IMPACT OF ETHICS COMMITTEES ON THE STUDIES OF GENETIC RISK FACTORS IN MENTAL DISEASES

1. Figura 3. Illness Spectrum Therapeutic Not Therapeutic Genetics Psychiatry Other IMPACT OF ETHICS COMMITTEES ON THE STUDIES OF GENETIC RISK FACTORS IN MENTAL DISEASES P. Carta, R. De Lisa, S. Serio, F. Ligas, C. Chillotti, M. Del Zompo Section of Clinical Pharmacology, Department of Neurosciences ‘‘B.B. Brodie’’, University of Cagliari, Italy Complex disease Local Guide Lines In the last fifty years, new scientific discoveries have been made in various fields of genetics. Indeed, genetics has numerous branches, each with different objectives and methodologies but which in any case are reflected in every aspect of human activity (Figure 1). • In the field of pharmacological experimentation, two branches of genetics are singled out: pharmacogenetics and pharmacogenomics. The former studies individual differences in the response to drugs linked to genetic variations. The latter is mainly oriented towards identifying the genes and polymorphisms involved in the development of the illness, the ultimate objective being to identify new targets against which to synthesise new drugs. • In planning this experimentation, both the criteria of scientific relevance and ethical feasibility must be respected, so that Ethics and Research share the same objective. • Genetic studies, even if they do not lead to immediate clinical benefits, attempt to produce information that will become useful in the future. For this reason, they must stand apart from the general concept of experimentation, as they represent a contribution to progress and to the growth of the scientific community. The crucial aspect is thus to find an “agreement” between the Population (the rights of subjects enlisted) and the Scientific Community (advancement of knowledge); it is in this scenario that the Ethics Committee comes into play to balance the above two. • All clinical experimentation requires the judgement of an Ethics Committee (EC) before beginning. • The Ethics Committee is: • • an independent organism, composed of medical and non-medical personnel • • guarantees protection of the rights of subjects involved in experimentation • • expresses an ethical and scientific opinion regarding the experimentation protocol • The Ethics Committee evaluates experimentation in agreement with Good Clinical Practice (GCP), the Helsinki Declaration and national regulations. • The Ethics Committee supervises applied pharmacological research and must express an opinion on both interventional/therapeutic research and genetic research. • The rapid expansion of genetic studies has directly involved Ethics Committees in evaluating study protocols, provided with evaluation guidelines. • The Clinical Pharmacology Section of the Department of Neurosciences “B.B.Brodie” of the University of Cagliari, functioning as Scientific Secretariat for local Ethics Committees, has drawn up internal guidelines in agreement with national and international literature to regulate the presentation of protocols at the local level. • In 2002, the Scientific Secretariat of the local Ethics Committees drafted internal guidelines for genetic studies to: • permit correct, homogeneous evaluation of protocols • aid experimenters in devising and requesting evaluation of such studies • increase the qualitative and quantitative impact of such studies locally Figure 1. Human Genome Project Advances in genetics have made it possible to classify illnesses differently on the basis of genotype and to identify new metabolic paths involved in their pathogenesis, leading to increased knowledge regarding the response to pharmacological therapy. The development of genetics has made it possible to study the concept of illness, and in particular complex illness, in greater detail. The difference between monogenic illness and complex illness is linked to the fact that in the former, the gene influences the phenotype, independently of the environment; on the contrary, the latter is determined by both genetic and environmental factors (Figure 2). Numerous illnesses, like diabetes, arterial hypertension, obesity and bipolar disorder are complex illnesses (Figure 3). Figura 2.Components influencing the phenotype Activity of local EC In the field of genetic research in psychiatry, additional problems arise. In general, the main question is respect for the rights of the psychiatric patient who, as a “weak” individual with diminished consensual ability, should never be included in experimentation unless it is specifically directed towards treating the disturbances from which he suffers; in other words, only therapeutic experimentation is permissible in the psychiatric sphere. Actually, this is not a simple matter; it would be opportune for those patients to contribute to non-therapeutic research when it does not involve any risk and at the same time promises great benefit for future patients. This is the case of genetics research, which could provide important knowledge on the biological bases of the disorder and on individual response to a specific drug. Pharmacogenetics The need on the part of local Ethics Committees for precise interpretive criteria arises from the fact that genetic studies present important problems, exceeding those encountered in evaluating pharmacological protocols. Genetic research requires special ethical consideration before being approved by an EC. The practical application of knowledge deriving from pharmacogenetic research consists of the possibility of foreseeing a patient’s response to a particular drug on the basis of a routine genetic test, to arrive at individualised therapy, “the right drug for the right patient." In the period of time between 2002 ad 2005, on the local level, genetic studies made up 7% of the total experiments evaluated by the Ethics Committee. This 7% may be further subdivided into: 81% genetic studies not related to psychiatry and 19% studies related to psychiatry (Figure 5). Studies on pathologies like bipolar disorder, schizophrenia and depression involved a sample of about 750 subjects. In evaluating these studies, the Ethics Committee, taking into account GCP, ethical and scientific principles and internal guidelines, and after discussion with the researcher proposing the study, expressed a favourable opinion, authorising its execution. The guidelines set up have been of benefit, aiding both evaluation and the setting-up of protocols and being of use to both the Ethics Committee itself and the researchers proposing the study. Knowledge deriving from genetic studies could lead to improvements in clinical practice. It would be possible to develop predictive medicine able to foresee individual response to a drug in terms of both effectiveness and safety (Figure 4 a,b). Figure 4b | One ideal goal that is anticipated from pharmacogenomics is to personalize or ‘tailor’ therapies, so that, on the basis of pre-genotyping, all patients who have a given disease will receive different drugs and respond to therapy with less risk of adverse events. Figure 4a | At present, only a limited number of patients are treated with a specific drug for any given disease due to adverse events. Of those patients who are receiving the drug, not all respond. Figure 5. Activity of local EC (2002-2005) Conclusions and Future Prospects In the last few years, pharmacological research has increased considerably, with the result that Ethics Committees are directly involved in evaluating relative protocols. The great development in this discipline has not been followed by simultaneous revision of specific national and international legislation, leaving as a result a legislative vacuum. Given the existence of various guideline proposals, standardised international norms would be opportune. Such standardisation would lay the foundation permitting proper interpretation of genetic studies. This would have important effects, determining an increase in and proper organisation of those studies. The direct, active involvement of important professional associations like the International Society of Psychiatric Genetics would also be appropriate; they could promote initiatives aiming to set up international guidelines for the carrying out of clinical studies on psychiatric genetics.