Moving Forward on Shifting Sands: Ethical Regulation of Gene Therapy Clinical Trials in the United Kingdom
Authors: Emma Morris, Martin Gore, Andrew Baker, Adrian J Thrasher
Journal: Molecular Therapy (2013)

The regulatory landscape for development and application of gene therapies worldwide is complex and surprisingly variable. This has been a source of considerable frustration to investigators in both academia and industry who are eager to bring novel therapies into the clinic. With this in mind, many countries are considering how to simplify the process while retaining good scientific and ethical oversight. The UK National Research Ethics Service (NRES) has recently taken the step of disestablishing its Gene Therapy Advisory Committee (GTAC). The reaction to this move has been somewhat mixed, so it is worth taking a closer look at its purpose and function as the gene and cell therapy community enters an era of increasing clinical activity and commercialization of products. Clinical trials in the United Kingdom involving advanced-therapy medicinal products (ATMPs) such as gene therapy, cell therapies (stem, somatic, or gene-modified), and regenerative medicine are increasing in number and “moving out” from specialist academic units into mainstream experimental medicine. To have maximal impact in relation to safety and treatment efficacy for patient benefit, timely accessibility to these novel therapies is critical—and for some applications an ethical obligation. The regulatory landscape for administration of ATMPs has necessarily evolved to meet the challenges of a new generation of therapeutics, but it remains unclear how best to shape this for early first-in-human studies through to commercial product. As a community of gene therapy scientists, clinicians, and trialists, we are immersed in a period of change, and it is therefore imperative that we remain proactively engaged in a regulatory process that is fit for the purpose. GTAC was set up to work alongside the Department of Health and other regulatory agencies in 1993, following the recommendations of the 1992 Clothier Committee Report on the ethics of gene therapy, with the following terms of reference:1.To consider and advise on the acceptability of proposals for gene therapy research on human subjects, on ethical grounds, taking account of the scientific merits of the proposals and the potential benefits and risks2.To consider and advise on the acceptability of proposals for research on human subjects using cells derived from stem cell lines, based on ethical grounds, taking account of the scientific merits of the proposals and the potential benefits and risks3.To provide ethical advice on the use of unlicensed gene therapy and stem cell line–derived therapies in humans4.To work with other agencies that have responsibilities in this field, including research ethics committees and agencies with statutory responsibilities5.To provide advice to UK health ministers on the above matters During the period from 1993 to late 2012, GTAC established a well-respected and two-way working relationship with UK scientists and clinicians to build a regulatory infrastructure to support the early use of gene therapy (and, later, stem cells) in patients. Collaboration among members with in-depth knowledge of the scientific detail and those with experience in law and regulation of medicines, as well as lay members with extensive ethical expertise, was enormously beneficial, providing scientific advice to inform ethical decisions on clinical trials. This unique polymathic group created a robust decision-making process aimed at ensuring patient safety and considering trial-specific risk–benefit analyses. It was also of enormous help to academic researchers with minimal experience in conducting human clinical studies. Scientific progress was ensured by approving trials designed to answer meaningful clinical questions. Such scrutiny was considered appropriate given the novel nature of gene therapy, and it matched the political concern that close involvement by a group of independent experts would reassure members of the general public who are anxious regarding developments involving genetic manipulation in human subjects. GTAC played a very visible public role in the explanation of risks and benefits for patients, most prominently following the discovery of leukemias arising in patients successfully treated with retroviral vectors for severe combined immunodeficiency. However, with the United Kingdom's adoption of the EU Clinical Trials Directive in 2001 and its subsequent amendment to address issues related to ATMPs,1European Community Commission Directive 2009/120/EC.http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:242:0003:0012:EN:PDFGoogle Scholar the complexity of regulation surrounding early-phase trials increased exponentially. Adapting to such changes in regulation was met more readily by big pharma than by academia, and as a result, clinical translation of exciting scientific developments emerging from the latter was significantly slowed. In October 2010, the UK government conducted a review of all advisory nondepartmental public bodies. It was recommended that GTAC no longer report directly to ministers and that responsibility for supporting its research ethics committee statutory functions be transferred to the NRES. This change signaled a move toward the mainstream ethics and regulatory approval systems in place for clinical trials involving more conventional medicines. In late 2012, GTAC was formally disestablished, and its functions were allocated to three dedicated and largely nonspecialized research ethics committees. The more pharmaceutical and toxicological aspects of studies (which previously were also addressed from a scientific standpoint by GTAC) would continue to be reviewed by the Medicine and Healthcare Products Regulatory Agency (part of the Department of Health) for final approval. The apparent move away from what had become a linked ethical and scientific oversight has alarmed some in the academic field who felt that detailed knowledge of gene transfer systems and disease biology was essential to inform ethical decision making. Others have welcomed it as an acknowledgment that gene therapy no longer warrants its “special case” or “high-risk” label of the past. Indeed, we would do well to consider that, although experimental medicine is perceived by many as risky, the numbers of adverse incidents observed in early-phase clinical gene therapy trials are extremely small compared with those associated with standard therapies and routine clinical practice. The goal for key stakeholders (patients, families, scientists, clinicians, regulators, NRES, research and development departments, trial coordinators, and funding bodies) is to be in a position where the (potential) commercialization and rapid translation of new therapies can impact as many patients as possible, as quickly as possible. For “UK Biomedical Research PLC,” gene and cell therapies are rapidly attracting interest from large pharmaceutical firms in both rare- and common-disease settings. Moving forward requires us all to adapt and change and, where appropriate, adopt changes in regulation. This should not preclude keeping an eye on the past. Retaining aspects of the process, particularly having dynamic expert committees with external peer review, improves scientific quality and credibility, and, most important, patient safety may be better safeguarded. The GTAC process encouraged a continuum of dialogue between investigators and expert regulators, which was recognized by many as enhancing both the clinical science and the ethical imperatives. These advantages are neither abstract nor exclusive to gene therapy; they apply to all advanced therapies and technologies as they enter the clinical arena. Hopefully they will be fully recognized by newly emerging regulatory structures, both now and in the future. GTAC filled a unique space that enabled ethical decision making in direct response to expert scientific review. Through dialog with investigators, it ensured that preclinical testing was rigorous and scientifically valid, and that first-in-human studies were maximally informative. It is now the responsibility of academia, industry, and the regulatory authorities to support a consummate regulatory framework that works for all, facilitates testing and commercialization of new therapeutics, promotes international harmonization, and, ultimately, brings health-care benefits to large numbers of patients. What is certain is that a disparate framework will not be able to coordinate these efforts effectively, and it may well be that expert panels such as GTAC still have an important place on the shifting sands.