Ethical Issues in a Stage 1 Cognitive-Behavioral Therapy Feasibility Study and Trial to Reduce Alcohol Use Among HIV-Infected Outpatients in Western Kenya

epidemics of both HIV/AIDS and alcohol abuse in sub-Saharan Africa have spurred the conduct of local behavioral therapy trials for these problems, but the ethical issues involved in these trials have not been fully examined. In this paper, we discuss ethical issues that emerged during the conduct of a behavioral intervention adaptation and trial using cognitive-behavioral therapy to reduce alcohol use among HIV-infected outpatients in Eldoret, Kenya. The study was performed within our multinational collaboration, the USAID-Academic Model Providing Access to Healthcare Partnership. We discuss relevant ethical considerations and how we addressed them.     

Gene therapy: ethical aspects and problems of genetic safety

Gene therapy (GT) is based on the introduction of various genetic constructions in the human organism. Rapid development of GT technologies and the increasing tendency to apply them in therapy for certain human diseases has created a number of ethical problems. These first and foremost concern direct intervention in the genome of germline cells, which may change the genome of further generations. According to current views, such manipulations are ethically unacceptable. Introduction of genetic constructs in somatic cells with therapeutic purposes (somatic GT) is considered permittable in principle but requires certain procedures to ensure the genetic safety (causing no damage) of both the patient and other people. The latter hazard is associated with a possibility of uncontrolled spreading of viral (especially retroviral) constructions used in many GT protocols. These and other ethical and genetic safety problems of modern GT are discussed.     

The challenge of including social and ethical aspects in the development of nanobiotechnology

Nanotechnology as an enabling technology for many future medical applications touches on issues such as sensitivity of genetic information, the gap between diagnosis and therapy, health care resources and tensions between holistic and functional medicine. On the other hand nanotechnology will add a new dimension to the bio (human) and non-bio (machine) interface such as brain chips or implants, which eventually might raise new ethical issues specific to NanoMedicine. This requires careful analysis of ethical aspect in view of existing standards and regulations by ethics committees at the European scale. At the same time new nanomedical inventions have to be evaluated for new ethical aspects by Ethical, Legal and Social Aspects — specialists. The most crucial point in this regard is an early proactive analysis of new technological developments to identify and discuss possible issues as soon as possible. This requires a close collaboration and co-learning of technology developers and ethics specialists assisted by communication experts to ensure open and efficient information of the public about ethical aspects (old or new) related to nanomedicine. This co-evolution will ensure a socially and ethically accepted development of innovative diagnostic and therapeutic tools in NanoMedicine.     

Healing genes in the nervous system

The evolution of gene therapy has led to the development of promising new therapeutic approaches. This NeuroView will introduce the variety of delivery vehicles currently available for gene therapy, a range of preclinical strategies for tackling major diseases of the nervous system, the clinical limitations, and ethical considerations.     

An extract from Prospects and Risks of Gene Technology: The Report of the Enquete Commission to the Bundestag of the Federal Republic of Germany

We are pleased to publish an English translation of the crucial section on germ line gene therapy from the Report of the German Enquete Commission. This section of the Report raises basic ethical questions concerning embryo research, as well as more specific questions relating to germ line gene therapy. This form of gene therapy involves genetic modification of the germ cells. Such a modification would be passed on to any descendents of the person whose genes had been altered. The Report had previously dealt with somatic gene therapy, which does not affect the germ line and hence is not passed on to descendents.     

Ethical and legal aspects of oncogenomics

The discovery of the genes and cellular pathways that play fundamental roles in several diseases, and the understanding of many diseases at a molecular level due to the advances in the field of genomics, have revolutionized the diagnosis, therapy and prevention of human diseases. Application of genetic testing in numerous medical fields, including pharmacogenomics and oncogenomics, raised numerous ethical questions and introduced legal instruments that are aimed at ensuring the appropriate protection of human research participants. For the effective development of human genomics and translation of novel, validated biomarkers into potentially useful clinical applications in personalized medicine, there is a need for clear ethical standards and principles in all phases of clinical research.     

Mesenchymal stem cells in neurodegenerative diseases: Opinion review on ethical dilemmas

The treatment of neurodegenerative diseases presents a growing need for innovation in relation to recent evidence in the field of reconstructive therapy using stem cells. Understanding the molecular mechanisms underlying neurodegenerative disorders, and the advent of methods able to induce neuronal stem cell differentiation allowed to develop innovative therapeutic approaches offering the prospect of healthy and perfectly functional cell transplants, able to replace the sick ones. Hence the importance of deepening the state of the art regarding the clinical applications of advanced cell therapy products for the regeneration of nerve tissue. Besides representing a promising area of tissue transplant surgery and a great achievement in the field of neurodegenerative disease, stem cell research presents certain critical issues that need to be carefully examined from the ethical perspective. In fact, a subject so complex and not entirely explored requires a detailed scientific and ethical evaluation aimed at avoiding improper and ineffective use, rather than incorrect indications, technical inadequacies, and incongruous expectations. In fact, the clinical usefulness of stem cells will only be certain if able to provide the patient with safe, long-term and substantially more effective strategies than any other treatment available.The present paper provides an ethical assessment of tissue regeneration through mesenchymal stem cells in neurodegenerative diseases with the aim to rule out the fundamental issues related to research and clinical translation.     

Observations on ethical problems and terminal care.

Progress in medical diagnosis and therapy has raised new problems with far-reaching ethical implications. Medicine must remain a profession and not become a business. Textbooks must address ethical problems in the context of health care decisions and not restrict themselves to pathophysiology and practical therapeutics alone. The relative roles of the principles of autonomy, non-maleficence, beneficence, and justice must be balanced and appropriately applied to individual situations in biomedical ethics. When therapy becomes futile and the suffering of the patient does not justify any anticipated benefit, the patient (and/or patient surrogate) may request withholding or even withdrawing life-prolonging interventions. In the persistent vegetative state, even nutritional support by an unnatural (tube) route may ethically be denied at the patient's (or surrogate's) informed decision. New areas of ethical evaluation have been raised by the desire of some individuals to prolongation of their lives at high expense to the society such that other individuals are denied services because of limitation of available resources. There has been a long-standing conflict of interest between the acceptance by physicians and/or medical institutions of money or gifts from pharmaceutical companies whose drugs they prescribe, stock, or sell. This practice increases the cost of the drugs and is, in effect, a "sick tax," which is morally wrong.     

UNCERTAIN TRANSLATION,UNCERTAIN BENEFIT AND UNCERTAIN RISK: ETHICAL CHALLENGES FACING FIRST‐IN‐HUMAN TRIALS OF INDUCED PLURIPOTENT STEM (IPS) CELLS

The discovery of induced pluripotent stem (iPS) cells in 2006 was heralded as a major breakthrough in stem cell research. Since then, progress in iPS cell technology has paved the way towards clinical application, particularly cell replacement therapy, which has refueled debate on the ethics of stem cell research. However, much of the discourse has focused on questions of moral status and potentiality, overlooking the ethical issues which are introduced by the clinical testing of iPS cell replacement therapy. First‐in‐human trials, in particular, raise a number of ethical concerns including informed consent, subject recruitment and harm minimisation as well as the inherent uncertainty and risks which are involved in testing medical procedures on humans for the first time. These issues, while a feature of any human research, become more complex in the case of iPS cell therapy, given the seriousness of the potential risks, the unreliability of available animal models, the vulnerability of the target patient group, and the high stakes of such an intensely public area of science. Our paper will present a detailed case study of iPS cell replacement therapy for Parkinson's disease to highlight these broader ethical and epistemological concerns. If we accept that iPS cell technology is fraught with challenges which go far beyond merely refuting the potentiality of the stem cell line, we conclude that iPS cell research should not replace, but proceed alongside embryonic and adult somatic stem cell research to promote cross‐fertilisation of knowledge and better clinical outcomes.     

Unanswered ethical and scientific questions for trials of invasive interventions for coronary disease: The case of single vessel disease

Trials in the 1990s demonstrated that medical therapy is as effective as invasive therapies for treating single-vessel coronary disease. Yet more recent studies enrolling patients with this condition have focused on evaluating only invasive approaches, namely, stenting versus coronary artery bypass surgery. Several ethical and scientific questions remain unanswered regarding the conduct of these later trials. Were they justified? Why wasn't a medical therapy arm included? Were subjects informed about the availability of medical therapy as an equivalent option? Was optimized medical therapy given prior to randomization? The absence of clear answers to these questions raises the possibility of serious bias in favor of invasive interventions. Considering that medical therapy is underutilized in patients with coronary disease, efforts should focus more on increasing utilization of medical therapy and proper selection of noninvasive interventions.     

Pancreatic transplant surgery and stem cell therapy: Finding the balance between therapeutic advances and ethical principles

The latest achievements in the field of pancreas transplantation and stem cell therapy require an effort by the scientific community to clarify the ethical implications of pioneering treatments, often characterized by high complexity from a surgical point of view, due to transplantation of multiple organs at the same time or at different times, and from an immunological point of view for stem cell therapy. The fundamental value in the field of organ transplants is, of course, a solidarity principle, namely that of protecting the health and life of people for whom transplantation is a condition of functional recovery, or even of survival. The nature of this value is that of a concept to which the legal discipline of transplants entrusts its own ethical dignity and for which it has ensured a constitutional recognition in different systems. The general principle of respect for human life, both of the donor and of the recipient, evokes the need not to put oneself and one’s neighbor in dangerous conditions. The present ethical reflection aims to find a balance between the latest therapeutic advances and several concepts including the idea of the person, the respect due to the dead, the voluntary nature of the donation and the consent to the same, the gratuitousness of the donation, the scientific progress and the development of surgical techniques, and the policies of health promotion.     

Conceptual,methodological and ethical issues in genetic engineering (1989)

An introduction to the potential of gene therapy to alleviate illness and death particularly for many rare human genetic disorders and specific forms of cancer is presented. At present, genetic engineering, that is gene therapy to correct some of these disorders based on new molecular biology procedures is a possibility in the near future especially those with single gene mendelian inherited transmission. After a short, comprehensive overview about the molecular biology of genetic engineering, a presentation of many of the ethical issues now under discussion by the international scientific community, world govenmental agencies and concerned laymen about the complex and sensitive ethical issues is provided. A report about a case history of investigators in the United States who disregarded current restrictions emphasized the concern of the scientific community as well as the governmental agencies in maintaining stepwise, careful approach to the introduction of the new, molecular methodologies. The continued maintenance of many of these restrictions, suggested by some ethicists, even after the threat of uncontrolled biological disorder as a result of these new procedures was found to be erroneous is discussed and challenged.     

An Example of a Monkey Assistance Program: P.A.S.T. - The French Project of Simian Help to Quadriplegics

ABSTRACT

All animal-assisted therapy programs raise ethical issues. These ethical issues are even more important when non-domesticated animals are used to help humans with disabilities. In their 1991 review, Iannuzzi and Rowan mentioned programs which use capuchin monkeys to help quadriplegics. The lack of technical or scientific information concerning these programs leads to misinformation. This paper describes the French Project (P.A.S.T. - Programme d'Aide Simienne aux personnes Tétraplégiques) which evaluates whether trained capuchin monkeys could be efficient helpers and companions to quadriplegic persons.     

The ethics of ectogenesis-aided foetal treatment

In this paper, we aim to stimulate ethical debate about the morally relevant connection between ectogenesis and the foetus as a potential beneficiary of treatment. Ectogenesis could facilitate foetal interventions by treating the foetus independently of the pregnant woman and provide easier access to the foetus if interventions are required. The moral relevance hereof derives from the observation that, together with other developments in genetic technology and prenatal treatment, this may catalyse the allocation of a patient status to the foetus. The topic of foetal medicine is of growing interest to clinicians, and it also deserves due attention from an ethical perspective. To the extent that these developments contribute to the allocation of a patient status to the foetus (and to its respective interests for medical treatment), normative questions arise about how moral responsibilities towards foetal interests should be balanced against the interests of the pregnant woman. We conclude that, even if ectogenesis could facilitate foetal therapy, it is important to remain sensitive to the fact that it would not circumvent the key ethical concerns that come with in utero foetal treatment and that it may even exacerbate potential conflicts between directive treatment recommendations and the pregnant woman’s autonomous decision to the contrary.     

What is a medical experiment?

Innovative therapy may appear to coincide with medical experimentation, raising ethical and legal issues, for instance on informed consent and institutional review. Medical treatments may be classified, however, to distinquish novel procedures from experimentation.     

Gene therapy. An ethical profile of a new medical territory

From early on, the possibility of genetic intervention in humans has been the subject of philosophical and ethical reflection in the scientific community. It became the object of public debate and parliamentary decision‐making under the rule of law even before the first authorized trials on human subjects could start. This article explains why the debate on germ‐line intervention and genetic enhancement is still ongoing. The focus is on somatic gene therapy. There is a political and academic consensus that it represents an adequate tool for a high‐ranking end if some points are considered and taken into account. But where do we stand and what are the ethical conclusions we can draw from recent clinical experiences? Copyright © 2006 John Wiley & Sons, Ltd.     

Generating pluripotent stem cells: Differential epigenetic changes during cellular reprogramming

Pluripotent stem cells hold enomous potential for therapuetic applications in tissue replacement therapy. Reprogramming somatic cells from a patient donor to generate pluripotent stem cells involves both ethical concerns inherent in the use of embryonic and oocyte-derived stem cells, as well as issues of histocompatibility. Among the various pluripotent stem cells, induced pluripotent stem cells (iPSC)-derived by ectopic expression of four reprogramming factors in donor somatic cells-are superior in terms of ethical use, histocompatibility, and derivation method. However, iPSC also show genetic and epigenetic differences that limit their differentiation potential, functionality, safety, and potential clinical utility. Here, we discuss the unique characteristics of iPSC and approaches that are being taken to overcome these limitations.     

Pluripotency and nuclear reprogramming

Embryonic stem cells are promising donor cell sources for cell transplantation therapy, which may in the future be used to treat various diseases and injuries. However, as is the case for organ transplantation, immune rejection after transplantation is a potential problem with this type of therapy. Moreover, the use of human embryos presents serious ethical difficulties. These issues may be overcome if pluripotent stem cells are generated from patients' somatic cells. Here, we review the molecular mechanisms underlying pluripotency and the currently known methods of inducing pluripotency in somatic cells.     

Making efficient use of patients in designing phase III trials investigating simultaneously a set of targeted therapies with different targets

Targeted therapies are a recent development in cancer treatment research. As these therapies can only be administered to patients with certain individual characteristics, it is a straightforward idea to investigate several of such therapies simultaneously in a given patient population in order to compare each targeted therapy with the current standard therapy. This raises the question how patients satisfying several characteristics should be handled. We consider in this paper several designs to allocate treatments in a random manner to these patients, such that the evaluation of each single targeted therapy can be based on a simple comparison of patients receiving the targeted therapies versus those receiving the standard therapy within a well defined subgroup of patients satisfying the corresponding characteristic. We show how one can ensure that patients with several characteristics can contribute simultaneously to the evaluation of several targeted therapies and that this is the key point for an efficient use of the patients available. We further discuss some ethical and practical issues in applying the new designs and outline strategies to evaluate the overall effect of all targeted therapies together.