability, and voices of patients should influence the values behind these decisions.

Judging Risk Acceptability During Selection of Subjects

Significant judgments about risk acceptability during study design are made when researchers decide which subjects are the most appropriate to recruit to a clinical trial and at which stage of disease it is most appropriate to offer gene therapy. In essence, this involves a balance between minimizing risks while maximizing the study's contribution to knowledge.⁵ Questions about the appropriate choice of subject have been raised in relation to recent gene therapy trials for two progressive disorders, which recruited subjects with an advanced disease state.^43,44 Gene therapy for Leber's congenital amaurosis was initially trialed on adult patients with low visual acuity who had lost photoreceptor function, and gene therapy for Parkinson's disease was trialed on patients with an advanced disease state who had not responded to existing treatments.

Generally, it is considered ethical to conduct research on patients with "little to lose," meaning they have a condition with limited treatment options and/or a dire prognosis. Early-phase toxicity testing of novel therapies is thus performed on patients with an advanced disease state. It is more difficult to justify trialing novel therapies on patients whose conditions can be managed by existing therapies with better characterized risks, especially when there is the potential for latent adverse events.^45,46 However, there are difficulties for researchers investigating the safety and efficacy of novel therapies on patients with an advanced disease state. Did the subject die as a result of the intervention's toxicity or the patient's advanced disease state? Did the intervention fail because it is not efficacious in humans, because the dose was too low, or because the patient's disease had progressed too far?

Researchers considering which patient population to recruit and at which stage of disease to offer gene therapy should take into account the principles of beneficence and patient welfare, as well as their own research aims. Similarly, regulators and IECs should balance imposing the risks of early-phase toxicity testing on patients with an advanced disease state compared to patients with more to lose but perhaps more to gain. Patients with an advanced disease state, already burdened with the likelihood of imminent death, may be more likely to consent to a novel but risky intervention. There could be situations where it is more ethical to offer gene therapy to patients who are in less desperate situations before disease has progressed to an advanced stage if the chances of gaining more useful scientific knowledge are likely to be higher, especially if the patient understands the risks and can give informed consent. Recently reported improvements in the vision of children and young adults treated in a phase I trial of gene therapy for Leber's congenital amaurosis highlight the scientific utility of extending early-phase trials beyond those with "little to lose."⁴⁷

Children as Research Subjects

Further difficulties arise when research subjects are children and consent is determined by a third party, such as a parent or guardian. Given the paucity of knowledge about the effects of therapies in children and the fallacy of extrapolating data from research conducted on adults, it is generally considered necessary and acceptable for children to participate in clinical research.^48,49,50 However, questions about the appropriate mechanisms for enrolling children in clinical studies have attracted divergent views and much controversy, especially regarding early-phase toxicity trials that are not intended to directly benefit subjects. An example of a conservative view was displayed in the University of Pennsylvania's phase I trial of gene therapy for OTC deficiency, which recruited adults and older children presenting with milder phenotypes, as neonatal infants lack the capacity to consent and parental consent was not considered genuinely voluntary.^51,52

Notions of emergent capacity, which have been developed in the law governing consent of children to medical treatment in western common law jurisdictions, may be able to provide useful guidance for researchers. Generally, parents and guardians consent for children as neonates, but this right dwindles as children gradually develop the capacity to consent, until they become adults, when they are presumed competent.^53,54 Although there is certainty at both ends of this spectrum, the grey areas in between are more challenging. Parental consent is generally required in addition to the child's assent. Older children in particular may wish to have the final decision to give consent.⁵⁵ Legal recognition of "mature minors," who can give informed consent when they achieve a sufficient understanding and intelligence to enable them to fully understand the intervention,⁵³ indicates the law's primary consideration is the child's comprehension of the treatment and its associated risks, rather than age.

Risk is an important consideration in the regulatory oversight of pediatric research. For example, US federal regulations prescribe when pediatric research is permissible according to the level of risk and the extent of benefit to the child,⁵⁶ including research involving "minimal risk" which is defined as not greater than risks ordinarily encountered in daily life or during ordinary physical or psychological testing. Similarly, the Declaration of Helsinki requires that research on subjects lacking competence entail "minimal risk".⁴⁰ The definition and interpretation of the term "minimal risk", however, is far from certain,⁵⁷ and it has been demonstrated to be difficult for different IECs to apply the US federal standard consistently in the absence of empirical data about every-day risks faced by children.⁵⁸ IECs overseeing pediatric research thus make a normative judgment about whether the risks associated with the proposed research pose "minimal risk" to the child.

A number of flaws in the conduct of the University of Pennsylvania's OTC trial were highlighted during the US Food and Drug Administration's investigation prompted by Jesse Gelsinger's death,⁵⁹ and the selection of subjects in this trial has already been critiqued. The trial's rejection of neonates as subjects, because they lack legal capacity to consent, contrasts starkly with the accepted practice of performing phase I studies on infants and children for conditions that do not present in adults. Examples of such interventions include surfactant for respiratory distress syndrome,⁶⁰ novel cardiac surgery techniques for congenital heart disease,⁶¹ drug treatment and dietary restriction for metabolic disorders,^62,63 techniques for treating and preventing neonatal brain injury,^64,65,66 and treatment of extremely low birth weight.⁶⁷ The OTC disease phenotype, and indeed, many other disease phenotypes, presents differently at different ages, meaning gene therapy is not necessarily the most appropriate treatment option for older patients with milder phenotypes that can be managed acceptably by less invasive means. The inclusion of children with a severe neonatal phenotype would have increased the validity and utility of the research done, but would not have eliminated the risk of subjects developing a massive inflammatory response against the adenovirus vector, as occurred in the case of Jesse Gelsinger.

The question of whether parents of children with limited treatment alternatives can make genuinely voluntary consent decisions does raise a real concern. However, this difficulty applies to all patients with few alternatives and not just in the context of clinical trials. Illness, cognitive and emotional development, culture, and religion can influence voluntarism in consent decisions.⁶⁸ Restricting parents from determining consent to research on behalf of their children, assuming they would be coerced by their child's illness, overlooks the many major decisions that parents make on behalf of their children, especially in relation to health and often under difficult circumstances. These decisions comprise a major responsibility of parenthood. Only a few interventions, such as irreversible sterilization, have been excluded from parental capacity by law. Researchers in other fields routinely obtain informed consent from children's parents and assent from children. A narrow interpretation of capacity should not prevent research from being conducted on children, especially when treatment options are very limited or nonexistent. Ultimately, better treatment options for children can only arise through clinical trials.

Communicating Risk Information During the Informed Consent Process

For any degree of risk that is to be accepted in clinical research, it is crucial that prospective research subjects understand the relevant "material risks" as well as the uncertain nature of risk in research so that they can give informed consent. The communication of complex information about risk is fraught with difficulty, because risk is understood and perceived differently by different people. It is well-documented that different methods of explaining risk to patients have profoundly different effects on their perception and understanding, and hence on obtaining consent.^69,70,71,72 For example, patients can comprehend risk statistics represented visually more easily than text,⁷³ and understand natural frequencies, such as 5 out of 100, better than percentages.⁷⁴ The magnitude of an adverse event is a stronger influence on subjects' decisions to participate in research than the probability of its occurrence.⁷⁵ Accepting that risk is difficult to communicate, researchers still have a responsibility to disclose information about risk during the informed consent process in a manner that maximizes comprehension in order to enable prospective research subjects to exercise autonomy.

The precise content of information disclosed in the research setting is a matter of judgment, shaped by legal requirements, guidelines, and institutional conventions. The legal obligation in North American and Commonwealth common law jurisdictions comprises a duty to disclose material risks, rather than merely listing all possible risks.^76,77,78,79 The meaning of material risk differs slightly across jurisdictions, which differentially emphasize risks a reasonable patient would be likely to attach significance to; risks the particular patient would be likely to attach significance to; and risks a reasonable body of professional opinion would disclose in the circumstances. These standards have quite different practical outcomes and researchers should consider whether the disclosure standards they are legally obliged to comply with are adequate.

Full comprehension of disclosed information by prospective research subjects who exercise full autonomy represents an ideal. It has been suggested, however, that minimum thresholds of substantial comprehension and substantial autonomy are more achievable.⁸⁰ It would be excessively demanding to expect subjects to fully understand all of the technical data and the risk probability calculus, and research subjects should not need to be geneticists to give informed consent. What they do need to fully understand is the researchers' reasoning with respect to why the trial is being conducted and why they would be a good candidate, as well as how participation will affect them. This kind of distinction helps address claims that patients and research subjects are unqualified to fully understand the procedures they consent to, and reflects the realities of decision-making faced by individuals in other aspects of life.

Risk communication during the informed consent process could be facilitated by exploiting the entrenched role of consent forms. Although consent forms are intended to document the informed consent process, there has been a shift toward more defensive uses of consent forms to protect against future liability, despite the law's emphasis of verbal dialogue. This has led to criticisms of consent forms as too complex and requiring a high reading level,⁸¹ concerns which have been raised in relation to consent forms used in gene therapy trials.^6,82 The Recombinant DNA Advisory Committee Informed Consent Working Group has already developed useful guidance for a number of matters relevant to gene therapy clinical research, including the appropriate level of language to use when communicating risks such as genotoxicity.⁸³ Consent forms could be used to facilitate the informed consent process through opening dialogue. For example, they could highlight matters prospective research subjects need to fully understand and may wish to ask further questions about, such as how participating in the research may affect them. Forms could include questions subjects could ask of themselves to assess their understanding.

Gene therapy researchers also need to contextualize the risks associated with participating in clinical trials. This involves balancing the risks and benefits of gene therapy against those associated with existing alternative therapies and the natural course of disease. Yet the subjective nature of risk means that what may appear to a researcher as an unacceptably high level of risk may appear as an only hope to an anxious patient with dire prospects. Such patients may not see a choice if the alternative is death. Or, conversely, what may appear to a researcher as an insignificant risk may cause a patient more concern. Given the risks and benefits of gene therapy are incompletely understood, balancing these risks and benefits is a demanding task for researchers, especially because prospective subjects have their own subjective interpretations of them.

Finally, when discussing the potential benefits of gene therapy, researchers should be mindful that the "therapeutic misconception" has been demonstrated in early-phase gene therapy trials.^84,85,86,87 This misconception refers to a false presumption by subjects that the primary purpose of early-phase clinical research is therapy rather than research.^88,89 It has been suggested the term "gene therapy" itself may contribute to this.^90,91 There is a difficult tension here that needs to be acknowledged, because therapeutic benefit for patients is the axiomatic goal of gene therapy and, indeed, many other areas of biomedical research. Research subjects in other fields have been demonstrated capable of understanding that early-phase research is primarily intended to benefit future patients.⁹² It is therefore crucial to communicate unambiguously that in early-phase studies, direct therapeutic benefit for research subjects is not the research question being asked and, unlike in the clinic, is not intended. Yet subjects who understand this may still nonetheless quite rationally hope that research will provide therapeutic benefit.⁹³

Conclusion

High-profile adverse events in gene therapy clinical trials have resulted in greater focus on the risks of gene therapy, and there is a danger this could lead to risk-aversion and inhibit progress in the field. The cases of leukemia in gene therapy trials for SCID-X1 emphasized some of the limitations of "evidence" generated during preclinical studies, while at the same time highlighting the need for ongoing clinical trials. SAEs in gene therapy trials raise philosophical questions about risk and uncertainty in clinical research in relation to who defines acceptable levels of risk; which categories of patients are the most appropriate; and difficulties in communicating risk information during the informed consent process, given the subjective nature of risk. There needs to be discussion about how acceptable levels of risk in clinical trials of gene therapy are judged, and the values that influence these decisions.

Gene therapy researchers need to acknowledge the difficulties posed by risk and the impossibility of avoiding all risk when science is uncertain. Researchers should consider whether and to what extent their decisions about taking research to the clinic are constrained by risk and whether this is restricting progress in the field. One way forward for researchers could be to engage with the patient community about their attitudes to risk and approaches to making decisions about risk, and to use these findings to shape the values underlying their own approaches to risk assessment. Focusing on subjects' comprehension of risks to improve the informed consent process will also help address the acceptability of risk. Regulatory authorities and IECs should consider whether the standards for assessing gene therapy risks are onerous in comparison to other research fields. Risk itself does not, and should not, predicate against clinical trials per se, even when the consequences are tragic. Disproportionate risk-aversion in clinical research, including gene therapy, is unrealistic and may stifle the development of better patient treatments.

References

REFERENCES

1. US Congress Senate Committee on Health, Education, labor and Pensions and the Subcommittee on Public Health (2002). Gene therapy: is there oversight for patient safety? 106th Congress, 2nd session, 2 February 2002.
2. Williams, DA (2007). RAC reviews serious adverse event associated with AAV therapy trial. Mol Ther 15: 2053–2054. | Article | PubMed | ChemPort |
3. Wilson, JM (2008). Adverse events in gene transfer trials and an agenda for the new year. Hum Gene Ther 19: 1–2. | Article | PubMed | ChemPort |
4. American Society of Gene Therapy (2008). ASGT position statement on informed consent. <http://www.asgt.org/
   position_statements/informed_consent.php>. Accessed 7 May 2009.
5. King, NM (2002). RAC oversight of gene transfer research: a model worth extending? J Law Med Ethics 30: 381–389. | Article | PubMed | ISI
6. Caplan, AC (2008). If it's broken, shouldn't it be fixed? Informed consent and initial clinical trials of gene therapy. Hum Gene Ther 19: 5–6. | Article | PubMed | ChemPort |
7. Shalala, D (2000). Protecting research subjects—what must be done. N Engl J Med 343: 808–810. | Article | PubMed | ChemPort |
8. Frewer, LJ (2003). Trust, transparency, and social context: implications for social amplification of risk. In: Pidgeon, N, Kasperson, RE and Slovic, P (eds). The Social Amplification of Risk. Cambridge University Press: Cambridge, pp. 123–137.
9. Eldridge J and Reilley J. (2003). Risk and relativity: BSE and the British media. In: Pidgeon, N, Kasperson, RE and Slovic, P (eds). The Social Amplification of Risk, Cambridge University Press, Cambridge pp 138-155.
10. Anderson, WF (1989). Human gene therapy: why draw a line? J Med Philos 14: 681–693. | PubMed | ISI | ChemPort |
11. Gaskell, G, Allum, N, Bauer, M, Jackson, J, Howard, S and Lindsey, N (2003). Ambivalent GM nation? Public attitudes to biotechnology in the UK, 1991–2002, Life Sciences in European Society Report. London School of Economics and Political Science: London, 19 pp.
12. Biotechnology Australia (2005). Public awareness research 2005: human health. <http://www.biotechnology.gov.au/
    assets/documents/bainternet/Summary_Humanhealth
    20051121093244.pdf>. Accessed 18 June 2009.
13. The New York Times (2009). Times topics: Jesse Gelsinger. <http://topics.nytimes.com/
    topics/reference/timestopics/people/g/
    jesse_gelsinger/index.html>. Accessed 7 May 2009.
14. US Food and Drug Administration Center for Drug Evaluation and Research (2009). Adverse event reporting system patient outcomes by year. <http://www.fda.gov/
    drugs/guidancecomplianceregulatoryinformation/surveillance/
    adversedrugeffects/ucm070461.htm>. Accessed 18 September 2009.
15. International Society for Stem Cell Research (2008). Guidelines for clinical translation of stem cells. <http://www.isscr.org/
    clinical_trans/pdfs/ISSCRGLClinicalTrans.pdf>. Accessed 18 June 2009.
16. US President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (1982). Splicing life: A report on the social and ethical issues of genetic engineering with human beings. Library of Congress card number 83-600500.
17. Kimmelman, J (2008). The ethics of human gene transfer. Nat Rev Genet 9: 239–244. | Article | PubMed | ChemPort |
18. Jaeger, CC, Renn, O, Rosa, EA and Weber, T (2001). Risk, Uncertainty, and Rational Action. Earthscan: London, 320 pp.
19. Royal Society for the Prevention of Accidents (1983). Risk Assessment: A Study Group Report. Royal Society: London.
20. Kaplan, S and Garrick, BJ (1981). On the quantitative definition of risk. Risk Anal 1: 11–27. | Article
21. Chicken, JC and Posner, T (1998). The Philosophy of Risk. Thomas Telford: London, 194 pp.
22. Garland, D (2003). The rise of risk. In: Ericson RV and Doyle A (eds). Risk and Morality. University of Toronto Press: Toronto, pp. 48–86.
23. Denney, D (2005). Risk and Society. Sage: London, 220 pp.
24. Tulloch, J and Lupton, D (2003). Risk and Everyday Life. Sage: London, 140 pp.
25. Althaus, CE (2005). A disciplinary perspective on the epistemological status of risk. Risk Anal 25: 567–588. | Article | PubMed
26. Slovic, P (2000). The Perception of Risk. Earthscan: London, 473 pp.
27. Ortwin, R and Rohrmann, B (2000). Cross-cultural Risk Perception: A Survey of Empirical Studies. Kluwer: Dordrecht/London, 240 pp.
28. Dosman, DM, Adamowicz, WL and Hrudey, SE (2001). Socioeconomic determinants of health- and food safety-related risk perceptions. Risk Anal 21: 307–317. | Article | PubMed | ChemPort |
29. Glendon, AI, Dorn, L, Davies, DR, Matthews, G and Taylor, RG (1996). Age and gender differences in perceived accident likelihood and driver competences. Risk Anal 16: 755–762. | Article | PubMed | ChemPort |
30. Slovic, P, Fischhoff, B and Lichtenstein, S (1980). Facts and fears: understanding perceived risk. In: Schwing, R and Albers, W (eds). Societal Risk Assessment: How Safe is Safe Enough. Plenum: New York, pp. 181–214.
31. Slovic, P (1987). Perception of risk. Science 236: 280–285. | Article | PubMed | ISI | ChemPort |
32. Weinstein, ND (1984). Why it won't happen to me: perceptions of risk factors and susceptibility. Health Psychol 3: 431–457. | Article | PubMed | ChemPort |
33. Perel, P, Roberts, I, Sena, E, Wheble, P, Briscoe, C, Sandercock, P et al. (2007). Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 334: 197. | Article | PubMed | ChemPort |
34. Hackam, DG and Redelmeier, DA (2006). Translation of research evidence from animals to humans. JAMA 296: 1731–1732. | Article | PubMed | ISI | ChemPort |
35. Macleod, MR, O'Collins, T, Howells, DW and Donnan, GA (2004). Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 35: 1203–1208. | Article | PubMed | ISI
36. American Society of Gene Therapy (2003). Report from the ASGT Ad Hoc Committee on retroviral-mediated gene transfer to hematopoietic stem cells. <http://www.asgt.org/
    position_statements/report_042003/index.php>. Accessed 18 June 2009.
37. Manno, CS, Pierce, GF, Arruda, VR, Glader, B, Ragni, M, Rasko, JJ et al. (2006). Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 12: 342–347. | Article | PubMed | ISI | ChemPort |
38. Mingozzi, F, Meulenberg, J, Hui, D, Basner-Tschkarajan, E, de Jong, A, Pos, P et al. (2007). Capsid-specific T cell responses in humans upon intramuscular admininstration of an AAV-1 vector expressing LPLS447X transgene. Hum Gene Ther 18: 991–992.
39. LaFollette, H and Shanks, N (1996). Brute Science: Dilemmas of Animal Experimentation. Routledge: London, 304 pp.
40. 59th World Medical Association General Assembly (2008). Declaration of Helsinki. <http://www.wma.net/e/policy/b3.htm>. Accessed 18 June 2009.
41. Dresser, R (2001). When Science Offers Salvation: Patient Advocacy and Research Ethics. Oxford University Press: New York, 215 pp.
42. Epstein, S (1996). Impure Science: AIDS, Activism, and the Politics of Knowledge. University of California Press: Berkeley, 466 pp.
43. Lowenstein, PR (2008). Clinical trials in gene therapy: ethics of informed consent and the future of experimental medicine. Curr Opin Mol Ther 10: 428–430. | PubMed |
44. Lowenstein, PR (2008). A call for physiopathological ethics. Mol Ther 16: 1771–1772. | Article | PubMed | ChemPort |
45. Kimmelman, J (2005). Recent developments in gene transfer: risk and ethics. BMJ 330: 79–82. | Article | PubMed | ChemPort |
46. Kimmelman, J (2007). Stable ethics: enrolling non-treatment-refractory volunteers in novel gene transfer trials. Mol Ther 15: 1904–1906. | Article | PubMed | ChemPort |
47. Bennett, J, Maguire, AM, Fraser Wright, J, Marshall, KA, Bennicelli, J, Leroy, BP et al. (2009). Gene therapy-mediated reversal of congenital blindness: demonstration of efficacy in a phase 1 safety trial. In: 12th Annual Meeting of the American Society of Gene Therapy, Plenary Abstract Session, May 29, San Diego.
48. Matsui, D, Kwan, C, Steer, E and Rieder, MJ (2003). The trials and tribulations of doing drug research in children. CMAJ 169: 1033–1034. | PubMed |
49. Meadows, M (2003). Greater access to generic drugs. New FDA initiatives to improve drug reviews and reduce legal loopholes. FDA Consum 37: 12–17.
50. Caldwell, PH, Murphy, SB, Butow, PN and Craig, JC (2004). Clinical trials in children. Lancet 364: 803–811. | Article | PubMed
51. Stolberg, SG (1999). The biotech death of Jesse Gelsinger. N Y Times Mag: 136–140, 149.
52. Wilson, JM (2009). Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol Genet Metab 96: 151–157. | Article | PubMed | ChemPort |
53. Gillick v West Norfolk & Wisbech HA [1986] 1 AC 112.
54. Secretary of the Department of Health and Community Services v JWB and SMB (Marion's case) (1992). 175 CLR 218.
55. Geller, G, Tambor, ES, Bernhardt, BA, Fraser, G and Wissow, LS (2003). Informed consent for enrolling minors in genetic susceptibility research: a qualitative study of at-risk children's and parents' views about children's role in decision-making. J Adolesc Health 32: 260–271. | Article | PubMed
56. US Department of Health and Human Services (2005). Code of Federal Regulations. Code 45, Section 46.404-46.407.
57. Glass, KC and Binik, A (2008). Rethinking risk in pediatric research. J Law Med Ethics 36: 567–576. | Article | PubMed
58. Wendler, D, Belsky, L, Thompson, KM and Emanuel, EJ (2005). Quantifying the federal minimal risk standard: implications for pediatric research without a prospect of direct benefit. JAMA 294: 826–832. | Article | PubMed | ChemPort |
59. US Department of Health and Human Services Food and Drug Administration (2002). Notice of opportunity for hearing. <http://www.fda.gov/
    RegulatoryInformation/FOI/ElectronicReadingRoom/
    ucm144564.htm>. Accessed 18 June 2009.
60. Sinha, SK, Lacaze-Masmonteil, T, Valls i Soler, A, Wiswell, TE, Gadzinowski, J, Hajdu, J et al.; Surfaxin Therapy Against Respiratory Distress Syndrome Collaborative Group (2005). A multicenter, randomized, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for respiratory distress syndrome. Pediatrics 115: 1030–1038. | Article | PubMed | ISI
61. Kanter, KR, Miller, BE, Cuadrado, AG and Vincent, RN (1995). Successful application of the Norwood procedure for infants without hypoplastic left heart syndrome. Ann Thorac Surg 59: 301–304. | Article | PubMed | ChemPort |
62. Enns, GM, Berry, SA, Berry, GT, Rhead, WJ, Brusilow, SW and Hamosh, A (2007). Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 356: 2282–2292. | Article | PubMed | ChemPort |
63. Mochel, F, DeLonlay, P, Touati, G, Brunengraber, H, Kinman, RP, Rabier, D et al. (2005). Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab 84: 305–312. | Article | PubMed | ChemPort |
64. Horn, A, Thompson, C, Woods, D, Nel, A, Bekker, A, Rhoda, N et al. (2009). Induced hypothermia for infants with hypoxic-ischemic encephalopathy using a servo-controlled fan: an exploratory pilot study. Pediatrics 123: e1090–e1098. | Article | PubMed
65. Mercer, BM, Miodovnik, M, Thurnau, GR, Goldenberg, RL, Das, AF, Ramsey, RD et al. (1997). Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. A randomized controlled trial. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. JAMA 278: 989–995. | Article | PubMed | ChemPort |
66. Whitelaw, A, Pople, I, Cherian, S, Evans, D and Thoresen, M (2003). Phase 1 trial of prevention of hydrocephalus after intraventricular hemorrhage in newborn infants by drainage, irrigation, and fibrinolytic therapy. Pediatrics 111: 759–765. | Article | PubMed
67. Juul, SE, McPherson, RJ, Bauer, LA, Ledbetter, KJ, Gleason, CA and Mayock, DE (2008). A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety. Pediatrics 122: 383–391. | Article | PubMed
68. Weiss Roberts, L (2002). Informed consent and the capacity for voluntarism. Am J Psychiatry 159: 705–712. | Article | PubMed
69. Iltis, A (2006). Lay concepts in informed consent to biomedical research: the capacity to understand and appreciate risk. Bioethics 20: 180–190. | Article | PubMed
70. Timmermans, DR, Ockhuysen-Vermey, CF and Henneman, L (2008). Presenting health risk information in different formats: the effect on participants' cognitive and emotional evaluation and decisions. Patient Educ Couns 73: 443–447. | Article | PubMed
71. Cox, K (2002). Informed consent and decision-making: patients' experiences of the process of recruitment to phases I and II anti-cancer drug trials. Patient Educ Couns 46: 31–38. | Article | PubMed
72. Timmermans, D, Molewijk, B, Stiggelbout, A and Kievit, J (2004). Different formats for communicating surgical risks to patients and the effect on choice of treatment. Patient Educ Couns 54: 255–263. | Article | PubMed
73. Zikmund-Fisher, BJ, Ubel, PA, Smith, DM, Derry, HA, McClure, JB, Stark, A et al. (2008). Communicating side effect risks in a tamoxifen prophylaxis decision aid: the debiasing influence of pictographs. Patient Educ Couns 73: 209–214. | Article | PubMed
74. Hoffrage, U and Gigerenzer, G (1998). Using natural frequencies to improve diagnostic inferences. Acad Med 73: 538–540. | Article | PubMed | ChemPort |
75. Reynolds, WW and Nelson, RM (2007). Risk perception and decision processes underlying informed consent to research participation. Soc Sci Med 65: 2105–2115. | Article | PubMed
76. Canterbury v Spence (1975) 464 F.2d 772.
77. Reibl v Hughes [1980] 2 S.C.R. 880.
78. Sidaway v Governors of the Bethlem Royal Hospital [1985] AC 871.
79. Rogers v Whitaker (1992) 175 CLR 479.
80. Faden, RR, Beauchamp, TL and King, NMP (1986). A History and Theory of Informed Consent. Oxford University Press: New York, 392 pp.
81. Berg, JW, Appelbaum, PS, Lidz, CW and Parker, LS (2001). Informed Consent. Oxford University Press: New York, 340 pp.
82. Kahn, J (2008). Informed consent in human gene transfer clinical trials. Hum Gene Ther 19: 7–8. | Article | PubMed
83. US National Institutes of Health Office of Biotechnology Activities (2003). NIH Guidance on Informed Consent for Gene Transfer Research. <http://oba.od.nih.gov/oba/rac/ic/index.html>. Accessed 18 June 2009.
84. Henderson, GE, Easter, MM, Zimmer, C, King, NM, Davis, AM, Rothschild, BB et al. (2006). Therapeutic misconception in early phase gene transfer trials. Soc Sci Med 62: 239–253. | Article | PubMed
85. King, NM, Henderson, GE, Churchill, LR, Davis, AM, Hull, SC, Nelson, DK et al. (2005). Consent forms and the therapeutic misconception: the example of gene transfer research. IRB 27: 1–8. | Article | PubMed
86. Kimmelman, J and Levenstadt, A (2005). Elements of style: consent form language and the therapeutic misconception in phase 1 gene transfer trials. Hum Gene Ther 16: 502–508. | Article | PubMed | ChemPort |
87. Kim, SY, Holloway, RG, Frank, S, Wilson, R and Kieburtz, K (2008). Trust in early phase research: therapeutic optimism and protective pessimism. Med Health Care Philos 11: 393–401. | Article | PubMed
88. Appelbaum, PS, Roth, LH and Lidz, C (1982). The therapeutic misconception: informed consent in psychiatric research. Int J Law Psychiatry 5: 319–329. | Article | PubMed | ChemPort |
89. Appelbaum, PS, Roth, LH, Lidz, CW, Benson, P and Winslade, W (1987). False hopes and best data: consent to research and the therapeutic misconception. Hastings Cent Rep 17: 20–24. | PubMed | ChemPort |
90. Kimmelman, J and Palmour, N (2005). Therapeutic optimism in the consent forms of phase 1 gene transfer trials: an empirical analysis. J Med Ethics 31: 209–214. | Article | PubMed | ChemPort |
91. Churchill, LR, Collins, ML, King, NM, Pemberton, SG and Wailoo, KA (1998). Genetic research as therapy: implications of "gene therapy" for informed consent. J Law Med Ethics 26: 38–47, 3. | Article | PubMed | ChemPort |
92. Bergenmar, M, Molin, C, Wilking, N and Brandberg, Y (2008). Knowledge and understanding among cancer patients consenting to participate in clinical trials. Eur J Cancer 44: 2627–2633. | Article | PubMed
93. Gullo, K (2005). New survey shows public perception of opportunity to participate in clinical trials has decreased slightly from last year. Harris Interact Healthcare News 5: 1–14.