N A T I O N A L B I O E T H I C S C O M M I S S I O N O P I N I O N Incidental Findings in Research and Clinical Practice Translation: Matina Chatzigianni HELLENIC NATIONAL BIOETHICS COMMISSION Neofytou Vamva 6, P.C. 10674 Athens Tel.: 0030 210- 88.47.700, Fax: 0030 210- 88.47.701 E-mail: secretariat@bioethics.gr, url: www.bioethics.gr 2 I. Introduction The Hellenic National Bioethics Commission reviewed the issue of "incidental findings" which may arise during research in human subjects or medical tests. In recent years, this issue has been a major cause for concern due to the new technologies which have been developed and are already being applied both in medicine and genetics. The term “incidental findings” refers to the findings of a medical test or research, which are (possibly) significant for the subject's health or reproduction and are coincidentally discovered, without falling under the original purpose of the test or research. The greatest challenge posed by incidental findings is to strike a balance between informing the interested party and his/her right "not-to-know", regarding data on his/her health, namely when there is a scientific uncertainty about the implications of incidental findings on one’s health. ΙI. The data Massively parallel DNA-sequencing technologies allow for the simultaneous study of many or all the genes of the human genome within a short period of time and, as a matter of fact, simultaneously in samples from different individuals. The cost of these technologies is gradually reducing, which results in their application not only in research but also in clinical practice. As a result, a great volume of incidental findings is produced, the importance of which covers a wide range. These are classified as follows: a) Pathogenic findings. These are gene mutations which are certain to cause a disease or DNA variants which are associated, to a certain extent, with predisposition to a disease. b) Non-pathogenic findings. These are DNA variants which do not have a direct impact on the pathogenicity of the individual. Nonetheless, there are certain cases where some non-pathogenic findings are indirectly linked to an individual’s 3 health: i. findings showing that the individual is healthy but carries a mutation with an autosomal recessive mode of inheritance which can, however, play a role in his/her reproduction decisions since these findings can have an impact on the health of his/her offspring, and ii. The incidental discovery of non-paternity, which does not have a direct impact on the individual's health, but is crucial for the individual to know his/her genetic make-up and genealogy, for example to prevent a disease. c) Findings of unknown clinical significance. These include findings whose clinical significance and extent of involvement to a disease are not (fully) known yet. In parallel, traditional diagnostic tests widely employed during clinical practice, such as ultrasounds, Magnetic Resonance Imaging (MRI) and Computerized Tomography (CT) scans, may produce incidental findings which do not fall under the patient’s initial clinical picture but have a diagnostic value or significance for the prevention of a disease. In accordance with the above, it is made clear that not all incidental findings share the same clinical significance for the individual’s health, which must primarily be taken into account both before and after conducting genetic or medical tests. III. The ethical issues 1. For the Commission, respect to the individual’s autonomy on issues regarding his/her health constitutes a position of principle. This means that, in principle, every individual shall enjoy the right of general information, regardless of whether he/she faces a particular health problem. This right is reasonably concluded by the fundamental rights to health (both individual and social), which are constitutionally recognized, as well [Articles 5(5), 21(3) of the Constitution]. In addition to this general right, especially a person who recourses with his/her own will to health services (for therapeutic, diagnostic or preventive purposes), must have full control over the relevant information that he/she receives from the physician. One usually seeks this kind of information, in order to be able to decide about the conduct of medical acts, pursuant to the fundamental principle of 4 “informed consent”1. The control in question is exerted in -even exceptional- cases, where the individual, although he/she wishes the conduct of medical acts, explicitly denies information, thus, authorizing the physician to proceed to the necessary acts at the latter’s own discretion. The possibility of this refusal has been recognized in modern medical ethics and law under the term “right not-to-know” or “right to ignorance”2. Therefore, an individual’s “consent” has a double meaning: it concerns both the choice of a medical act (for which there has been prior relevant information) and the information itself. In the case of incidental findings, the interested party is by definition unable to express his/her will in advance, neither for general nor for specific information. The “activation” of his/her will exclusively depends on the physician’s (or the researcher’s) initiative. Nonetheless, the wish of ‘’information’’ or ‘’ignorance’’ cannot be outright presumed. The Commission holds that here lies the basic moral dilemma of the return or not of incidental findings. 2. The second -absolutely relevant- issue concerns the extent of the physician’s3 or the researcher’s “duty to tell the truth”. Supposing that this duty prevails over the individual’s autonomy, then, regardless of the latter’s will, incidental findings would have to be returned. The Commission considers, however, that the principle of autonomy prevails and, therefore, the duty to tell the truth becomes meaningful only once the interested person has an active will to be informed. The problem of incidental findings lies in the fact that, even though such a will exists, it only covers findings generated by means of a particular test as opposed to other ones. 3. Another issue refers to the management of incidental findings as sensitive data. The Commission deems that knowledge of such data by a third party, while the interested person doesn’t know, renders the former par excellence responsible for their safety. Any processing of these data must be excluded, until the interested party is informed -once he/she wishes it. This also applies for the return of incidental 1 See Article 5 of the Oviedo Convention, Articles 11, 12 of the Code of Medical Ethics (Law 3418/2005). 2 See Article 10(2) of the Oviedo Convention, Article 11(2) of the Code of Medical Ethics. 3 See Article 11(1) of the Code of Medical Ethics. 5 findings back to the interested party’s relatives, except for the case when he/she has allowed it, even in the case that him/herself refused to be informed about the findings4. If the interested party exercises his/her right to ignorance, these data must be immediately destroyed. 4. Especially the return of non-paternity findings upon genetic testing, raises a serious moral issue. In this case, there is a conflict between protecting one’s family life (especially to the interest of the child who could definitely suffer from a possible rupture in the parents’ relationship) and, again, protecting the interest of the child to be informed about his/her biological identity. These are fundamental values that conflict each other, and this conflict has not been specifically addressed by law in this field. ΙV. Recommendations Considering the above, the Commission shall commence from the principle of the physician’s duty to tell the truth towards the patient. Accordingly, the researcher also owes to reveal the truth to the participant in a biomedical research. Nevertheless, this duty is activated by the patient’s or the research participant’s right to self-determination, by his/her explicitly expressed wish, that is, to be informed either about specific or about all findings generated by a test. If such a wish has not been expressed, the duty to tell the truth remains inactive. More specifically, the Commission produced the following set of recommendations: 1. The individual’s informed consent to reveal or not the potential incidental findings, which may arise both during research and during a clinical act, is crucial. Consultation between the interested party and the physician or the researcher is deemed necessary prior to any test, in order for the former to be informed about the possibility of incidental findings and understand their potential significance. This will help the interested party to make conscious 4 See Article 11(2) of the Code of Medical Ethics. 6 decisions about whether or not he/she wishes to be informed about incidental findings once they are produced. 2. Under this necessary condition, the Commission stresses that the return of incidental findings must, however, be limited to findings of known clinical significance at the time of testing, which must be based on valid scientific data under the attending physician’s or the researcher’s responsibility. The evaluation of the clinical significance of incidental findings shall be subjected to constant reassessment, on the basis of the growing experience of scientists, as well as the consideration of new data and their impact on an individual’s health. 3. However, there are cases of incidental findings with known clinical significance, which are associated with diseases with no available treatment. The Commission notes that the potential return of such findings is at the physician's or the researcher's discretion. Nonetheless, a necessary condition is for the physician or the researcher to have evaluated the scientific data at the time of testing regarding their utility in preventing or delaying the development of a disease. 4. Regarding incidental findings associated with late onset diseases, the Commission deems that the physician or the researcher has the duty to inform the interested adults, only once this information can contribute to decisions about the treatment or the delay of the disease. 5. Once again, the Commission stresses that an exception to points 2,3 and 4 (regarding adults) would be the case where the interested party has explicitly stated during the process of informed consent that he/she does not wish to be informed about any incidental findings (opt-out), thus exercising the right to ignorance. 6. In the case where the patient's or research participant's prior consent is not available, the Commission considers that the physician or the researcher has the duty to inform ad hoc, even on an ex-post basis, the interested party 7 about the presence of incidental findings and act in accordance with the latter's will. 7. As far as children are concerned, informing or not about incidental findings depends on the parents' consent (or whosever exercises parental care). An exception must be made in case the child is deemed mature enough to decide him/herself, in accordance with what applies to consent in any medical act5. Moreover, the Commission reiterates its previous position as expressed in its Opinion on "Direct-To-Consumer (DTC) Genetic Testing" (March 2012), according to which, if there is no medical emergency, asymptomatic children must not be informed about findings associated with late onset diseases. 8. Finally, the Commission highlights that regarding incidental findings of non- paternity, the decision of disclosing them depends, once again, on the interested parties' previous consent. In practice, this would mean that: a) Consent to genetic testing must be written and, in any case, prior to the test. In the consent form, it is proper to pose a relevant question about the wish to specifically return an incidental finding of non-paternity. The consent form must explain the reason behind this question. b) Once the question has not been answered in the consent form prior to conducting the test, the physician or the researcher is entitled to assume that the interested party exercises his/her right to ignorance, in the interest of protecting his/her family life. c) In any case, these findings must be kept in secure archives. The Commission deems that a child has the right to access his/her biological identity once he/she reaches adulthood, especially for health reasons, in accordance with what applies for medically assisted reproduction6. Athens, 26 June 2015 5 See Article 12(2)(b) of the Code of Medical Ethics. 6 See Article 1460 of the Civil Code. 8