En Route to Ethical Recommendations for Gene Transfer Clinical Trials

In Geneva, Switzerland, on 2–3 April 2007, Clinigene-NoE (the European Network for the Advancement of Clinical Gene Transfer and Therapy) and Consert (program on Concerted Safety and Efficiency Evaluation of Retroviral Transgenesis for Gene Therapy of Inherited Diseases)—two European Union (EU) programs that aim to facilitate the development of sound, safe, and effective human gene transfer—held a joint “think tank” on the ethics of human clinical gene transfer (GT).1Clinigene/Consert The ethics of human clinical gene transfer: en route to ethical recommendations for gene transfer clinical trials Program of meeting held 2–3 April 2007, Geneva, Switzerland Google Scholar The ethics of human GT research has much in common with that of research involving other new biotechnologies,2King NMP Defining and describing benefit appropriately in clinical trials.J Law Med Ethics. 2000; 28: 332-343Crossref PubMed Scopus (199) Google Scholar,3Kimmelman J Recent developments in gene transfer: risk and ethics.BMJ. 2005; 330: 79-82Crossref PubMed Scopus (70) Google Scholar but it has always raised special ethical concerns4Churchill LR Collins ML King NMP Pemberton S Wailoo K Genetic research as therapy: implications of “gene therapy” for informed consent.J Law Med Ethics. 1998; 26: 38-47Crossref PubMed Scopus (47) Google Scholar that arise from the history of the field, public perceptions of genetic manipulation, and the novelty of GT technologies. Continual reexamination of ethical issues as GT science and technology evolve is thus an important task for both the scientific community and its oversight bodies, to be undertaken independently. Thus, the aim of the meeting was to identify special ethical issues that might arise in GT research, with the ultimate goal of generating recommendations from the field. The meeting was organized around three primary questions: (1) why should GT research be pursued?, (2) when is GT research ethically appropriate?, and (3) how should GT research be designed and conducted? This Commentary presents a synthesis of the issues addressed, in light of the current state of translational GT science, from vector design to animal models to first-in-human trials and beyond. GT uses a diversity of methods and encompasses a variety of diseases, ranging from rare inherited disorders, cancer, cardiovascular diseases, and neurodegenerative disorders to metabolic disorders and diabetes. Nonetheless, each application of GT must identify several prerequisite factors: (1) the nature of the putative target cell, (2) the gene of interest, or the therapeutic gene, (3) the ideal route of GT, such as direct in vivo application or by implanting autologous or heterologous genetically modified cells ex vivo, and (4) whether transient or stable expression of the gene is required, and, if stable, whether additional levels of regulation are required. These assessments involve a high degree of uncertainty, and what we think we know can change over time. For example, type 2 adeno-associated viral (AAV) vectors were initially regarded as nonintegrative and nonpathogenic, but there is new evidence that they are integrating.5Donsante A Miller DG Li Y Vogler C Brunt EM Russell DW et al.AAV vector integration sites in mouse hepatocellular carcinoma.Science. 2007; 317: 477Crossref PubMed Scopus (471) Google Scholar The problem of immunogenicity and effective strategies for avoiding immunotoxicity also deserve attention.6Mingozzi F Hasbrouck NC Basner-Tschakarjan E Edmonson SA Hui DJ Sabatino DE et al.Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver.Blood. 2007; 110: 2334-2341Crossref PubMed Scopus (187) Google Scholar How should we respond to this high degree of uncertainty in basic GT technology? First, optimism should always be tempered with caution. Second, improved sharing of expertise across disciplines and increased integration of research along translational pathways are essential to reduce uncertainty, to conduct research efficiently with the minimum necessary number of subjects, and to make genuine progress toward safe, effective, and ethically sound GT research and, ultimately, gene therapy. Elements of GT trials that influence ethical assessment and oversight are: (1) novelty and complexity, (2) limited experience and evidence of potential risks and benefits for the subject, (3) optimistic and pessimistic public views of genetic modification, and (4) the fact that risks may extend beyond the participants. Some have argued that issues unique to GT include long-term follow-up and unintentional and deliberate germline modification. Whether these issues are indeed unique to GT or simply appear more controversial in this research is a key question. Review bodies—institutional review boards (IRBs) in the United States, ERBs or REBs in the EU countries—may lack experience and expertise in the science of GT research, which increases the likelihood that oversight could fail to address the most salient issues while giving excessive attention to less important aspects of GT research protocols. This issue is not unique to GT research but is perhaps a good example of the need to improve IRB/ERB education and coordination in multicenter trials, especially those that are multinational.7Churchill LR Nelson DK Henderson GE King NMP Davis AM Leahey E et al.Assessing benefits in clinical research: why diversity in benefit assessment can be risky.IRB. 2003; 25: 1-8Crossref PubMed Scopus (36) Google Scholar,8King NMP RAC oversight of gene transfer research: a model worth extending?.J Law Med Ethics. 2002; 30: 381-389Crossref PubMed Scopus (32) Google Scholar For example, one large GT study was set up in nine countries to enroll 250 patient-subjects. Despite the similarity of the application package in each country, there were major differences in each country's approval process, which was anticipated to take a maximum of 180 days per country. The time for response ranged from 3 months in some countries to 14 months in the Czech Republic, where, because expertise in GT review was lacking, ultimately the trial could not go forward. The principal obstacle to its approval was not the assessment of the trial design itself but biological safety, environmental protection, and ethical issues. Increasing the expertise of the ERB/IRB and establishing ways to facilitate access to thorough and validated information are necessary measures to ensure timely review based on good science and appropriate attention to subject safety and ethics. Clinigene-NoE has compiled a general database on vectors and their use (http://www.clinigene.eu/gtref). Collection and sharing of unpublished preclinical data from phase I trials with high-risk medicines would be helpful, as would collection and sharing of data (safety, toxicology) from trials that have been stopped. However, economic and competitive considerations remain, as well as the reluctance of both industry and journal editors to publish negative results, which is yet another barrier to data sharing. It is widely acknowledged that when investigators provide oversight bodies with clear and thorough information on which to base their review, especially review of novel and rapidly changing technologies like GT, those oversight bodies become better educated in the science and are better able to evaluate the ethical and scientific justification for a given research protocol. This is especially important when first-in-human studies are proposed; study rationale should describe the fundamental background of animal/preclinical studies within the framework of the literature and provide arguments for moving into the clinic. Europe lacks a Recombinant DNA Advisory Committee (RAC)–like structure with independence and accountability. In the United States the RAC has had long-term success in leading the field and improving the quality of GT research, by means of publicly accessible data. This includes the development of GeMCRIS, a comprehensive federal database of clinical GT trials (http://www4.od.nih.gov/oba/RAC/GeMCRIS/GeMCRIS.htm), besides the general database at http://www.clinicaltrials.gov. A first step in the EU may be exchange of GT trial reviews among national ERBs. A further step, ideally, would consist of consolidating evaluation data in common. More centralized expert review in the EU countries would be more efficient and less time-consuming, and should also circumvent the relative lack of a critical mass of expertise in individual countries. The RAC has also developed a Web-based guidance document on informed consent in GT research,9National Institutes of Health NIH Guidance on Informed Consent for Gene Transfer Research Google Scholar which is intended to assist investigators and IRBs. This guidance provides suggested language about the purpose of the study, potential direct and societal benefits, and surrogate end points. Consent forms must be explicit in explaining the difference between research and treatment, and in distinguishing hope from reasonable expectations for patient-subjects. Recommendations include presentation of potential benefit to society as the sole or primary goal of clinical research. In 2006 Clinigene-NoE created a centralized EU database designed to include all clinical GT trials. It contains minimal but essential information, and it omits confidential data. The UK Gene Transfer Advisory Committee (GTAC) database, Orphanet, Euregenethy and the Swiss database are included so far. There are more than 600 entries with links to publications and a database search engine. In addition, there are plans to add nonconfidential trial data from EU projects registered in the European Medicines Agency's EudraCT database since 1 May 2004. The clinical approach to GT starts with the disease, defines the target tissue, and then develops the gene delivery system. The basic research approach, however, is the inverse of that strategy. Diseases are selected on the basis of their favorable characteristics for GT. Pertinent questions include whether a therapeutic gene is available and whether its function is clear, whether the target cell is accessible, whether simple gene regulation is possible, whether it is possible to treat a sufficient number of cells to produce a therapeutic effect, and whether ectopic expression of the gene is harmful. According to specific features of the disease of interest, an “ideal” combination of GT vector, transgene, method, and route of application is chosen that is best predicted to lead to effective treatment. 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