Genetic Research in Human Populations

 

This module was prepared by members of the CITI Genetics Workgroup: Elizabeth Bankert, Dartmouth College; Kenneth Goodman, University of Miami Ethics Programs; and Anil Sharma, IRB Company, Inc. It is based on a module originally written by Goodman.

 

Introduction

Thirty years ago, a drop of human blood provided information on blood chemistry and identified its source as falling into one of four blood groups. Today, in a pharmacogenomic world, that drop of blood identifies its source as a member of a large number of genetic subcategories; can, at least in principle, help predict the response to specific treatments; provides precious information about predisposition to disease; helps investigators study the role of genes in the etiology and mechanisms of disease; and, when stored in a biorepository, represents a valuable source of information for those whose research seeks deeper understanding of genotype-phenotype correlations. The availability of genetic information in that drop of blood represents one of the most exciting opportunities in the history of biomedicine. It also constitutes some of the most difficult challenges in the history of human subjects research. This module is intended to help researchers and IRBs sort through some of the implications of this new technology.

 

Section I: Varieties of genetic research

1. Genotyping and genome-wide association studies

The human genome consists of approximately 3 billion nucleotide bases, and the goal of determining its sequence was reached with the completion of the Human Genome Project in 2003. Determining the sequence of a genome, or a portion of a genome, of an individual is called “genotyping.” The analysis of DNA sequences and of variations between individuals’ nucleotides (that is, single nucleotide polymorphisms or SNPs) is enabling the science of personalized medicine. SNPs affect the development of disease and response to medication, and their analysis is the cornerstone of pharmacogenetics. Genetic research is increasingly a component of human subject trials. In addition to pointing the way to new generations of drugs and treatments, however, SNP analysis can be used to assess the risk of disease, determine (non-) paternity and predict individuals’ vulnerability to certain environments and substances.

 

In Genome-Wide Association Studies (GWAS), SNPs across the entire genome can be identified and associated with various maladies – and the likelihood of their development in population subgroups. An important tool in molecular or genetic epidemiology, GWAS and genotyping raise interesting issues related to management of information and of laboratory discovery.

 

Genotyping studies have long posed interesting and difficult challenges to the protection of confidentiality and privacy – including the “privacy” of population subgroups – and the consent process. These challenges are particularly important for IRBs to address. Federally supported GWAS must now de-identify and upload all data to central databases; these studies are tremendously expensive and data-sharing allows researchers to make maximum use of information.

 

2. Pharmacogenomics and pharmacogenetics

Pharmacogenetics is the study of how the genetic makeup on an individual may affect his/ her response to a particular drug. Pharmacogenomics is a science that examines the inherited variations in genes that dictate drug response and explores the ways these variations can be used to predict how a patient will respond to a drug. In general, pharmacogenetics is the study of various responses to drugs, and pharmacogenomics is the study of drug response in the context of the entire genome.

Pharmacogenomics is the key to personalized medicine; the use of knowledge about an individual patient's genetic make-up can influence the treatments, drugs, and doses physicians choose for that patient. An anticipated benefit of pharmacogenomics includes the development of more powerful drugs. This is the basis of personalized medicine.

As above, this research requires special attention to privacy and confidentiality, the role and scope of the valid consent process and the appropriate approach to and process for the secondary use of data and stored biological samples.

 

3. Biorepositories

Biorepositories have come to play an increasingly important role in genetic research. Nearly all research institutions maintain collections of biological material. The growth of pharmacogenetics and the goals of personalized medicine have accelerated the utility of these collections. Analysis of these materials, usually blood or biopsy specimens, pose important challenges for institutions, investigators and IRBs:

 

•How specific must consent be to permit research on stored samples?

•Do investigators have a duty to warn people who are the sources of samples of health risks?

•Who owns and should control biorepositories?

 

Despite their rapid growth and utility, governance of biorepositories remains one of the most interesting – and underaddressed – problems for investigators and institutions. The intersection of privacy and consent is especially significant, and points to additional challenges for managing data sharing and collaborative research. IRBs are increasingly needing to determine the adequacy of policies for de-identifying and re-identifying genomic data and samples. Moreover, some “bio”repositories have been rendered digital, and it is reasonable to infer that at least some and perhaps most future research will involve studies of the content of electronic data bases rather than that of sample tubes or of frozen sections.

 

Section II: Ethical Issues

Privacy and confidentiality of individuals and communities

The terms “privacy” and ”confidentiality” are not synonymous. Generally, ”privacy” refers to persons and “confidentiality” to information. If, for instance, one surreptitiously obtains a quantity of residual blood from hospital testing and analyzes it for cancer markers or mutations, then we should say that the blood source’s privacy has been violated. If, on the other hand, one were to sneak a look at the source's medical record and learn that she has breast cancer, her confidentiality has been breached.

 

For a number of reasons, including increased risk of bias, discrimination, and stigma, genetic privacy and confidentiality are sometimes thought to be more important than privacy and confidentiality in other kinds of research. Genetic information is, for these reasons, sometimes compared to information obtained from research involving sexually transmitted diseases, or psychiatric illnesses, in that hidden social behavior which the subject wishes to keep confidential may be revealed. This is, however, controversial, and there are strong arguments against what has been called “genetic exceptionalism.”

 

Investigators preparing to conduct genetic research must tell potential participants which entities and persons will have access to the data. This might include investigators at other institutions, corporate sponsors, a government, employers, etc. If information obtained during research will be placed in a patient’s medical record, this too must be disclosed. Subjects should also be told of the risks of others having access to his or her genetic information. Principal investigators must also discuss the risk of information being re-identified or accessed with future technology. Many of these risks are difficult to measure and, unlike the physical risks of traditional biomedical research, are often subtle, social and psychological.

 

Unlike most other kinds of health information, genetic information applies to or is about more than one person. Analyze genomes and you will learn something about a person’s parents, siblings, children, and others. This means that these individuals can lose privacy and/or confidentiality even if they are not the source of the specimen or of the information or topic being studied. For instance, confirming a genetic diagnosis of Huntington’s disease in a person also means that at least one of his or her parents carries this gene and is at risk of developing the condition. But the parent is not a subject in the research and did not consent to it. More broadly, it has been pointed out that genetic research can produce discoveries about entire subpopulations, some of which correspond to racial or ethnic groups. It has consequently been suggested that investigators and institutions must take seriously the concept of “group privacy” and take steps to include community members in the planning and management of genetic research, and the disclosure of research results.

 

Research that includes follow-up studies and attempts to identify clinical correlations requires that a subject’s unique information be linked to his/her genetic information. These links, in conjunction with particular aspects of research protocols, might be used to seek out or re-contact subjects in the future. These links and their uses must be disclosed to subjects at the start of the study.

 

For this and other reasons, many investigators seek to unlink or decouple personal identifiers from genetic information or biological specimens. Successful unlinking reduces or eliminates some threats to privacy and confidentiality. However, it is increasingly possible to take even “unlinked” information or samples and use “surrogate identifier ensembles” (demographic information, birth date, postal code, diagnostic code, etc.) to identify an individual. Some scholars question whether genetic samples can ever be completely “anonymized.”

 

It is important for institutions to consider policies surrounding the use of genetic information. These processes should address data collection and management, encryption, destruction of specimens and/or genetic information, and loss of data. Many institutions have adopted “trusted broker” (or “honest broker”) systems to oversee the flow of data from patient to investigator. (See Section IV, on “Stored biological samples.”)

 

Informed or valid consent

Ethical research on humans generally requires that three conditions be met. Subjects must be:

 

•Adequately informed,

•Free from coercion or undue influence, and

•Able, generally, to understand and appreciate the risks, potential benefits and alternatives of participating. This is sometimes called “competence” or “capacity,” where the former is usually reckoned to refer to a legal standard.

 

Note that the term “valid consent” is increasingly preferred to “informed consent” because it captures the fact that other criteria, in addition to adequate information, are needed to ensure the legitimacy of the process. There are many challenges in genetics research in fulfilling these conditions. For instance:

 

•In the case of traditional medical and behavioral research, it is difficult to determine how much information is adequate and, moreover, what level of complexity or detail is appropriate. This problem is magnified in genetics research.

•The informed consent process should describe the limitations of genetic testing: Testing alone cannot may not be able to verify (i) whether the individual will have symptoms of the disease or condition; (ii) the severity of symptoms; or (iii) the rate of disease progression.

•It is often unclear how to describe risks of harm to potential subjects. In genetics research, the risks are generally not physical but psychological, social, economic, etc., and these are sometimes more difficult to present and evaluate.

•In pedigree (studies involving family ancestry) and other studies, information collected might affect entire families, including members who do not wish to know or participate. If relevant, has considerations been given to these concerns in the consent process? Special precautions are needed to protect against or to manage pressure or coercion and to communicate risk. There is growing urgency to include genetic counseling in the consent process for this purpose.

•Is community consent required? How are individual autonomy and community consensus balanced in this process?

 

The consent process must take into account whether and when investigators will re-contact subjects. Options include:

 

•The samples will be unlinked from subjects’ identifying information and researchers will not inform subjects of any results. If subjects are interested in obtaining genetic information about themselves, they can then be advised to be tested independent of the research. Note that if a sample is successfully unlinked or anonymized, it might be impossible for the source of the sample to withdraw from research (his or her sample cannot be found to remove it). This constitutes one of the few exceptions to the rule that research participants must always be allowed to withdraw from studies.

•If re-contact is possible but not planned, subjects should be so informed, for the same reason.

•If re-contact is planned—perhaps to measure subsequent clinical correlations—disclosure is crucial for those who might not want to know their genetic status.

 

Researchers and research ethics reviewers should address the issue of clinically suspicious or significant incidental findings, and whether and how they will be communicated to subjects. Incidental findings can be of great interest to subjects, and a comprehensive consent process should make clear whether such findings will be disclosed. Indeed, the case could be made that risks associated with the disclosure of significant incidental findings are among the most interesting and difficult in genetics and genomics research.

 

In general, the following should be disclosed to prospective subjects during the consent process:

 

•The purpose of the research, in lay language.

•How the specimens will be stored and who will have access to them or the information they contain.

•Whether subjects will be re-contacted later with information about the study findings or their individual results.

•Whether the samples or genetic information have a code that can be linked to the identity of individual subjects. If a link to identifiers is retained, the sample/information is not anonymous.

•Whether the researchers will use specimens to develop commercial products or assays, and whether the subject will be able to share any financial gain from these products.

 

Section III: Legal and Regulatory Issues

 

In the United States, the passage of the Genetic Insurance Nondiscrimination Act (GINA) in 2008 (http://www.genome.gov/24519851) provided, at least in principle, sweeping protections for patients and subjects. GINA prohibits discrimination in health care insurance and employment based on genetic information. However, the law admits a number of exceptions, and there is extensive debate about whether the law enforcement mechanisms are adequate to its anti-discrimination intent. The extent to which GINA changes or reduces the risks of participation in genetic or genomic research should arguably be included in the consent process.

Individual states have laws related to genetic testing for diagnostic, prognostic, or research purposes. These laws vary in their scope and intent. Some state laws explicitly require consent for genetic testing of any sort. Some do not explicitly address research. It is of great importance that investigators and their institutions be familiar with state laws, governing procedures, and disclosures for research and other purposes. Research should follow the more restrictive regulation, be it at the state, provincial, or national level.

 

NIH regulations require the following:

 

•The data submission is consistent with all applicable laws and regulations, as well as institutional policies;

•The appropriate research uses of the data and the uses that are specifically excluded by the informed consent documents are delineated;

•The identities of research participants will not be disclosed to the NIH GWAS data repository; and

•An IRB and/or Privacy Board, as applicable, review and verify that:

oThe submission of data to the NIH GWAS data repository and subsequent sharing for research purposes are consistent with the informed consent of study participants from whom the data were obtained;

oThe investigator’s plan for de-identifying datasets is consistent with the standards outlined in the policy;

oThe risks to individuals, to their families, and to groups or populations associated with data submitted to the NIH GWAS data repository have been considered; and

oThe genotype and phenotype data to be submitted were collected in a manner consistent with 45 C.F.R. Part 46.

 

Section IV: Stored biological samples

 

Research on stored biological samples allows investigators to conduct studies long after subjects have completed all research procedures – and in some cases even if they were not research subjects before. It is helpful to think of research on stored samples as of two kinds:

 

•Retrospective, in which investigators use blood, tissue, etc. from pre-existing collectionsor biorepositories

•Prospective, in which investigators obtain samples to create new collections

 

If the research is retrospective, and if adequate steps are taken to prevent identification of the individual subjects, genetic research can often proceed without an IRB requiring that individual subjects provide valid consent. The scientific benefits of such research can be great and may outweigh the customary requirement of obtaining informed consent from all sources of stored biological samples. However, IRBs must scrutinize such waivers of consent carefully.

 

Even if federal regulations may permit research on existing samples without consent, an IRB may determine that consent is necessary if the cohort is small, the health condition or trait is stigmatizing, and there are concerns about maintaining confidentiality. If it is possible to re-contact individuals who were the sources of specimens, the following issue needs to be considered:

 

Suppose you have received IRB approval to study banked tissue without obtaining the consent of subjects. Your protocol meets the federal criteria for waiver of consent. Now imagine that you discover a medically important mutation in the sample belonging to patient XYZ. You do not know who XYZ is, or even if he/she is alive. But you can find out XYZ’s identity because the sample is linked to patient records with a code number. Should you use the link to find and warn XYZ? What if XYZ does not want to know of this condition, and you tell him/her anyway? What if he/she would want to know and you do not tell him/her? What about XYZ’s children? Is there a duty to warn or inform them? Laws and regulations do not usually address these difficult ethical issues.

 

IRBs face knotty challenges when investigators seek permission to bank or archive biological specimens for future, unspecified research. If investigators want to bank tissue but are unable to say what it will be used for, it is difficult to obtain valid consent at the time of recruitment, as subjects must know the purpose of the research in order to decide whether to consent to it.

 

It is possible to inform prospective subjects that their tissue will be banked for future, unspecified research, but this is increasingly difficult. Will the samples be used for research in cancer genetics or behavioral genetics? Will results be analyzed by race or ethnicity? Will the results be used to develop commercial products? These are all questions that prospective subjects increasingly want answered before they consent to participate in research.

 

Indeed, the secondary use of tissues or the information they contain is emerging as one of the greatest challenges of genetic and genomic research. Researchers must consider all potentially relevant analyses of genetic information, so that subjects can be as fully informed as possible.

 

The growth of bioinformatics or computational genomics makes it clear that, in the near future, the concern will not be so much with stored biological samples but with digitalized samples—electronic data that can be stored, transmitted, and analyzed with new ease and power. The use of this technology may also provide a process for contacting research subjects. Thus, IRBs might wish to consider the role of stepped consent/re-consent as part of the consent process.

 

If human genetic material is to be placed into a biorepository or data bank as part of an approved IRB protocol for unspecified research purposes other than that outlined in that protocol, a separate consent form obtaining approval of the source should be obtained. This is a controversial matter. Placement of human genetic material into a biorepository for future research could require the completion of an institution-specific data base development form which has been reviewed and approved by an institutional official (often the department chair) and filed with the IRB office. The genetic material, accompanied by a copy of the approved consent agreement, signed by the tissue source, can then be placed into the approved biorepository or data bank for unspecified future research purposes.

 

Conclusion

The genomic sciences have changed biomedical research. Concepts as fundamental as privacy and valid consent are now seen through lenses that have reshaped the ethical and legal duties of investigators and institutions to research participants. Indeed, it has been suggested that a regulatory environment crafted in the wake of Tuskegee is probably inadequate to the subtleties of genotyping and genome-wide association studies.

 

For those who believe the job of IRBs is to parse federal law and give thumbs up or down to individual projects, the genomic science revolution is likely a source of great consternation –the law barely contemplates that revolution. For those who regard IRBs as a grand exercise in applied ethics, then SNPs and GWAS offer exciting obligations to explore the protection of subjects in highly probabilistic sciences posing novel and complex new risks.

 

Put differently, the genetic and genomic sciences of the 21st century present opportunities both to fledge potentially exciting new treatments – and to underscore the unwavering importance of ethics in the service of shared values.