ETHICAL ISSUES FOR THE GENOMEUTWIN MANUAL
This is a population based genetic epidemiological study to identify genes that predispose to common diseases.. The results are generally not of clinical relevance to individuals but assess risk and effect at the population level. This is an observational study and does not involve experimentation on human beings or animals. Only adults who are fully mentally and legally competent to consent are included in the study. . Given the genetic emphasis in this design, we are very much aware of the potential ethical issues, and therefore have included an Ethical Core as a key component of the study. Below we reply point by point to the ethical issues of the proposed research for which further information has been requested.
1. Describe the potential ethical aspects of the proposed research regarding its objectives, the methodology and the implications of the results.
The major ethical questions associated with the objectives of this study arise from the production of genome-wide scans from the participants. These issues include1) Informed consent
2) Data security and confidentiality and
3) Questions related to information obtained from the study
1.1 Informed Consent
Here we address the aspects of informed consent that must be addressed, and under point 3.3.1 we indicate how the informed consent process will be developed. The informed consent will include purpose of the study, that genetic and phenotypic information will be collected and linked to each other, and how results will be used. Any individual in the proposed research may decline to complete a questionnaire or may decline subsequent participation without penalty of any kind. Requests not to participate are honoured. Data to be collected are for research purposes only. At any point in the future participants may request that their data are deleted from the database without explaining why.
1.2 Data security and confidentiality
A major emphasis will be given to data security and confidentiality. This includes how to protect the identity of the participants; how to guarantee that only investigators have access to genetic information; how the data will be stored and how the data will be shared. The Co-coordinating Institute, the National Public Health Institute in Finland has many decades of experience in data security issues and has been responsible for data security in several multinational studies (e.g. multinational MONICA and MORGAM Projects). Additionally, Dr. Peltonen is a member of the International Bioethics Committee of UNESCO. Thus the project is well conversant with burgeoning rules and regulations on ethical issues related to genetic research and the leading investigators of the Proposal are in a position to participate in this debate a global level.
1.3. Questions related to information obtained from the study.
1.3.1. Individual genetic information
It is possible that this Project will produce relatively detailed information on either genetic or traditional lifestyle risk factors that could have prognostic or preventive value to individuals participating in the study. As a general rule, for data security and confidentiality reasons, the genotypic and phenotypic data will not be linked to personal identification data. Because the study results are intended for specific scientific purposes only, the genotype or other genetic data will not be released to participants and their consenting has been based on this information. The Ethics Core will develop procedures, in conjunction with local Ethics Committees, to deal with special circumstances that may lead to release of genetic results to certain participants. However, it must be emphasized, that the information produced by this Project will not meet clinical service laboratory standards and all individual results must be reproduced in a setting providing a) pre-laboratory counseling, b) adequate confirmation by a clinically-approved laboratory and c) post-laboratory counseling with adequate quality control in place.
1.3.2. Risk profiles
The objective of the Project is to produce genetic and life style risk profiles at the population level. The eventual aim is to produce risk profiling that could be used in the future to advise an individual and/or her/his physician in making lifestyle and other choices that may influence health. Risk profiles are not open to abuse, for example, by insurance companies or employers. Information on such profiles, including genetic, environmental and lifestyle profiles will be invaluable in selecting study samples for phase II and III trials in drug development. Such profiles will pave the way for tailored drug choices for various patient groups, thus increasing the success of treatment, reducing complications and reducing drug development and treatment costs. However, the study data will not be made available to any third parties such as insurance companies or employers.
2. Justification of the Methodology and Research Design
This Project consists of a genetic epidemiological, multinational, multicentre study. This is needed in order to attain sufficiently large study samples to address risk factor and gene variations, which only have a modulating effect on a phenotype. Although clearly significant, the genetic risk factors for most common traits have not been identified, despite extensive international effort. The Investigators responsible for the Project's components recognize the importance of combining epidemiological expertise with the most modern molecular genetic and biocomputing techniques to create a unique, worldwide, genetic epidemiological collaboration -vital for both the identification of genetic risk factors and genetic-epidemiological training of European investigators.
The study participants will include 16 000 individuals recruited through European twin registries and 6000 individuals from various population cohorts participating in the MORGAM Project (page 9 in the Proposal work plan). About 30% of the samples have already been collected in previous studies. The medical risk incurred by participation is minimal, only one blood or buccal cell sample being required from participants. The major risk will involve data security, which is considered below (See section 3.3.2). No fees are given for participating – only travel costs are reimbursed if needed.
The internationally recognized European twin data sets have special advantages for genetic studies, unobtainable in regular family or case-control studies. First, members of twin pairs are perfectly correlated for age and many major environmental influences (in particular, intrauterine and childhood conditions), which are important factors in studying common traits, including chronic disorders. Second, members of twin cohorts have participated actively in these longitudinal studies, mostly by responding to questionnaires/interviews, and their continued commitment to participating in twin cohorts reflects their favourable attitude towards research. Third, twins provide a good route to collecting both information and biological samples from additional core family members, necessitated by some study designs. Fourth, paternity is generally more reliable than in other kinds of sib ships. Fifth, concordant monozygotic (MZ) twin pairs are ideal for association studies and for determining the genetic and environmental factors affecting disease development. They also offer the unique opportunity to search for genes which influence trait variability (e.g. genes x environment interaction). Sixth, twin cohorts represent excellent population cohorts for which ascertainment-bias typically does not pose a problem because sample selection has not occurred with reference to any specific phenotype. Seventh, twin data are particularly valuable for conducting quantitative trait loci analyses. Importantly, many additional, beneficial components for genetic studies exist in the European populations from which these twin cohorts are recruited. Population registers and statistics through church records of deaths, births and migration have been collected continuously since the 17th century for all the participating countries. A particular advantage for genetic studies is the possibility to track pedigree data back several generations through reliable and well-preserved population registers. Just as the twin studies, the WHO MONICA (www.ktl.fi/monica) Collaboration has a long and successful history of conducting multicentre research (participating countries in MONICA are: Australia, Belgium, Canada, China, Czech Republic, Denmark, Finland, France, Germany, Iceland, Italy, Lithuania, New Zealand, Poland, Russian Federation, Spain, Sweden, Switzerland, United Kingdom, USA, Yugoslavia), which makes it ideal for embarking on genetic studies of complex, multifactorial diseases. This is being undertaken in the MORGAM (Monica, Risk, Genetics, Archiving and Monograph) Project, which will focus on genetic and environmental predictors of chronic diseases, in particular coronary heart disease (CHD) and stroke. The value of this cohort to the research described herein is in the immediate validation of any gene(s) identified behind a trait in genetic studies of twin cohorts. Thus, a finding from the twin studies can be tested for its significance using the MORGAM Project sample. This holds for any common trait, especially cardiovascular traits and their components and any trait with a major population impact. Eighth, and perhaps most importantly, the participating centres have carried out epidemiological and genetic research for 10-20 years and have well established, ethically solid study protocols approved by their institutes and local/national boards or committees. This provides a sound basis for mounting genetic epidemiological studies on these study samples.
3. Addressing ethical questions
3.1 Ethical review board
A project of this magnitude, with study samples being collected in several European countries, poses multiple ethical issues. The Investigators are fully aware of this and therefore have proposed to setup a special Ethical Core as part of the proposal to address such issues (page 32 in the original proposal). This Ethical Core is directed by Dr. Jennifer Harris, who is currently on special assignment to the National Institute on Aging, USA, where she develops international research directions in ethical, legal and social implications (ELSI) of human genetic and genomic research. The core is reinforced by internationally-acknowledged experts on medical ethics, including Professor Bartha-Maria Knoppers, University of Montreal, Canada. The Ethics Core will operate across centres, and each centre will have a representative who is knowledgeable about their respective countries ethics code and who is responsible for the implementation of the Core’s policies concerning ethical issues. The Ethical Core is also responsible for training and publishing the ethical guidelines and it will formulate the type of informed consent used in the study (this can be modified according to national regulations and laws) and will write the Ethics Manual for the participating centres. This Manual will be made public and a copy will be put on the Project website along with contact information. The Ethical Core will keep track of the local ethics committees' authorizations and opinions and give advice to local centres when applying for local approval, if requested. The Ethical Core meets whenever necessary, however at least once a year a meeting is held where special emphasis is placed on ethics training of the young scientists participating in the Project. Strong collaboration between the Database Core and Ethical Core is integral to this project. All participating centres have authorization from local ethics committees for their studies. However, due to the multinational nature of this Project, the first task of the Ethical Core will be to harmonize the protocols and prepare additional codes of practice in co-operation with the national Investigators.
3.2 Use of human tissue.
3.2.1 Tissue type: Venous blood / Buccal cells.
A maximum of 20ml venous blood will be collected from the participants for DNA extraction and dense genome wide mapping. From some participants, only buccal cells will be collected, usually when the number of genotypes needed is low. The medical risk from both these sampling procedures is minimal. However , participants will be insured. No other medical procedures will be performed on the participants. The Ethical Core will produce a Blood Sampling Manual. Blood will be drawn from an ante cubital vein after signed informed consent is obtained. The blood drawing will be done by a health care professional (nurse). The buccal cells will be collected according to standard procedures (mouthwash) from adults who have given their consent. The collection devices are pre-labeled with bar codes, no personal identification will be written on the tubes. The coding of the individual participants will be done by the participating twin registries and of the MORGAM centres; no personal identification will leave the individual centres at any point. The code is forwarded to Database Core, which is responsible for quality control and harmonization of the coding. The Database Core will print out and send the patient sample labels to the participating centres, which are then responsible for enrolling the participants. In rare cases, usually when the DNA yield from a given sample is insufficient, further contact may take place for additional sampling, in such cases, fresh informed consent will be obtained.
3.2.2 Justification of the sampling
The amount of DNA needed for the Project is approximately 60 micrograms per participant (25ng per genotype x 2000 genotypes + 20% re-genotyping/pipetting surplus). In our experience, 10ml of venous blood produces an average yield of a little less than 300 micrograms of DNA. Table 1 presents some data from the extraction of the 1997 FINRISK blood samples.
Table 1. DNA yield from 10ml of EDTA blood collected for 1997 FINRISK epidemiological collection and extracted in National Public Health Institute, Finland.
| DNA yield, geometric mean (mg) | DNA yield, arithmetic mean (mg) | SD (mg) | Range (mg) | skewness | number of individuals with less than 50 mg | |
| Females (n=3902) | 262.0 | 309.9 | 185.9 | 8-1690 | 1.72 | 314 |
| Males (n=4024) | 208.7 | 256.9 | 164.3 | 2-1496 | 1.63 | 349 |
| All (7926) | 233.5 | 283.0 | 177.2 | 2-1690 | 1.69 | 663 |
As can be seen, the variance and the range are high so there will be a significant proportion of participants whose DNA yield might not be adequate for complete genotyping. Because the DNA level in blood is mainly determined by the number of leukocytes, selecting participants by their DNA yield level would seriously bias the sample towards people with high leukocyte levels. To avoid this, two tubes will be collected and the second is only extracted if the first does not produce enough DNA . . When the study is completed, any surplus DNA and/or blood/buccal cells will be returned to the participating centres . Buccal cell samples, using the mouthwash technique, produce only approximately 20 micrograms of DNA, however, the variance is smaller and not linked to pathological conditions relevant to study phenotypes . However, because of the smaller yield, the buccal sampling will only be used when the blood sampling is unfeasible or when little DNA is required (for example, sampling for a replication of a positive result in a genomic region).
3.3 Use of personal data and genetic information
3.3.1 Obtaining informed consent
The Ethical Core will produce a form for the collection of informed consent from participants . This form will reflect international and local and European Union laws and agreements. Informed consent will be (is) collected at the point of participation. For individuals whose sample and/or information has already been collected, fresh informed consent will be collected when necessitated by the study setting. As this is an observational study, it does not involve experimentation on human beings or animals. However, for a study of this magnitude, including the genotyping of large epidemiological cohorts, the ethical questions are of paramount relevance and will be carefully reviewed by both external and internal boards. The principles of the Helsinki declaration and those of the Nuremberg Code will be followed. Furthermore, each partner’s national or local judicial scientific-ethical requirements and laws on data protection will be strictly adhered to.
3.3.2 Protection of the confidentiality of the information
Each participant is assigned her/his own study number before DNA extraction, which is then used at all times, name or other identifiable data is not used at the Genotyping Center at any time. All questionnaire and registry data are obtained in coded format, based on the assignment of individual study numbers to each twin, for each individual member within each family and every participant in the population cohorts. This assignment is made at the individual level, so that coding will be unique to the research files, and no one other than immediate local project staff can ever identify any individual. No outsiders can identify individuals or families in the subject samples. No names appear in any research data files. Only specified researchers in the individual study centres have access to the name and identification number of participants. Therefore, already in the local databases, the personal identification will be stored separated from the data that are available for data analysis. As a general rule, the genotypic and phenotypic data will not be linked to personal identification data. A special emphasis is laid on the coding of the phenotypic data so that identifying individuals by specific phenotypic information will not be possible. For this reason, only a minimum amount of restrictive phenotypic information will be collected. The Ethical Core oversees the centres to ensure highly confidential storage and handling of personal data. Because the Project results are meant for scientific purposes only, the genetic data will not be released to participants. As stated above, the Ethics Core will develop procedures, in conjunction with local Ethics Committees, to deal with special circumstances that may lead to release of genetic results to certain participants. To emphasize the importance and essence of proper ethical conduct, the integrated project has an ethical core consisting of leading experts and population cohort representatives. The Steering Group will organize harmonization of data protection protocols across centres.
4. Relevant National Legislation
The European Commission has as of yet not formed a firm position on the ethics of genetic consent. The key document is the Draft Additional Protocol to the Convention on Human Rights and Biomedicine, which is being prepared by the Steering Committee on Bioethics (CDBI) of Council of Europe. CDBI delegations will carry out consultations on the national level and submit comments to the CDBI. The Council of Europe Secretariat will carry out consultation with Pan-European non-governmental organizations. Afterwards, the CDBI will review the Protocol in June 2002. If agreed, the draft Protocol will be submitted to the Parliamentary Assembly for consultation prior to submission for final adoption by the Committee of Ministers. This study will follow the principles stated by this draft document, as well as the principles of good research practice set by international conventions and regulations. This doctrine will be modified only if specific national regulations so require.
Guidelines are being developed in the Nordic countries concerning the use of human biobanks. Public law aspects are described in “The Use of Human Biobanks: Ethical, Social, Economical and Legal Aspects”, Mats G. Hanson (ed.) 2001, Uppsala University Press. We are well aware that both international and national legislative actions regulating genetic epidemiological studies are “work in progress”. We will recruit legal consultants for the Ethical Core who will finalize the necessary internal rules to ensure compliancy with the developing European legislation.
In Denmark, data storage and handling is ruled by the the Act on Processing of Personal Data, Act No 429 of 31st May 2000, which implements the Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on the free movement of such data. (http://www.datatilsynet.dk/attachments/20001061548/ENGELSK%20LOV.doc)
Biomedical research is regulated by the Act on Scientific Ethical Committees. The Act on the Scientific-Ethical Committees system and the evaluation of biomedical research projects, Act No 69 of 08/01/1999; The Act on informed consent and use of human subjects in biomedical research, Act No 161 of 12/10/2000 With regards to biological banks these are to some degree regulated by the acts above and furthermore there is Evaluating report from the Danish Medical Research Council, The Danish Council on Ethics and the Central Scientific- Ethical Committee on Medical information - biological banks, SSVF/CVK 1996 It should be noted from the above regulations, that if any information is released to the participants, it is needed to have both the consent of the National Data Protection Agencies, and judicial counseling of the participant.
Relevant legislation in Finland includes the law on Patient’s rights (1992:785 and 1998:333), which has mandated the creation of a National ethics board. The board supervises the activities of all local ethic boards that are based on hospital districts, but also issues guidelines regarding genetic research and consent, particularly for multinational projects. The Personal Data Act (1999:523, and addition regarding data transfer in the EU 2000:986) are based on the EU directive 95/46/EY. The Act on Medical Research (1999:488) legislates on all medical research, specifying procedures for informed consent, and ethical committees.
In Italy, the new Data Protection Code (legislative decree n. 196 of 30 June 2003) was published in the Italian Official Gazette on 29/07/2003. It entered into force on 1 January 2004. It replaces the Data Protection Law (Law n. 675/1996) as well as a number of other legislative and regulatory provisions. The new code is also called "Single Text for Privacy" ("Testo Unico Privacy"). It is meant to update and complete the national data protection legislation, introducing innovations and conforming national legislation to European regulations, in particular Directive 2002/58/CE. In addition to the Data Protection Code itself, the "Single Text" comprises a number of code of conducts for the processing of personal data for some specific purposes (e.g. journalistic or historical purposes), as well as a technical appendix setting the minimum security measures for the protection of personal data, in particular when processed electronically. The official documents are available at the website www.garanteprivacy.it
In Netherlands, there is a law concerning
regulations on medical research involving human subjects (Medical Research
Involving Human Subjects Act, 26 February 1998)
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Norway, doesn’t currently have and national legislation regarding biobanks. The regulations are being developed, and are informed by similar work in Denmark and Sweden. The biobank legislation is expected to be established in the spring of 2002. However, the extant comprehensive set of laws (listed below) directly or indirectly relate to various aspects of biobanking.
These include:
The
Law of Health Personnel (LOV-1999-07-02-64)
This describes the requirements for the approval of health personnel,
including those associated with biobanks. Issues of confidentiality
and reporting of information are contained within this legislation.
The
Law of Patients Rights: (LOV-1999-07-02-63)
Among other things this includes the rules and regulations for informed
consent.
The
Law Regarding Medical use of Biotechnology:(LOV-1994-08-05-56)
The Law on Personal Information from 1 January, 2002, which replaced
the earlier legislation on personal register from 1998. Previous differences
between European lands regarding this have now been harmonized in the
EC areas according to EUs Directive 95/46/EF regarding the protection
of individuals in connection with the use of personal information and
data sharing.
Legislation regarding health registers is currently being developed and will be reviewed by Sosialkomittee (Social Committee) on March 27, 2002.
In Sweden, there are laws governing collection of biological and health related information (the Health and Medical Services Act (1982:763). Data collection and confidentiality are regulated by the Medical Records Act (1986:203), the Personal Data Act (1998:204), the Health Data Registers Act (1998:543) and the Medical Care Registers Act (1998:544). There is no law governing maintenance of biobanks, however, a proposal is currently under review.
The population-based cohort component of this study (MORGAM) includes in addition to above listed countries, participants from France, Ireland, Russia, Spain and United Kingdom. MORGAM samples differ from those of twin registers since all the samples represent archived samples. Importantly, a prerequisite for any centre to be a part of MORGAM is to have proper national ethical committees' acceptance as well as informed consent from the participants. MORGAM will follow the same guidelines as the twin registers, set by the Draft Additional Protocol to the Convention on Human Rights and Biomedicine, prepared by the Steering Committee on Bioethics (CDBI) of Council of Europe, or the national regulations when stricter.