Britishlournal oJUrology (1995), 76, Suppl. 2, 71-74

Ethical and regulatory issues in gene therapy S. NICHOLSON, H.S. PANDHA, J.D. HARRIS and J . WAXMAN Department of Clinical Oncology, Royal Postgraduate Medical School, London, UK

Introduction and medicolegal aspects

Genetic manipulation or gene therapy can be divided into two basic categories. Somatic cell therapy is the correction of genetic defects in somatic cells of the body. By contrast, germ line gene therapy attempts to correct the cells of patients so that their offspring will not have a genetic defect. As with any other type of therapeutic strategy, gene therapy carries its own risks. The eager- ness to develop and use this particular treatment modality must be balanced by comparison with currently available treatments and, in particular, whether there are any advantages for the patient over conservative or palliative measures. There should be no reason to con- sider genetic therapy in a different context to any other medical treatment.

The possibilities of genetic-based therapies were real- ized over 20 years ago. Discussions on the ethics of this novel treatment began almost at the same time [l]. By the early 1980s it was becoming clear that the ethical debate had progressed from scientific circles into religious ones. Religious leaders approached the USA government to express concern over the potential hazards of the new genetics. Subsequently, a commission was set up to assess the ethical issues of gene therapy, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioural Research [2]. Following this, a congressional hearing was held on genetic engin- eering, and the Recombinant DNA Advisory Committee (RAC) was set up. The RAC is almost the last stop along the way for the approval of gene therapy trials in the USA. All protocols must be previously approved by local institutional review boards (IRB). The IRB determines each study’s scientific and ethical basis. A decision is usually made in conjunction with the institution’s bio- safety committee, which ascertains the risk of the recom- binant DNA work involved. Following approval by IRB, the protocol is passed to national review boards and then to the RAC, if approval is granted by review boards. The approved clinical protocol is passed to the Food and Drug Administration’s (FDA) Centre for Biologics Evaluation and Research for final approval before being implemented in the clinical setting.

The Human Gene Therapy subcommittee produced the important ‘points to consider’ document in 1990, outlining the methods by which genetic therapy should

be carried out [ 3 ] . Among the major points were a number of considerations that dealt with safety, e.g. the assessment of risk of the gene transfer process and the prevention of spread of foreign DNA. The FDA has also drawn up a similar document of points to consider in the submission of clinical protocols for gene therapy [4].

In Great Britain, where genetic therapy trials have recently been initiated, an advisory committee was set up to recommend ways in which gene therapy could be regulated. The Committee on the Ethics of Gene Therapy suggested a number of important points [S]. Because potential gene therapy strategies raised no new ethical issues at that time, existing ethical standards were presumed to apply. All treatments would be regarded as research, as the procedures were so novel, and gene therapy would be restricted to ‘alleviation of disease in individual patients, and should not be used to change or enhance any normal human characteristics.’ The committee also made the recommendation that a non- statutory, expert body be set up to advise and oversee the approval of clinical genetic therapy trials. This was set up recently and will give guidance on procedures to be followed in genetic therapy clinical protocols [6]. The Gene Therapy Advisory Committee (GTAC) under Dame June Lloyd has replaced the Committee on the Ethics of Gene Therapy, which was chaired by Sir Cecil Clothier. GTAC will be responsible for reporting to the health minister. Interestingly, it has been decided that there will be no new legislation at present covering gene therapy practices in the UK.

Somatic gene therapy

Somatic gene therapy is no longer a scientific dream, divorced from clinical reality. The next few years will see a burgeoning of phase 1 and phase 2 trials of gene therapy for cancer. If any ethical questions remain unanswered, they should be addressed now. This brief review aims to show that, where somatic gene therapy is concerned, no new ethical dilemmas have arisen [7]. The problems arise where standard ethical questions are applied to gene therapy. Frequently, reviews describe problems as ‘ethical’ when they are really questions of safety. Although ethical issues involve safety issues, the two are not synonymous and should not be confused.

This paper will discuss the ethics of somatic gene

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therapy in terms of the ‘four principles’ of medical ethics, which may be used as a guide in determining the ethical probity of any new treatment [S].

Autonomy

Respect for the autonomy of patients is the moral principle underlying the concept of informed consent. This requires the imparting of enough information for the patient to make informed judgements, and imparting this information in such a way that the patient can understand it. This procedure is no different from that used when obtaining consent for any other trial or experimental treatment, although the demands made on the explanatory powers of the clinician may be greater.

Good communication is essential in discussing subjects that are usually enshrouded by jargon. Fortunately, the idea that patients should be kept fully informed at all stages of their disease is well established in modern cancer medicine.

It is claimed that allowing patients to participate in preliminary trials of new therapy may engender a sense of hope, even when the disease is progressing and the trial therapy has no chance of effecting a cure [9]. This may well be true in many cases, but one has reservations where the treatment on offer is so intimately bound-up with the intricacies of molecular biology. The danger of offering this highly ‘industrialized’ form of medical care is that patients may feel alienated from the decision- making process: propelled into the ‘high-tech’ world of gene therapy, they may feel unable to say ‘no’ [lo].

Non-malejkence

The prima facie principle of non-maleficence directs that we should aim to do no harm to our patients. Clearly this does not mean that clinicians never do harm, rather that all possible precautions are taken to reduce the risk of harm being done. The risks of the treatment are balanced against the possible benefits. It is in this area that the safety of gene therapy for patient and attendants is considered, frequently with the focus being the latter. Who can argue that insertional oncogenesis, where the therapeutic gene might cause activation of a neighbour- ing oncogene, is more of a worry for the patient with cancer than for the nurse or doctor, particularly when the initial recipients of gene therapy are likely to have progressive disease that is incurable [ 1 l]? All standard cancer therapy can kill the patient, so the issue of non- maleficence in cancer management is not restricted to gene therapy. The implication that investigators would tolerate the death of the patient so long as the gene therapy was technically successful is slanderous nonsense.

Beneficence

The question of beneficence is always problematic with phase 1 and phase 2 trials in cancer patients. Initial recipients of new treatments are usually those with advanced disease, for whom all anti-cancer treatments are futile and for whom a high-standard of palliative care is probably the best management. Any real benetit of such treatment is liable to be seen when it is adminis- tered in the adjuvant setting, a lesson that has been learnt from the experience of chemotherapy in breast cancer [12]. The rationale for allowing treatment in inappropriate patients is that they have ‘nothing to lose’. This is not, however, the same as having ‘something to gain.’

Defence of the beneficence of gene therapy hinges on the potential for net benefit in the whole population while doing minimal harm to the individual. Given the potential risks in a healthy patient, the common approach is to offer new treatment to a patient who has ‘nothing to lose’. There is nothing inherently wrong in this strategy, exploiting the altruism of the patient, so long as it does not impinge upon the principles of autonomy and non-maleficence. Novel treatments may induce a sense of hope in the patient, but this should not be introduced by the doctor as an inducement to patients to participate. One might envisage that this might be the case where minor clinical responses, of no real benefit to the patient, are used to secure massive funding in the shape of research grants.

Justice

‘The moral obligation to act on the basis of fair adjudi- cation between competing claims’ is one of the most difficult principles to implement in modern healthcare [8]. It includes the issues of the rationing of healthcare resources and conflict between decisions made by organ- izations, as exemplified by government and hospitals, and those demanded by the moral responsibility of the individual. This issue is made more acute by the stagger- ing cost and resource implications of successful gene therapy of cancer. The current debate about rationing of resources to those most likely to benefit is already highly charged when dealing with patients with cancer in the context of a limited public purse: who is to judge the relative value of the enormous cost of gene therapy in cancer? Given the media appeal of gene therapy, the demand for the expansion of facilities will undoubtedly compete with funding for other areas of healthcare [13]. One wonders if there is any way of avoiding a media war, fought between the early proponents of the new frontier and the representatives of all the other medical specialities, forced into the trenches of reactionary

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traditionalism. Where gene therapy is concerned, justice would be the first casualty.

Germ line gene therapy

The evolution of germ line therapy from the current somatic therapy programmes is a logical progression. Recent advances in the micromanipulation of embryos and the laboratory development of transgenic mice models have made germ line gene manipulation for life- threatening disease technically possible in the immediate future. However, new ethical and legislative responsibilit- ies come hand in hand with this exciting new technology, in particular because of the realistic possibilities of rede- signing the genotype. Like somatic therapy, the complex moral and ethical issues associated with this treatment modality have long preceded the scientific advances that may make such therapy possible. It is essential that these issues are brought immediately to open public debate, paralleling the initial forums on somatic gene therapy which began in 1967 [14].

It is possible, with current technology, for germ line gene therapy to be effected either before fertilization or in the early post-fertilization stages of embryonic develop- ment. In considering the ethical issues of germ line manipulation one cannot differentiate between germ line gene transfer into pre-implantation embryos and gene transfer into gametes or the cells that produce gametes. Currently, most of the experimental work involves DNA transfer into one of the pronuclei of the zygote, the delivery of DNA into a four- or eight-cell embryo by a vector, or the use of embryonic stem cells.

The numerous ethical arguments for and against germ line gene therapy reflect the cultural and social values of the society in which the individual resides, but are also influenced by previous experiences with related or novel therapies, such as transplantation surgery and in vitro fertilization. In addition, the rights of the individual, whether parent or unborn child, have to be considered, as well as existing legislation which will already have attempted to allow new therapies to develop within strict guidelines. Even if the technical obstacles to targeted human germ line gene therapy can be overcome, there remains the question as to whether this should ever be used in humans. The obvious advantages to the few individuals for whom such therapy may be appropriate is overshadowed by fears of the possible consequences of germ line intervention. There may be unknown side- effects or it is possible that such technology could be abused for eugenic purposes.

The arguments for allowing germ line manipulation are based on the possibility that this form of therapy may be more efficient than the repeated use of somatic therapy over successive generations. Disease prevention

through germ line modification may be the most efficient way of eradicating certain genetic diseases. In common genetic disorders such as cystic fibrosis, which occurs in 1 in 2500 births, it could also be argued that germ line gene therapy would be the most cost-effective of all treatments when it is considered that the disease could be completely eradicated, thus eliminating the problem for future generations.

There is an argument that once the technology is available it is our ethical duty to offer the most effective modes of therapy to prevent or treat disease, provided that the techniques are of an acceptable degree of safety and proven efficacy. For example, cardiac transplantation now has a low cost-effectiveness compared to the use of equivalent funds for public health campaigns to limit heart disease and smoking. Transplantation, however, remains the best therapeutic option in selected patients, despite the cost implications.

It could also be argued that, for those parents with a child afflicted with a fatal disease, for which gene therapy may be an option, we should encourage the use of this technology to increase their chance of having a healthy child. Furthermore, it would not be appropriate ethically or legally for society to prevent families with potentially lethal genetic disorders seeking to correct these genetic defects using germ line gene therapy, and then eliminate the genes from ensuing generations. Because the advances in gene manipulation and targeting make germ line gene therapy possible, and this may not be appro- priate to use in humans, we should not be deterred from this area of inquiry. This reflects the intrinsic value of knowledge in science and medicine, and this should be pursued. Similarly, speculative fears of the misuse of such technology based on a political bias should not be allowed to interfere with investigations based on con- trolled clinical trials in approved medical units.

On the other hand, there are powerful and compelling reasons for us not to embark on germ line gene manipulation. The most familiar reservation about germ line modification is that, although it may initially have been intended to correct serious diseases, it may lead to genetic enhancement and attempts to introduce desir- able characteristics into individuals. This so-called eugenic genetic engineering might be used to improve upon complex human traits coded by several genes. such as personality and physical attributes such as height or intelligence. In this way normal, fit individuals may be altered to promote elitism and concentrate power [lS]. This misuse of new technology in many ways can been seen readily today. The use of recombi- nant human growth hormone was intended for the sole use of treating dwarfism due to deficiency of growth hormone. Instead, this recombinant hormone is now also being used to treat healthy children with short

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stature who have no evidence of underlying hormone deficiency [ 161.

Germ line gene therapy is an expensive intervention that would benefit few individuals at this time of rational- izing public resources. This is reflected by the fact that genetic diseases only affect 2% of all live births and, furthermore, the diseases applicable to germ line inter- vention are extremely rare.

Instead of forging ahead with extremely complex intervention strategies it is clear that alternative approaches already exist for avoiding genetic diseases, particularly if the methods of pre-implantation and pre- natal diagnosis could be improved. Blastomeres can be removed from frozen animal and human embryos and multiple genetic and chromosomal disorders may be screened by molecular probes using the polymerase chain reaction. Overall, genetic testing before implant- ation represents significant advances over amniocentesis and chorionic villus sampling, where there is a viable pregnancy and for which the only intervention possible is termination.

Con c 1 us i o n The potential for mistakes during genetic experiments, whether related to the genes transferred or the vectors, is of clear and obvious concern for the patient and ‘gene therapist’ alike. Any undesired gene mutation or inte- gration of replication-competent virus may potentially be reflected in all cells and subsequent generations. For example, subtle effects on brain development are not necessarily obvious from pre-clinical studies on animal models, and may present after treated individuals have themselves had children.

It is entirely appropriate to discuss the ethics of germ line gene therapy before the technology is established, and thereby benefit from previous experience gained from tackling these issues in the context of somatic gene therapy. Whether germ line modification is too danger- ous, morally wrong or indeed justifiable therapy in certain selected individuals should be decided in public forums involving all sections of the community, and should not be the territory solely of politicians and health administrators.

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Authors S. Nicholson, MRCP, Clinical Research Fellow. H.S. Pandha, MRCP, FRACP, Clinical Research Fellow. J.D. Harris, BSc, MSc, Research Fellow. J. Waxman, BSc, MD, FRCP, Reader in Oncology. Correspondence: Dr J. Waxman, Department of Clinical Oncology, Royal Postgraduate Medical School. Hammersmith Hospital, Du Cane Road, London W12 ONN, 1JK.

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