Ethical considerations
By Alun Evans, MORGAM Coordinator
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Ethical considerationsBy Alun Evans, MORGAM Coordinator |
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© National Institute for Health and Welfare
and the MORGAM Project investigators Last updated: 8 April 2003 For more information, please contact Alun Evans (a.evans@qub.ac.uk) |
Central to the Project is the analysis of DNA from individuals in different European Union Member States. Even at the planning stages of the Project I sought advice from the Commission but could get no firm guidelines on the ethical issues involved. I was referred to various documents, which, at best, were several years out-of-date. Since our study began on 1 May 1998, concern has increased about the ethics of analysis of DNA and the subsequent ownership of the data. There is the moral dichotomy between the vested interests of private companies such as Craig Ventner's CELERA and the openness of scientists involved in the Human Genome Project. More recently, Nature carried a News Feature1 on the controversy aroused by the Icelandic Parliament's decision to grant the company deCODE privileged access to the necessary data to study heart and other diseases in their population. Thus it seemed prudent to the Management Group that the ethical foundations of the Study should be sound.
I, therefore, sought further advice from the European Commission and on Thursday 27 January last, I had a meeting with a Laurence J Cordier, Administrator in Life Sciences II-Bioethics in the European Commission, Research Directorate General. We discussed various documents and she promised to send me copies. I received an email from her on 2nd May including a document, "A Draft Protocol on Biomedical Research" which emanated from the Council of Europe2. Subsequently, hard copies were received of Ethics and Epidemiology: International Guidelines, CIOMS Conference, Geneva, Switzerland, 19903; Directive 95/46/EC of the European Parliament and of the Council, 19954; Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology in Medicine: Convention on Human Rights in Biomedicine 1997, Council of Europe5; and Directive 98/44/EC of the European Parliament and of the Council, July 19986. Laurence Cordier was "afraid that all which is available is very vague and may be not directly helpful" and advised that, in order to finalise our Project, I should consider consulting Dr David Evered (who represents UK on the Working Group on Medical Research of the Council of Europe and who was, in part, responsible for drafting the Draft Protocol which she emailed to me). I subsequently had a face-to-face discussion with David Evered on 26 September. It transpires that basically the European Commission has no firm position on the ethics of genetic consent. He sees the key document to be the Draft Protocol on Biomedical Research, which is being prepared by the Council of Europe2, another draft of which will be out shortly. Laurence Cordier had stated that, when it is finalised, it will become Law in Europe. We also discussed the MRC Human Tissue and Biological Samples for use in Research Interim Operational Ethical Guidelines, issued by the MRC November7; the Royal College of Physicians, London, Research Based on Archived Information and Samples8; and The American Society for Human Genetics Report: Statement on Informed Consent in Genetic Research9. Dr Evered also advised me to talk to the EPIC Investigators in Lyon. This I successfully achieved on 3rd October, 2000 and there seems to be a broad accord between what is planned in our Project and the EPIC Study. After my discussions with Dr Evered I produced a short report which received his approval.
This is still at a draft stage2. It does, however, (Chapter I, Article 2) cover 'the full range of biomedical research activities involving individuals, groups or populations. This includes research into molecular, cellular and other mechanisms in health, disorders and disease; (including epidemiological studies) and it 'includes research based on personal data and biological materials of human origin'. Article 6 (Chapter II) is important in that 'Every research project on personal data including anonymised personal data, or biological material should be submitted to the authorised body or bodies for independent examination of its scientific merit and ethical acceptability in each country in which research is to take place'. Article 7 (new) makes the point that the authorised body should be independent and not subject to undue external influence. Article 8 covers any unforeseen commercial use of data or biological materials (See below). Article 10 refers to 'Duty of care' and states that results must be made accessible to those included in the research. This should be done within the framework of health care or counselling and efforts must be taken in order to protect confidentiality and to respect the right of the data subject not to receive results, ie it covers peoples' right not to know as well as peoples' right to know. The important issue is that participants are given a choice at the outset. Chapter 1V relates to additional requirements for research on personal data or biological samples: article 33 states that clear, documented information shall be provided to the authorised body or bodies for the assessment of ethical acceptability of each research project on personal data or biological materials regarding (i) arrangements for anonymisation and their effect on confidentiality, protection of private life and on communication of relevant results related to the health of the subjects; (ii) information to be provided to those whose data or biological materials are to be utilised in research; (iii) the type of consent sought etc. Article 35 deals with Consent for Research on Archived Data or Biological Materials, it states that 'Archived data or biological materials are those which have been collected prior to the entry into force of this Protocol. Whenever possible, consent should be obtained for the use of archived personal data or biological materials for biomedical research purposes. However, such data or biological materials may be used, after review by the authorised body or bodies without consent for the purpose of a defined biomedical research project provided that: (i) the person has not expressly opposed this disclosure; and, (ii) despite reasonable efforts, it would be impracticable to contact the person to seek consent; and (iii) the interests of the research project justify the authorisations;' . . . and that 'Personal data used for biomedical research may not be published in a form which enables the person to be identified, unless consent has been given for the publication and publication is permitted by law'. These appear to be the main points of the Draft.
The Foreword of this document discusses the need to develop guidance for researchers on ethical, legal and management issues relating to the use of samples of human tissues for research. 'Technical advances, for instance, in the ability to extract genetic material, meant that the potential to use old samples for research was increasing'. It is also recognised that large numbers of well-documented human DNA samples would be essential for the research needed to translate the knowledge obtained from the human genome sequencing into real benefits for public health and health care . . . to ensure that collections of samples can be used optimally for research to benefit human health.
Under Item 1.3 the point is made that samples can be stored for a long time, and may be of considerable value for research which was not, and could not have been, envisaged at the time the material was obtained. However, the use of materials for studies not planned at the time they were obtained raises difficult ethical issues in relation to consent. It is often not possible, and usually impracticable, to go back to the donors for new consent and that information obtained from research using biological samples can have implications for the individual donor and their relatives. The Guidelines recommend that, because of legal difficulties, tissue samples donated for research should be treated as a gift: this is preferable from a moral and ethical point of view, as it promotes the 'gift relationship' between research participants and scientists and underlines the altruistic motivation for participation in the survey.
Under Item 2.3 it is considered NOT [Sic] appropriate for any one company to be given EXCLUSIVE rights of access to collections of samples made with the benefit of public funds and, if so, it is essential that research participants are made aware that their samples, or products derived from it, may be used by the commercial sector, and that they will not be entitled to a share of any profits that might ensue. Under 2.4 it is recommended that personal data should be stored, processed and analysed in a form that does not allow individuals to be identified, unless there is a strong ethical or scientific justification for not doing so. Under 2.5 custodians of sample collections are encouraged to make it a condition of access to the samples that copies of all data generated by other users are provided to the custodian after a suitable period . . . '.
Item 2.6 recommends a two part consent process, the donor being first asked to consent to the specific experiments that are already planned, and then to give broader consent to the storage and future use for certain types of research. The crucial issue is that Ethics Committee approval should be obtained even if it is impracticable to obtain consent for studies conducted on stored samples.
Item 2.7.1, Genetic Research gives rise to some specific issues in feeding back research results. Participants should be advised of the possible implications of genetic information for other family members and the potential impact on family relationships, and also of the implications of genetic risk information for the ability to obtain insurance. However, the uncertain predicted value of most genetic information obtained for research purposes is also an issue.
Item 3.4 states that Ethics Committee approval must be obtained for all new studies not planned at the time the samples were collected for which specific consent has already been obtained. It makes the point that the Committees may be a useful source of independent advice, for instance, on whether to feed back unexpected findings of clinical significance etc. Specifically, the Guidelines state under 4.2 that, generally, established collections can be used for research when samples have been coded or anonymised, and there is no potential harm to the donors of the material, individually or as a group. The HUGO Ethics Committee suggested that such research is permissible on coded samples. The MRC believes that where a genetic test is of known predictive value, or gives reliable information about a known heritable condition, samples must be irreversibly anonymised before testing unless specific consent is obtained. Even when a donor is dead, genetic test results can have implications for surviving relatives. If the predictive value of the genetic information to be obtained is not known, research on securely coded samples is permissible, provided there is a strong scientific justification for not irreversibly anonymising the samples. Others would strongly question the irreversible coding of samples when the test has a high predictive value. This runs counter to the 'Duty of Care' argument. However, in MORGAM the polymorphisms which will be studied should have relatively modest risk associated with them.
Under Item 5, Special Circumstances, 5.1 deals with the issue of samples obtained from abroad which is, of course, relevant to MORGAM. In such cases, researchers must be satisfied that samples have been ethically obtained. Researchers should obtain from the clinician providing samples assurances that they were obtained with proper consent in accordance with, not only with these guidelines, but with guidelines applicable in the country of origin. At the time of writing these remain Interim Guidelines.
The first part of this Report covers familiar territory, addressing itself to the importance of individual consent with the approval of an independent, credible and publicly accountable Research Ethics Committee. Where biological samples have been previously taken and are in excess of requirement for their original purpose and constitute 'left-over' portions, an additional hazard is foreseen. In some studies, data or samples are anonymised at a very early stage of the research process, so that the individual research subjects are not identifiable even to the researcher. The risk of psychological harm or invasion of individual privacy is thereby eliminated. Indeed 'The resources of medical information and medical samples, already in existence, for which such consent has not been sought are enormous. To attempt to contact very large numbers of people, often long after the event in question, and seek such consent, would be impracticable and probably unethical, since it would certainly involve, in some instances a considerable and unexpected intrusion into people's lives'. The Royal College, therefore, reached the view that the kinds of non-intrusive medical research on human subjects which they describe may be ethically conducted without the express consent of individual patients or subjects. Amongst the conditions to be fulfilled are: i) anonymisation of material at the earliest possible stage, ie the minimum level of anonymisation is that which precludes the identification of individuals from the output of the research; ii) there is no inconvenience or hazard, psychological or physical, to the subjects; iii) where doubt exists . . . appropriate consent should be sought and the appropriate Research Ethics Committee should have reviewed and agreed the research protocol, and specifically agreed to exempt the research from the general requirements for individual consent from each research subject. The first recommendation is that the use of archived data and material for research must be preserved. It should be pointed out, however, that at no time does this document mention analysis of DNA.
This Report at the outset states that it is committed to protecting the rights and welfare of those who participate in genetic research as subjects. It endorses the use of anonymous samples [Sic] for genetic research. Importantly, in retrospective research proposing to use samples collected anonymously, or anonymised, there is no possibility, or need to obtain consent. For many studies, there may be benefits to making identifiable samples anonymous, because this effectively protects subjects from some of the risks of genetic research. Importantly, making samples anonymous will eliminate the need for re-contact to obtain informed consent. This will also reduce the chance of introducing bias due to inability to contact some, or possibly refusal of others to participate. On the other hand, investigators should consider the appropriateness of anonymising samples, especially when there is available medical intervention for the disorder being tested. It should be pointed out that this Report is the oldest of those reviewed.
The recent GMC document on Confidentiality, Protecting and Providing Information10 does not address the issue of genotyping. It stated that where it is not practical to contact patients to seek consent, this fact should be drawn to the attention of the Research Ethics Committee so it can consider whether the likely benefits of the research outweigh the loss of confidentiality.
Another document11 emanating from the Centres for Disease Control and Prevention in Atlanta entitled 'Draft Report: Ethical and Policy Issues in International Research September 29, 2000' refers back to the 1993 (2000 Paper) CIOMS Report12. In any case its remarks are limited to the ethics of randomised controlled trials. A recent commentary on the Declaration of Helsinki, CIOMS and the ethics of research12 on vulnerable populations similarly is not applicable to randomised controlled trials.
Lastly, the Virginia Commonwealth University recently caused a membership Alert by the American Society of Human Genetics13 because of contact with proband's next-of-kin in a sib/pair study. Happily, this is not a feature of the design of MORGAM.
From the foregoing it is plain that there are a number of problems relating to the mounting of international collaborative genetic studies such as the Genetic Component of MORGAM. Within the BIOMED 2 Programme there was a Research and Ethics Review Panel and this is continued under the Fifth Framework but unfortunately this is not a policy setting forum. However, the need for mounting large prospective genetic studies in chronic disease are overwhelming as is clear from the Estonian proposal, the Medical Research Council's prospective, General Practice-based proposal, and the EPIC Study1.
It seems that if the data are suitably anonymised, central analysis can take place. This does not obviate the necessity for local ethical clearance and written informed consent in individual centres, but it does seem to be a core message emanating from the various documents. Approval from your local Ethics Committee is necessary for centralised genotying and data analysis relating to your Centre. As your genotypic data will be returned to your Centre on request, you should discuss their storage, and/or dissemination to participants, with your local Ethics Committee.