A 'Contract Model' for Genetic Research and Health Care for Individuals and Families
- Hans-Martin Sass, Ph.D.
The evolving revolution in human genetics knowledge soon will lead to revolutionary modifications in concepts of health and disease, in prediction and prevention, in clinical research, in health literacy of lay persons, and last but not least, in health care and its priorities. Health cannot simply be understood anymore as 'a state of complete physical, mental and social well being and not merely the absence of disease or infirmity' [13:459], rather as processes of challenge, response, and balancing. Health is not just a status, as the WHO formula suggests. Health results from balancing care with support and access: health-literate and risk-competent care of one's own physical, emotional, and social well being and well feeling, achieved in competent understanding, modification and enhancement of genetic, social and environmental properties, the support of health care professionals and through equal access health care information including predictive and preventive services [9;10]. Bioethics, therefore, needs to focus more the ethics of the lay person in health care matters [1;10].
Three areas of health care and research seem to need immediate modification in the clinical, ethical and regulatory setup of modern medicine as a result of new paradigms from genetics: (1) clinical research in drug development, (2) disease-specific clinical research in genetics, (3) carrier screening and consultation for the treatment of specific genetic disorders. The relationship of self-determination and privacy, with rights and obligations to know, to get consultation and best possible medical care has to be re-assessed, and the traditional soft-paternalism model of 'informed consent' could be replaced by an 'informed contract' model between carriers, their physicians, researchers, and research institutions .
Improving Efficacy and Reducing Risk In Drug Metabolism
It is well known that certain drugs act differently in different people, some having severe side-effects, even causing death; other are not efficacious. Efficacy and side-effects are controlled by the individual enzymatic setup. Now, accurate genotyping for drug metabolism can produce great improvements in drug development and individualized prescription .
Fears that genotyping for drug metabolism will lead to genetic discrimination are ethically and clinically not convincing. Blood typing did not lead to discrimination, even though some individuals have rare blood-types and therefore less favorable access to blood replacement. Blood profiles and medication profiles do not describe disorders, i.e. an individual aberration from a generic image, rather they constitute different types, none of which is the 'normal' one. This is a model of 'variation', not a model of 'order and disorder'. It would have been a crime against humanity and an unexcusable wrong towards patients if blood-typing would not have been developed and fully introduced into routine clinical practice. While normal differences between types of metabolizers cannot be called disorders, as we would not call one or the other of blood type a disorder, there are certain genetic disorders for which for over three decades typing has been occurred such as typing of the major histocompatibility complex MHC, the genetic property controlling what antigens are recognized by T-lymphocytes . It has not been reported that people carrying this MHC cards had been discriminated against by employers or insurers. Genotyping for drug compatibility would be similar to blood typing; it causes no significant other ethical concerns than those associated with blood typing: clinical reliability of typing procedures, equal access to typing services, no (medication prescribing) intervention prior to typing.
Controlled clinical trials can and should be restructured so that new drugs be tested for their metabolic properties and groups of patients and probands be typed accordingly before included in the trial. Such a restructuring will lead to ethically required more efficient research protocols with less probands and better biostatistics. Unfortunately, the recent 'Operational Guidelines for Ethics Committees' by WHO [15: 4G, 5C, 6C] do not address those important moral and clinical requirements. Given existing pharmacogenetic knowledge, it is unethical not to include genotyping into drug development and not to establish efficacy, dosage, and side-effects for major types of metabolizers based on cytochrome P450 isoform properties and composition.
Informed Contracts In DNA-Banking And Clinical Research
Of particular bioethical concern is the risk of misleading and exploiting patients and subjects in the race to collect DNA samples within highly defined groups of patients or populations. The mapping of genetic properties of those higly defined subgroups contributes to detailed understanding of the innerworkings of the human genome. As such, it is in the interest of promoting genetic knowledge and therapy, e.g. in areas such as analyzing, interpreting, and treating disorders associated with the minute individual differences in small molecular signposts, SNP's. Whether or not individuals or collectives want to contribute to scientific knowledge and medical progress, depends on their cultural and ethical attitudes and must be decided by them only . They might present it as a gift, or they might ask for reimbursement of costs associated, additional fees, and compensation for any risks associated with their gift or donation. They also could benefit collectively from subsequent description of their genetic properties in regard to medication, nutrition, lifestyle, and predisposition to or prevalence of certain disease . In the case of ADPKD, an autosomal dominant late-onset polycystic kidney disease , it has been reported that specific diet in transgenic polycystic kidney rats has caused the non-development of cysts. Science (Oct 22, 1999), reported that the long searched for enzyme beta-secretase had been discovered by a research team of Amgen in Thousand Oaks, California; successfully blocking this enzyme might prevent or slow down the process of this brutal disease.
If governments or social or religious communities contract with research parties on behalf of their population or parts thereof, then individuals at least should be given the choice to opt out of such contracts; naturally those individuals will simultaneously loose specific benefits provided in the contract. The contracts between the paternalizing government of Iceland and DeCode Genetics or of the Mormon Church in Utah and Myriad Genetics must provide detailed information on privacy and potential benefits, allowing for subcontracting by individuals and families [4; cf www.genengnews.com; Chang L, Chang L (2000) Geneticists focus on a controversial treasure: all the DNA in China The Wall Street Journal Sept 13, B1-3.- Wong JF (2000) The bulls are rallying the biotechnology sector's rise GEN 20(15):47f.].
It seems to be unlikely that traditional informed consent, even if valid and meaningful , can be modified enough, so that probands and their families will get those benefits in information and possible predictive and preventive services. For genotyping in patients from subgroups of cancer or other diseases, informed consent forms rarely have addressed multipurpose screening, future screening, long term storage, and future benefit to patients and their families. The Framingham study, starting 52 years ago, could not conceive those issues and their ethical implications; therefore researchers now sifting through stored material for genetic clues definitely have ethical problems in using those samples . It has been suggested that only for the present moment specific informed consent should be requested and that further use should be covered by new specific re-consent . However HUGO ethics committee considered this too rigid a system . On the other hand generic consent forms - in particular for prenatal and newborn screening - were proposed, but others criticized such an approach as lowering the standards of informed consent [10;12].
Given these new ethical problems in cross-purpose genotyping, these issues should be worked out in a contract model, rather than in a consent model [8;9]. The contract must describe the obligation of the researchers to inform the patient on all or some of their findings: 'We ask you to sign a contract for genetic testing on information and properties which might or might not be associated with your disease and how they are associated with it. This might take a long time and we might look for information we don't know yet. We make it our legal and moral obligation to inform about any finding which might in our judgment benefit your treatment and which might be beneficial to members of your family. Also, at any given time, you or your representative has the right to cancel this contract and to request that your biological properties be destroyed and you or your representative be given information obtained up to that point of when the contract is cancelled. If you want to share in possible financial gain associated with this particular research, we will provide you with a separate contract.' This is a generic declaration only. Contractual rights and obligations, based on assumptions of traditional research ethics and proband's interest, have to be defined in more specific terms, giving both sides a number of choices.
Contracts can be written differently, depending on the parties involved and their interest and preference, as long as essential human and civil rights are not harmed. Within the contract, patients or their legal representatives at least must be informed on standard data-protection, complex issues of privacy and disclosure, the right not to know, and the duty to know. The contract must also provide, that patients can make their own choices (a) for mandating disclosure of predictive, preventive, or therapeutic knowledge to themselves, (b) for refusal of all or some information, and (c) for postponing such a decision for later based on then existing individual circumstances or clinical results. The moral and legal issues of informing and protecting family members similarly will have to be addressed within the contract by allowing the patient to choose among a number of procedures by which family members of various degree may or not be involved, informed, or invited to be tested or to choose to be informed or not. As most future clinical research will involve genetic information, sometimes long-term storage and follow-up research and findings, the informed consent model is not capable of addressing ethical and clinical issues appropriately and should be replaced by a 'contract model' in which both parties, research and patient or proband, delineate their contract-specific rights, duties, obligations. It remains an open question, however, whether patients can effort legal fees if research companies break the contract or re-negotiate; nevertheless, the contract model gives patients and probands a much stronger position than the consent model.
New Parameters for Professional-Lay Interaction In Health Care
Genotyping provides an entire set of new tools for individuals, families, and communities to better understand the human condition, to better care for health, and to fight against and to avoid sickness and disease. But as all tools, new and old, genotyping can be used in a virtuous and in a vicious way. Public discourse and education and the appropriate protection of human and civil rights will be needed to steward and accompany the transition into a new millennium of health literacy and health care. Our charter into the new territories of self-understanding and self-destination, of better health care and improved quality of life for all will not be made easier if we hold on to old models of requesting simple informed consent only, by conducting clinical trials without specific consideration of genetic properties of patients and future beneficiaries, or by withholding information and predictive and preventive services, already made possible by new parameters of human genetics.
Different people have different types of blood or liver enzymes, some have a defect in controlling antigens in their MHC , others have other capabilities or incapabilities, abilities, inabilities or disabilities, talent or lack thereof. As all of us have our own specific set of ability, inability, and disability, a new form of solidarity might arise, a solidarity to help each other to overcome or live with incapacities and to cherish each other's capacities, to build on one's gifts and to learn to live with one's shortcomings [1;7]. New challenges require the re-definition of interactive health care maxims, re-defining rights and obligations of health care stakeholders:
(1) Educated and responsible people have moral rights and duties to learn about their genetic properties and how to make the most out of these properties; they also have a moral duty to help fellow humans in taking care of their individual genetic properties, in particular towards members of their family.
(2) Health care professionals are obligated not to suppress or to withhold genetic information from patients; they have the duty to do their utmost to educate their patients and to guide and to serve them in caring for their health.
(3) Lay persons and health care professional should feel bound by an invisible contract of communication-in-trust and cooperation-in-trust, sharing responsibilities, rights, and obligations, also in the care of the less fortunate, the less healthy, and the less competent.
(4) Governments, national and international institutions and organizations must provide legal, regulatory, and information networks for the protection of human and civil rights, for the development and improvement of health literacy, and for the protection against exploitation and discrimination; regulatory ethics in human genetics should be based on the ethics of information and education, also the promotion of predictive and preventive services and the protection of privacy.
1. Kielstein R, Sass HM (2000) Ethical Issues in kidney disease Ethics and the Kidney, ed Levinski NG, Oxford: Oxford U Press, chapter 10.
Kennedy Institute of Ethics
Georgetown University (2001P)
Washington, DC 20057-1212, USA
Eubios Journal of Asian and International Bioethics 11 (2001), 130-132.
Towards 'Informed Contract' Models In Health Care And Research
2. Kolata G (2000) Boston U. founds a company to sift landmark heart data New York Times June 17, A9.
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6. Sass HM (1989) Ethics of Drug Research and Drug Development Arzneim.Forsch./Drug Res. 39 (II) 8a:1041-1047.
7. Sass HM (1995) Some Cultural and Ethical Reflections on Molecular genetic Risk Assessment Proceedings of the International Bioethics Committee 1994, vol. II, Paris: UNESCO.
8. Sass HM (1998) Genotyping in clinical trials J. Med. Phil. 23:288-296.
9. Sass HM (2000) Ethical issues in genotyping for pharmacogenetics and genetic disorders Proceedings 2nd Hong kong Genetics Conference, ed S Lam, Hong kong. Georgetown University Medical Center's Division of Clinical Pharmacology maintains a list of known properties of drug metabolizing by the cytochrome P450 system, <www.drug-interactions.com>; [DA Flockhart et al, Lancet 352(1998):suppl 4:SIV2..
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11. Sugarman J et al. (1999) Empirical research on informed consent HCR, special supplement Jan/Febr.
12. Wells RJ, Biesecker LG, Wilfond BS, Sherman E, Annas GJ (1994) Generic Consent for Genetic Screening: Letters and Response NEJM 331(15)1024-25.
13. World Health Organization (1958) The First Ten Years of the W.H.O, W.H.O. Geneva.
14. World Health Organization (1998) Proposed International Guidelines on ethical issues in medical genetics and medical services Geneva: WHO [doc.ref. who/hgn/gl/eth/98.1].
15. World Health Organization et al. (1999) Operational guidelines for Ethics Committees reviewing biomedical research, draft discussion document, version 1.4, Nov 18, 1999, Geneva: WHO.
16. HUGO Ethics Committee Statement on DNA Sampling: Control and Access (March 1998).
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