Ethics
In this section you find answers to ethical issues surrounding Gene Therapy.
When it comes down to application of new insights and therapies, ethical issues start playing an important role. In particular for gene therapy that influences the basis of life: the DNA. Ethics come into view for example, when determining the necessary safety protocols, clinical trial setups and inclusion criteria of patients for research and treatment. This webpage gives insight into the patient’s perspective on ethical questions related to gene therapy clinical trials.
1. Is it necessary to develop a new concept of therapy with unknown risks when there are alternatives?
2. Is gene therapy ethically right or wrong?
3. When is it safe enough to move from animal studies to clinical trials?
4. How to deal with paediatric patients participating in clinical trials?
5. Is somatic gene therapy more or less ethical than germline gene therapy?
6. Do gene transfer clinical trials with genomic insertion always require a long-term follow-up?
7. How to deal with viral gene and transgene shedding?
8. How can patients help scientific research?
9. How to obtain a valid informed consent?
10. What are the regulations for participants? Are they too rigid or too loose?
11. Should information on clinical trials be made public?
1. Is it necessary to develop a new concept of therapy with unknown risks when there are alternatives?
Many patients and their families consider gene therapy as a route to tackle the fundamental biological cause of their disorder: the faulty gene being replaced by a healthy gene. It might ultimately eliminate the need for complex services of integrated interventions, care and support, many of which may need to be lifelong.
Most genetic conditions are complex, multi-system disorders: they affect multiple organs in the body. To treat or prevent such a disease, an effective therapy would need to intervene broadly in all affected organs. Even where interventions currently exist, these are often demanding and of limited benefit for the affected person (e.g. the daily treatment regime for children with cystic fibrosis). For those patients it is necessary to develop a new concept of therapy even when there are unknown risks: they don’t have an acceptable alternative. Gene therapy offers a new perspective on life, on hope and on a future that can be full of plans, instead of living from day to day.
2. Is gene therapy ethically right or wrong?
The minute a stakeholder has a very strong benefit, it will make him personally eager, and for that he also has to be on the alert. Because a benefit alone should not be a guidance in the policy developing processes and decision making on a personal level. In ethical issues with regard to gene therapy, patients are very eager, they know they will benefit from these developments. And from what they heard, the benefit must be huge.
But when is something ‘ethically well to do’ and when do we consider something as ethically wrong? Where are the boundaries and who sets them? This is a crucial, but in itself also rather difficult problem. We can say that something is ethically ‘right’, when we do ‘good’. But when do we consider something as a good act?
There have been numbers of famous philosophers discussing this subject and they did that more thoroughly then we can do it here. But what is evident, is that we need criteria. For example: in the tradition of the philosopher Kant we could say: the criteria to consider gene therapy as an ethically ‘good’ development, is the question whether we use patients as a goal or as means. And since we do not plan to use patients as a tool, in order to do research on gene therapy, it is ethically right to develop new research. Because the wellbeing of patients is at stake, and not their role in research itself.
3. When is it safe enough to move from animal studies to clinical trials?
This is always a difficult issue. Animals models never completely match the human disease situation and species-specific differences for the safety and efficacy assays might exist. Protocols of research groups and coordinating supervising organizations such as ethical commissions of academic research centres and the European Medicine Agency determine the right moment for clinical application. Patients have great confidence in these protocols.
However, especially in the case of life threatening, progressive diseases, patient organisations emphasize the need for quick evaluation processes. Scientists report that bureaucratic processes often delay research developments, much to the disappointment of patients.
In the case of gene therapy, the research protocols should be continuously evaluated to perceive opportunities for standardization and simplification. Best practices and new insights should have an effect on protocols as soon as possible.
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4. How to deal with paediatric patients participating in clinical trials?
Questions about the safety for the patient are raised in the case of gene transfer in very young patients for orphan diseases in which there is no other efficacious treatment. Especially in the case of life threatening, progressive diseases, where no adult patients are available.
To date, only children who are seriously ill or have illnesses incurable by conventional means have been involved in clinical trials using gene therapy. For those with serious illnesses that aren't responsive to conventional therapies, gene therapy may offer hope that didn't exist just a short time ago.
Special consideration is needed to identify the stage of the disease where gene therapy is hoped to be effective. For example, to enter clinical trials, existing treatments must fail and patients need to progress to advanced disease. But probabilities of success are sometimes likely to be higher when patients can enrol earlier.
Especially in those cases involving paediatric patients, collaboration with patient organizations is of importance. They have expertise in how to deal with informed consent and getting into contact with parents and their children. Children cannot give informed consent. Consent implies a full understanding of the potential risks and other considerations of a clinical trial, an understanding which may be far beyond the child’s intellect. However, children may be asked, and should be heard, to their "assent" or "dissent”.
5. Is somatic gene therapy more or less ethical than germline gene therapy?
Somatic gene therapy involves introducing a "good" gene into the patient’s cells to treat the disease, but it won't change the chance that the disease will be passed on to the patient's children. The procedure may have to be repeated in future generations. This is the more common form of gene therapy being done.
Germline gene therapy involves modifying the genes in egg or sperm cells, which will then pass any genetic changes to future generations. Although it has potential for preventing inherited disease, this type of therapy is controversial. Germ-line transmission of an undesirable trait could nowadays be prevented by pre-implantation genome diagnosis, and germ-line gene transfer then remains open only for enhancement, which is considered unethical.
However, in the practice of chemotherapy and clinically indicated irradiation, inadvertent germ-line genomic changes cannot be excluded and are even expected (semen is often collected and banked before such treatments). Thus with any somatic cell therapy which is systemic, germ line changes could be an unavoidable consequence. In these non-gene therapy situations the risk is apparently taken, whereas in experimental human gene therapy the issue of putative germ-line gene transfer, i.e. genetic modification, receives more emphasis in evaluating the risk/benefit ratio.
6. Do gene transfer clinical trials with genomic insertion always require a long-term follow-up?
Patients are willing to cooperate in safety protocols, but these should have a legitimate basis. There should always be an extensive evaluation of the risks and benefits. Long term follow up is not necessary when there is no significant benefit for the health of patients or society. Patients can of course be asked to cooperate in follow up studies for scientific reasons.
7. How to deal with viral gene and transgene shedding?
Patients have the same goals and interests regarding safety as society in general and this counts for shedding issues as well. Shedding is documented as environmental dissemination of the viral gene or transgene via excreta (urine, faeces, sweat, saliva, skin, semen) and blood.
Patients want to protect their families and friends from potential hazardous effects of shedding. The risks of shedding should be evaluated thoroughly but also pragmatic. There should be a balance between risk management and quality of life of patients.
Life long screening programmes should have a scientific basis and otherwise lower regimens of control should be chosen. Scientific curiosity can not be the sole basis for intensive screening programmes, unless patients voluntarily participate.
8. How can patients help scientific research?
Patient organisations are relevant partners in setting research agendas in a meaningful, societal context. Patient organisations do not wish to take away the intellectual freedom of scientists when they make choices in prioritizing research questions, but they want to add their perspective in order to make the research relevant and to make visible the need for certain research paths. Patient organisations can help researchers find funds and society’s approval and support.
9. How to obtain a valid informed consent?
When asking patients for their informed consent when they participate in clinical trials it can be very helpful to consult patient organisations in advance. They can give insight into the available knowledge amongst patients and can help to make sure the patients are fully informed when they give their consent. This can avoid later problems.
Patient organisations can evaluate informed consent forms to make sure they are complete and comply to ethical standards. This will increase the transparency and will result in a greater trust that the system is working well for participants.
10. What are the regulations for participants? Are they too rigid or too loose?
Regulations on clinical trials are applied by governments to minimize risks for people participating. Any gene therapy that looks like it is going to work will have to be licensed by the relevant competent
authority.
The European Commission has introduced regulations (the Advanced Therapies and Tissue Engineered Products Regulations). Patient organisations played a key role in persuading the European Parliament and the Council of Ministers of the importance of these legislative proposals.
Issues as “age of consent”, “failure of currently approved standards of care” and “life versus quality of life” are ethical principles applied in regulation. They are sound principles to protect patients from undue risks. However, sometimes is it necessary to loosen these principles in order for the patient to experience the greatest benefit. For example, to enter clinical trials, existing treatments must fail and patients need to progress to advanced disease. But probabilities of success are sometimes likely to be higher when patients can enrol earlier.
Too rigid implementation of the ethical principles imposed by law can unnecessary obstruct the already long road for gene therapy. The patient is the one who can connect with the effects of new developments in gene therapy very easily. He will set his boundaries lower and is overall speaking enthusiastic and willing to take more risks; what does he have to lose anyway? Without the patient’s willingness to participate, gene therapy can never become a cure or true gene medicine.
11. Should information on clinical trials be made public?
A central database for all clinical gene therapy trials should help to decide on why a new trial should start and how. The rationale for a database with information on gene therapy clinical trials also includes the right of all patients, the clinicians, the research community and the tax payers to know about these trials. A central databank that is transparent and public is important to gene therapy's acceptance.
Trial results are usually published in journals, but only positive results of completed trials are published. However, negative results are equally important, since one can learn from these findings as well. A database including all trial results, positive and negative, is thus necessary for sharing information and maximizing knowledge to expedite the development of safe gene therapies.
With thanks to diverse patients organisations for contributing to the patient’s perspective on gene therapy.