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Journal of the Academy of Hospital Administration

Statement of Specific Principles for Human Genetics Research

Author(s): Editors

Vol. 14, No. 2 (2002-07 - 2002-12)

Abstract:

Ethical Guidelines for Medical Research Part-IV. Recent developments in frontier areas like genome mapping, genetic re-combinant engineering, assisted reproductive biology, stem cell research have resulted in the formulation of Ethical Guidelines for Biomedical Research by Indian Council of Medical Research. In the fourth part of the ongoing series, this issue provides a "statement of specific principles for human genetics research", which we hope will be of immense use to our readers. (Editors)


Introduction

In no other area of biomedical research there has been a greater concern for ethical issues than in the field of human genetics. It has largely stemmed from the movements of eugenics and nazism in nineteen twenties and thirties. In recent years this concern has grown even further because of the possibility of commercial eugenics. While the advent of recombinant DNA technology has provided one of the most powerful tools in the hands of mankind to unravel the mysteries of the human genome, it has also led to a great deal of concern about our ability to handle the information so derived. With the successful completion of Human Genome sequencing in June 2000 there is an urgent need for clear-cut guidelines and dissemination of information to all stakeholders through media and public debates as there is a great need for improving awareness and understanding of human genetic disorders amongst public, the majority of whom have little knowledge of genetics.

The knowledge about human genes and genetic diseases prior to fifties was so poor that there was hardly any human genetic experimentation. Since then, and especially in the past two decades, there has been a veritable explosion in knowledge in the field of human genetics which has culminated in gene therapy (the ultimate in therapy for genetic diseases) and various other therapies based on genetic engineering including the glib talk of "Designer babies". Serious issues related to participation of human subjects in genetic research are raised particularly when the intervention involves rights of human embryo and subjects who are not competent to give informed consent. Besides the Human Rights issues of dignity, autonomy, and justice, the Human Genome Project (HGP) has also precipitated an unprecedented concern for Intellectual Property Rights. Recent experiments on cloning sheep and mice have brought human cloning into the realm of possibility, raising additional set of Ethical, Legal and Social Issues (ELSI). This calls for laying down of special guidelines to contain the potential harm without clamping a moratorium on research and service in this field. Also, there should be no restrictions in availing the gains of latest technology, which are beneficial to the mankind. In fact ensuring access to genetic services to all irrespective of their ability to pay, particularly to those who need it the most, is an equally important moral concern.

In this rapidly evolving field there is a need for a watchdog body to continuously monitor such developments and respond to emerging ethical issues promptly and judiciously.

General Guidelines

Clinical research in fields of human genetics and human genome, including gene therapy, besides being subject to general ethical considerations of protection from harm and voluntariness of participation has following additional considerations:

(i) The harm may not only be physical, but also psychosocial. Psychologically, the genetic information may produce anxiety and depression or damage familial relationship, which should be safeguarded. Appropriate communication skills are necessary for genetic counselling. There is a likelihood of social stigmatisation and discrimination in schooling, employment, health and general insurance, which requires much greater care in recruiting subjects in research study, obtaining informed consent and maintaining confidentiality of research findings, than in any other area of research.

(ii) There is great importance of spoken word in medical genetics, since genetic counselling is akin to therapy in other fields. In that sense in medical genetics, the "word" is equivalent to drug/intervention in other fields of medicine. Written explanation understandable to layman about presentation and natural course of the disease, interventions available and their outcome, as also implication of the information for progeny and family has special place in clinical research in this field.

(iii) Genetic counselling deals with discussion on personal matters such as reproductive options, and the couple may have to make a choice with far reaching social implications. Therefore, it calls for special care that should be documented in research proposals and carefully considered by the Institutional Ethics Committee.

(iv) Genetic manipulations have consequences for the future, some of which are unknown. Hence, greater care towards potential dangers is necessary.

(v) There is greater likelihood of situations cropping up where there is conflict of interest between an individual, and that of family and society at large. Careful guidelines need to be evolved by peers in the profession to tackle such situations. The professional societies should actively participate in these activities.

(vi) The science of Medical Genetics is progressing very rapidly. Therefore, there is a need for frequent updating of any guidelines for research in this field. To meet this challenge not only the guidelines should be flexible, but there should also be a built-in mechanism to review the guidelines from time to time.

(vii) The Institutional Ethical Committees reviewing research proposals related to research on human genetics should have necessary expertise, which includes knowledge of latest developments in the field of human genetics. In areas of doubt, open discussion should be encouraged. This has to be the responsibility of National agencies e.g. Central Ethical Committee (ICMR) and/or National Bioethics Committee (DBT) to organize national debates on such issues to evolve consensus on them.

(viii) Concerned with the misuse of genetic tests, particularly for the pre-selection of sex, the Government of India has enacted a law known as "The Prenatal Diagnostic Techniques (Regulation & Prevention of Misuse) Act 1994". All researchers in this area shall follow the provisions of this act (and such other acts which may be passed in future).

I. Pedigree Studies

These involve obtaining history of other members of the family of the proband under investigation. It may reveal information about the likelihood of individual members of the family being either carriers of genetic defects or being affected by the disease.

Special privacy and confidentiality concerns arise in genetic family studies because of relationship between the participants. It should be kept in mind that within families each person is an individual who has the right to keep the information about himself or herself confidential. Family members are not entitled to know each other's diagnosis.

Before revealing medical or personal information about individuals to other family members, investigator must obtain consent of the individual to do so. In view of the cultural background of out country where woman is still a vulnerable and exploited subject, revealing information to the husband that his wife is the carrier of balanced chromosomal translocation (leading to recurrent abortions or a genetic syndrome in her child) or that she is a carrier of a single gene causing "X" linked or recessive disease, may lead to ground for a divorce despite the fact that the husband himself is a carrier of the autosomal recessive disorder. While general principles of counseling require presence of both the spouses, necessary care must be taken not to end up in breaking the families.

Subject Recruitment

The familial nature of research cohorts involved in pedigree studies can pose a challenge for ensuring that recruitment procedures are free of elements that unduly influence decision to participate. The very nature of research exerts pressure on family members to take part, because more complete the pedigree, the more reliable the resulting information. Problems of the following kind could arise:

  1. Revealing who else in the family has agreed to participate may lead to breach of confidentiality.
  2. If a proband is used for revealing his personal interest he/she may put undue pressure on relatives to enroll in the study.
  3. Direct recruitment by telephone calls etc. maybe seen as an invasion of privacy by family members.
  4. Contact through personal physicians may imply that their health care may get compromised if they do not agree to participate. There is no satisfactory alternative, which can be recommended. The likely problems are listed, so that appropriate caution may be exercised.

Informed Consent

For biogenetic research involving human subjects certain special considerations have to be kept in mind while obtaining informed consent of the prospective subjects enrolled in the study. These are in addition to general principles that are applicable to all medical research.

Confidentiality of Data

This includes codification of the biological samples, where necessary. The investigator must establish secure safeguards for the confidentiality of the research data. Subjects should be told of the limits of the investigator's ability to safeguard confidentiality and of the anticipated consequences of breach of confidentiality. When commercial companies, are involved in research, it is necessary to protect researchers and subjects from possible coercion/inducement to participate in the study.

Academic institutions conducting research in alliance with industries/commercial companies require a strong review to probe possible conflicts of interest between scientific responsibilities of researchers and business interests (e.g. ownership or part-ownership of the investigator in the company developing a new product). In cases where the Ethics Committee determines that a conflict of interest may damage the scientific integrity of a project or cause harm to research participants, it should advise accordingly. Institutions need self-regulatory processes to monitor, prevent and resolve such conflicts of interest.

Prospective participants in research should also be informed of the sponsorship of research, so that they can be aware of the potential for conflicts of interest and commercial aspects of the research.

Undue inducement through compensation for individual participants, families and populations should be prohibited. This prohibition, however, does not include agreements with individuals, families, groups, communities or populations that foresee technology transfer, local training, joint ventures, provision of health care or of information infrastructure, reimbursement costs of travel and loss of wages and the possible use of a percentage of any royalties for humanitarian purposes.

Defining Risks and Benefits

Potential risks and benefits should be discussed thoroughly with prospective subjects. In genetic research, the primary the risks are psychosocial rather then physical.

Adequate counseling should be given to subjects on the meaning of genetic information they receive. Only those persons who are qualified and experienced in communicating the meaning of genetic information should undertake genetic counseling.

II. Genetic screening

Genetic screening implies search in population of individuals who have, or are susceptible to have a serious genetic disease; or who, though not at risk themselves, are carriers and thus at risk of having children with the particular genetic disease.

It is essential that screening must be purposive. Also, besides validation of screening tests, it shall also be ensured that a suitable intervention is possible. Rarely, screening may be permissible to individuals may vary. It should not entirely be a matter of individual"s choice, but should be determined after careful evaluation by the health care provider. Depending on nature of the genetic defect that is identified and its pattern of inheritance, siblings and other blood relations as well as existing and future offspring's may be affected. This raises ethical questions that differ significantly, from the normal rules and standards applied to handling of personal medical records.

A well informed consent is, therefore, essential. Those being screened are entitled to receive sufficient information in a way that:

  • they can understand what is proposed to be done.
  • they must be made aware of any substantial risk.
  • they must be given time to decide whether or not they would like to participate or withdraw from screening.

Details about the disorder to be screened and its inheritance pattern, reliability of the screening test and what will be done with the samples should be explained. Information about the implications of a positive screening test (abnormal) should also be explained.

Confidentiality should be maintained in handling of results with emphasis on responsibility of individuals with a positive (abnormal) result to inform partners and family members. It needs to be emphasized that consent for screening or a subsequent confirmatory test does not imply consent to any specific treatment or termination of the pregnancy.

General guidelines have to be followed for a vulnerable individual i.e. minors, mentally ill, prisoners, students, subordinates and people who do not speak the language of the investigator etc.

Genetic counseling should be readily available for those who are being screened. Law protects confidentiality of medical information, but this is not absolute. Information may be disclosed where it is in the public interest to do so, or if required by the court of law. However, great care is needed in this regard as well.

Screening new borns:

Screening of new borns is permissible to detect those genetics diseases like phenylketonuria where serious effects of the disease could be prevented by a suitable intervention such as special diet or treatment. It should not be done when there is no immediate cure/intervention for diseases manifesting later in life. The same applies to investigations to detect genetic, chromosomal, metabolic abnormalities, etc. The diseases can be screened as the when intervention/therapy becomes available in future.

Prenatal testing:

It is aimed at detecting presence of abnormalities in the foetus. The foetal sample for examination may be obtained through amniocentesis, chorionic villi sampling, placentocentesis, cordocentesis (blood sampling from the umbilical cord) and skin or other biopsies. Foetal cells in maternal circulation ;can ;also be used for prenatal testing. Non-invasive methods should be preferred whenever available.

Anonymous testing:

Researchers may conduct anonymous testing on general population in order to establish prevalence of genetic traits diseases. Blood spots collected for screening newborns for treatable disorders could also be used for this purpose. In case information derived from stored specimens might be useful to an individual, the code of anonymity may be broken with the approval of the Institutional Ethics Committee (IEC).

III. Therapeutic trials including gene therapy

Recombinant protein products

Genetic disorders, which require replacement therapy like ADA deficiency, do no pose any ethical problem. Replacement with animal products should follow the rules as stipulated for other diseases.

Gene Therapy

The goal of human genetic research is to alleviate human suffering. Gene therapy is a proper and logical part of this effort. Gene therapy should be subject to all the ethical codes that apply to research involving patients.

Somatic cell gene therapy

is the only method that may be permissible for the purpose of preventing or treating a serious disease when it is the only therapeutic option. It should be restricted to alleviation of life threatening or seriously disabling genetic disease in individual patients and should not be permitted to change normal human traits. However, rapid advance in science necessitates periodic review of guidelines in this area. This includes evaluation of safety and efficacy of DNA vaccines and transgenic foods as well.

Gene Therapy trial consists of two parts. The first part is preparation of the "gene construct" to be administered, and the second part is evaluation of the efficacy and safety of the administered "gene (construct)". As far as the first part is concerned, the guidelines and clearance for it is to be regulated by the National Bioethics Committee under "Department of Biotechnology (DBT) and for the second part clearance from the local IEC and Central Ethical Committee (CEC) of the ICMR shall be obtained.

Safety should be ensured especially because of the possibility of unpredicted consequences of gene insertion. All gene therapy trials should have the provision for long term surveillance. Informed consent must be taken especially regarding uncertainties about outcome. Children could be candidates for therapy, if the therapy is meant for a childhood disorder.

a) Germ Line Therapy is prohibited under the present state of knowledge in these areas.

b) Gene Therapy for enhancement of genetic characteristics (so called designer babies) should not be attempted, as we possess insufficient information at present to understand the effects of attempts to alter/enhance the genetic machinery of humans. Also, the influence of environmental interaction on the expression of genetic characters is poorly understand.

It is safe or ethical for parents to give, for example, growth hormone to their normal offspring in order to produce very large football or basketball players. Similarly it would be unethical use genetic engineering for improvement of intelligence, memory etc. even if specific gene/genes are identified in future.

c) Eugenic Genetic Engineering for selection against personality, character, formation of body organs, fertility, intelligence and physical, mental and emotional characteristics is prohibited.

IV. Human Genome Project (HGP)

The human genome project (HGP) is an international research effort, the goal of which was to determine the location of estimated 40-1,00,000 genes and to sequence the entire human DNA. Another component of the programme is to analyze the DNA of a set of non-human model organisms, which may contribute to understanding of the human genome. The project began formally in 1990 and has been completed by June 2000. This project has resulted in exploring the potential for profoundly altering our approach to medical care from treatment of advanced disease to prevention, based on the identification of individuals at risk, and designing it specific to targets/individuals.

Implications of using this genetic knowledge pose a number of questions for:

i. individuals and families - whether to participate in testing, with whom to share the results, and how to act on them;

ii. health professionals - when to offer testing, how to ensure its quality, how to interpret the results and to whom to disclose information;

iii. employers, insurers, the courts and other social institutions - the relative value of genetic information to the decision they must make about individuals;

iv. governments - about how to regulate the production, and use of genetic tests and the information they provide and how to provide access to testing and counselling services for society; and

v. the society - how to improve public understanding of science and its social implications and increase participate in of the public in science policy making. The above questions should be addressed to be the scientific community before application of this knowledge could be considered as ethically valid.

V. DNA Banking

Primary use:

Primary use is the use for original intent for which consent and approval of Local IEC has been obtained. It is recommended that normally the use of the samples shall be reserved for this purpose only.

Secondary Use:

Every request for secondary use shall be examined by the Institutional Ethical Committee:

  1. to ensure that the proposed use does not transgress the original consent given for the earlier study;
  2. the validity of the objectives of the new study; and
  3. provisions for ensuring anonymity of the samples for secondary use.

VI. DNA Diagnosis

The general principles of informed consent, confidentiality and other criteria used for any investigation in genetics should be followed.

Since the knowledge in this field is new, and relatively complicated, a DNA test must be preceeded and followed by appropriate genetic counselling.

Pre-implantation DNA diagnosis:

It is a type of prenatal diagnosis. Same precautions and safeguards should be adopted for this purpose also.

Pre-morbid diagnosis in children:

Parents are advised not to get the diagnosis done especially in cases like Huntington"s disease etc. for which there is no available intervention till the child reaches the age of proper "consent"

Pre-morbid diagnosis in adults:

It may be carried out with informed consent. However, appropriate genetic counseling must be provided and documented before offering such services.

DNA Diagnosis in Forensics:

The laboratories carrying out DNA diagnosis in forensics should follow the guidelines evolved by National Accreditation Board for Laboratories functioning under the Department of Science and Technology.

The consequences of DNA testing for conditions for which no treatment is available or for conditions manifesting late in life e.g. breast cancer, Alzheimer"s disease etc. should be seriously considered before embarking on such studies. Information so derived should not disclose the identity of the individuals.

VII. Assisted Reproductive Techniques

This includes any fertilization involving manipulation of gametes outside the human body and the transfer of gametes or embryos into the body.

Informed consent should include information regarding use of spare embryos. It should be made clear whether embryos that are not used for transfer could or could not be used for research purposes or implanted in another woman"s womb, or "preserved" for use at a later date or destroyed. Investigators should ensure that participants are informed and consent is taken in writing on the above issues.

Investigators should clarify the ownership of the embryos that they belong to the biological mother or the laboratory. Abortions should never be encouraged for research purposes.

There is no ethical objection at the moment for IVF or any other related procedure for research or for clinical application. Respect for embryo can be shown by:

  1. accepting limits on what can be done in embryo research,
  2. committing to an inter-disciplinary process of peer group review of planned research, and
  3. carrying out an informed consent process for gamete and embryo donors.

Further, respect for the embryo"s moral status can be shown by careful regulation of conditions of research, safeguards against commercial exploitation of embryo research, and limiting the time within which research can be done to 14 days i.e. when the primitive streak appears. This restriction is in keeping with the policy in several nations that permit research with embryos. At this time, the development of nervous system begins and the embryo begins to become a distinct individual.

Women have a special position as care givers for children with disabilities. Since the bulk of care falls upon the women, she should make the final decision among reproductive options, without coercion from her partner, her doctor, or the law. Choice is more than the absence of legal prohibition or coercion. Choice should include the economic and social ability to act upon a decision, including disability. There should be a positive right to affordable genetic services, safe abortion and medically indicated care for children with disabilities.

Cloning (through nuclear transplantations or embryo splitting):

The possibility of human cloning cannot be rejected since sheep and mice have already been cloned. However, since its safety success, utility and ethical acceptability is not yet established, research on cloning with intent to produce and identical human being, as of today, is prohibited.

VIII. Prenatal Diagnosis

This should be performed only for reasons relevant to the health of the foetus or the mother. Prenatal diagnosis should not be performed solely to select the sex of the child (in the absence of an X-linked disorder). Sex selection, whether for male or female, denigrates the fundamental personhood of those yet to be born, and has the power fundamental personhood of those yet to be born, and has the power to harm societies by unbalancing sex rations. The potential harm to large groups of people outweighs any immediate benefits to individuals or families. The Government of India has already passed legislation banning diagnosis of se for non-medical reasons.

Prenatal diagnosis can be used to prepare parents for the birth of a child with a disability. Therefore, prenatal diagnosis should be available to such parents who request it but oppose abortion, provided that they understand and are willing to accept the risks to the foetus.

In some cases, prenatal diagnosis may be performed to protect the health of the mother. These include clinically confirmed cases of morbid anxiety or situations where prenatal paternity testing would benefit the mother's mental health (e.g. if rap occurred while a couple was trying to conceive).

Professionals should recognize the human and economic costs involved in prenatal diagnosis and should limit its use to situations where there is a clear benefit.

Definitions

Genetic material/genome: Genetic material refers to DNA or any other material carrying hereditary information in each cell of an organism. It consists of unique, single copies of genes, which make up approximately 10% of the DNA. The total informational content of an individual is known as "genome".

Chromosome: The thread-like DNA in a cell is divided into several separate lengths. Each length forms a structure called a chromosome. There are two copies of each chromosome in every cell. Human cell contain 23 pairs of chromosomes.

Gene: A gene is a length of DNA that contains the information needed to make one polypeptide. For example, the beta globin gene contains the information needed to make the beta globin polypeptide found in hemoglobin of red blood cells. More than one gene may be involved in making one protein, and more than one polypeptide may be formed from one gene as a result of alternate splicing.

Genetic Engineering: It is the process of creating new DNA such as be cutting and patching (recombinant DNA technology). Several other technologies such as site directed mutagenesis, vector mediated integration or deletion of DNA etc. have evolved and are continuing to evolve.

Heterozygote: Each cell of an organism contains two copies of each gene. In a heterozygote, the two genes of a pair are different from each other (allelic).

Homozygote: Each cell of an organism contains two copies of each gene. In a Homozygote, both copies of the gene are identical to each other.

Mutation: A process by which the DNA of an organism changes or mutates. In humans this can lead to disease such as thalassemia in which the mutation results in decreased production of beta or alpha globin. The mutant gene is passed on from parent to the offspring, so the condition is inherited. In viruses and other infectious organisms, mutations can lead to emergence of organisms with new characteristics. It can make them more virulent or resistant to antibiotics thus increasing their infectivity.

Recombination: A cross-over between two members of a homologous pair of chromosomes results in the formation of a recombined chromosome wherein a new set of gene (allele) arrangement is created.

Transgenesis: This refers to the introduction of a foreign gene into an animal or other organism. The transferred gene is called a transgene.

Human Genome Diversity
Department of Biotechnology, Government of India has brought out a document on genomic diversity which envisages the following:

i) There is worldwide interest in the study of genomic diversity of anthropologically well- defined populations for understanding the origin of people which has evolutionary implications.

ii) This may require establishment of national repository of biological samples (DNA, cell lines etc.) but it should be done with appropriate safeguards and regulations to ensure anonymity of the sample (the identity of the sample should not be no traceable) and protection of the rights of the people.

iii) It shall be ensured that participation in these studies is entirely voluntary, and no coercion or inducement is employed for the purpose. The intent for collection of these samples and possible impact of the information desired shall be explained to the participants.

iv) The analysis of DNA samples shall be carried out by Indian scientists/laboratories. No sample shall be sent out without following the guidelines of the Government of India (GOI) in this regard. In the event of failure of agreement the guidelines of the country (India) shall prevail. International collaboration, if any, shall be carried out with well-documented MOU, which is approved by the Institutional Ethical Committee. This should include the scope of utilization of exchanged material and related IPR issues, as well as concerns for human rights.

Scientists involved in these studies shall ensure that rights and sensitivities of the participating individuals and populations are protected. Relevant issues like (a) consent for collection of samples, (b) access to these samples and for what purposes, (c) Property rights of the DNA; and (d) quality control of the laboratories shall be appropriately documented in the research proposal for scrutiny by the Institutional Ethical Committees.

A major concern regarding these studies is the possibility that generated information may produce ethnic disharmony. Therefore, great care is necessary for handling of this data, particularly, in reference to release of news to media and publication of research results.

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