Grasp of genetics basics makes IRB review easier

Expert offers genetics primer

More institutional review boards are seeing proposals for studies involving some type of genetic research, but many IRB members feel unprepared to appropriately review the study design and assess the potential risks involved.

Because experiments that involve analyzing or manipulating genetic information can pose novel risks to human subjects and because members have often not had sufficient education about genetic principles and terms, they tend to be very cautious when reviewing these protocols, says Barbara Handelin, PhD, the CEO of Kenna Technologies Inc., a drug discovery company in West Chester, PA.

In 2000, Handelin, a trained geneticist, helped conduct a research study funded by the U.S. Department of Energy that evaluated the challenges IRBs faced when reviewing genetic studies.

"What you very quickly hear, if you sit down in room with a dozen or so IRB folks and ask them about their concerns involving a genetic protocol, they will very quickly list for you 25 issues or questions that are somehow related to genes, but only about 10% of them would be relevant for any given protocol," she says.

For example, concerns about gene transfer and heritability of altered DNA are not relevant to family studies designed to discover genetic traits that might indicate an increased risk of developing disease because gene therapy will not be administered and no changes in anyone’s genetic makeup will take place.

Likewise, concerns about the revelation of genetic information about family members are not usually relevant to gene modification studies, Handelin adds.

And while it’s true that some genetic protocols can present unusual risks for study participants, in many cases the risks presented are the same or very similar to concerns that other biological studies raise, she adds.

Privacy issues

A concern frequently cited in conjunction with gene studies is that genetic information obtained about one person also reveals information about that person’s family members.

However, that also is true to some extent, in infectious diseases research studies, she notes. Therefore, procedures that would be used to address privacy in those studies might also be helpful in studies involving genetic information, she says.

"The other common comparison that we make is with tumor registries," Handelin adds. "They’ve been doing those for decades. You have these huge databases of people with cancer, and you know, for many years it was never disclosed to people who: a) they were in a tumor registry; and b) what was going to be done with that information, and that, in fact, the information was not anonymized."

The key issue that distinguishes studies that involve analyzing genes vs. other types of research, Handelin says, is the potential for genetic information to be predictive of future disease.

"The two biggest impacts that we expected from our ability to understand the genome better were: a different way to define disease because we would recognize more specific causes of disease, there would be a new way to do differential diagnosis; and we would more specifically define diseases that we had mischaracterized or lumped together because we had only been able to see the effects or the pathology of the condition and not its molecular bases," she says. "The second concern, is that it is really different when you begin talking about future disease. Medicine, traditionally, is a totally reactive discipline, people have illness and you try to respond. Preventive medicine is sort of the Holy Grail for genetics, but there are complications associated with finding out about something before it happens."

Different types of genetic research

To more accurately evaluate the potential risks and benefits to human subjects of a particular research trial involving genetics, it might be helpful for IRBs to have a system for triaging the proposals, or categorizing them according to the type of genetic information that will be analyzed or manipulated, Handelin says.

In doing so, the IRB can then be sure to evaluate the risks that are posed by that type of research and discard concerns that are not relevant.

Genetics research can be categorized into three basic types of studies, she says. These are:

Family studies — Studies in which specific families are recruited based on the high prevalence of a genetic trait in the family. Twin studies are one type of family study, and familiar examples of family studies include the searches for genes causing Huntington’s disease, the breast cancer gene BRCA1, cystic fibrosis, manic depressive disorder, or the high-iron disorder, hemochromatosis.

Population association studies — Investigators seek an association between a particular genetic marker (a polymorphism) with a trait by analyzing the coordinate presence and absence of a genetic marker and the trait of interest in a broad population of unrelated individuals. The structure of the study is the same as any statistical correlation study; the only thing setting these studies apart from the traditional ones is that the subjects’ genome is being analyzed as one of the correlates.

Add-on genotyping studies in a drug trial are a typical type of population study seen today. Large studies of archival tissues in which a wide variety of genes or random genetic polymorphisms are going to be analyzed are another common type of population association study.

Familiar examples of population studies include: Alzheimer’s disease association with the ApoE4 polymorphism; association of violent behavior with gene markers; association of another ApoE4 variant with heart disease.

Gene modification studies — These studies include any study that involves the transfer of an external gene into a human subject regardless of whether there is going to be modification of the subject’s genome, which is rare.

Genes are modified by installation into a delivery vehicle (vector) that serves to trans- fer the gene into cells and upon delivery are intended to modify the activity of the cell in some way. These studies are often called gene therapy, which is misleading in that it implies that the genes are the target of the therapeutic effort rather than being the therapeutic product themselves.

Familiar examples of genetic modification studies include: treating cystic fibrosis with the CFTR gene; treating ornithine transcarbamylase deficiency (OTC) patients with the OT enzyme gene.

Evaluating the risks

Once the studies are categorized, IRB reviewers can proceed to considering the list of risks relevant to that type of genetic research.

IRBs should share their lists of the relevant risks with investigators at their institutions in advance of receiving protocols, Handelin adds.

The potential risks involved in the different categories of genetic research1 are listed below:

Family Studies — aspects of family studies that determine specific potential risks:

  • Subjects are members of the same family, sharing genetic traits frequently.
  • Investigators may intimately know some family members and be strangers to others.
  • Recruitment may be convenient at family reunions or other family gatherings.
  • Individual subjects may have the trait under investigations or may not; their membership in a family may be the only connection to study the study.
  • The trait under study may be a significant part of the family’s identity and dynamics, including familial and parental guilt, anxiety, honor, etc.

Reproductive decisions may be profoundly influenced by the subject of the study especially in the case of major life-limiting illnesses in children.

Potential risks peculiar to genetic studies conducted on related subjects:

Coercion in recruitment: Since the family is identified as a desirable set of subjects through perhaps a single affected member, recruiting other family members must be conducted carefully to avoid coercion by family members.

Risk to reveal nonfamilial relationships: Since multiple family members will be studied using genetic markers that are purposefully chosen to reveal both relatedness and differences between family members, there is a high likelihood that false familial relationships will be uncovered (nonpaternity, nonmaternity, nonsibling, etc). Subjects must be informed and a policy set forth on whether this type of information will be shared with any participants.

Family dynamics: Recruitment and the study itself will be conducted in the context of family emotional and psychological dynamics. Since genetic traits are transmitted from parents to off-spring, a range of emotions from guilt to pride in such sharing of traits between generations can be a powerful component of family dynamics. How does the protocol recognize and manage this aspect of recruitment and ongoing relations between the principal investigator and subjects?

Reproduction: In studies, especially involving highly morbid diseases in children, subjects or relatives of subjects may be undergoing reproductive decision making that may be seriously impacted by either new information created through the study or by the increased focus within the family on the disorder. How does the protocol address this sensitive issue?

Familial privacy: Since genes are shared between relatives (50% of genetic variants between first-degree relatives, 25% between second-degree relatives, and so on), if one subject obtains information about their genetic status, relatives may believe that they too have received information on their own genetic status by inference. How does the protocol deal with the risk of inadvertently conveying gene status information beyond the direct subject?

Publishing pedigrees: Since publishing results is a desirable outcome of all research, the investigator needs to proactively address how familial information will be presented in the public press so as to protect the anonymity of the family subjects. For example, publishing pedigrees is necessary when reporting on a family study, but even if names are omitted, family members will easily recognize themselves and others along with deriving genotype information from a published pedigree. This breach of privacy must be avoided.

The American Society of Human Genetics has published guidelines on modifications to pedigrees that do not compromise the reporting but which mitigate the likelihood of Uncle Steven discovering the genotype of his estranged daughter without her consent.

Right not to know: Persons may volunteer to participate in a family study as a subject but may have a deep commitment to not learning any genetic information about themselves (or others) that results from the study. (Indeed, this can be a strong reason for not participating at all.) This degree of privacy and one-way communication of information (only from participant to investigators) must be made available and a special side protocol may even be necessary to adequately provide assurances to such subjects.

Population Association Studies — aspects of population studies that present specific risks:

  • Fishing expedition nature of many correlation genetic studies.
  • Identifiable populations may have undesirable genetic correlations reported as results of the study.
  • Use of stored tissues as sources of DNA is common in these protocols.
  • Traditional drug trials are increasingly including genetic studies as add-ons.
  • Having access to longitudinal clinical information enables many (if not most) correlation studies.
  • Evergreen characteristic of DNA as the lingering remains of subjects creates future opportunities for research beyond the duration of the current protocol.

Potential risks to subjects:

Access to personal genetic information: Many population based genetic studies have an open-ended protocol that includes the possibility that genotype information could be discovered about an individual’s health sometime in the future. Because DNA can be stored virtually forever, the samples are everlasting. Subjects need to be informed as to whether they will be contacted about such information at any time and why or why not.

Unknown future studies: Because DNA is a very stable sample and because technology continues to improve for both sparing and creating a renewable DNA sample, this material from subjects can become an everlasting resource for research. Many population-based studies will therefore include a proposal to maintain this rich experimental resource for future — as yet to be determined — research. Subjects should be informed about such future use when donating a new sample, in the context of the degree of anonymity afforded by the protocol.

Group stigma: Population based studies may be designed around the prevalence of a genetic trait in certain defined populations: ethnic groups, gender or behavior-driven groups, etc.

If results about the population become publicly available and the results reflect a defective or undesirable attribute associated with the group, then the entire group, as well as individual members, is at risk for stigmatization and potential discrimination. Investigators need to provide a plan for how such group stigmatization will be avoided in handling both publishing and presenting all data.

Genetic Modification Studies — aspects of genetic modification studies that create specific risks:

  • These are therapeutic experiments, or trials; they are thus in a different category from family studies or correlation studies in that subjects are being treated with unknown compounds as opposed to having their genome analyzed.
  • DNA (gene) is a "living drug" in that it is a natural, integral part of all cells in all living beings.
  • Genes are completely novel compounds compared to all other drug trials.
  • Genes, if they integrate into the genome of the recipient, can be permanent residents of cells.
  •  There is a small but measurable possibility that the genome of a recipient’s germ cells (eggs or sperm) accepts a permanent new gene and then the therapy has the potential to be transmitted to offspring of the subject.
  • The delivery vehicles (vectors) are poorly understood and are also biological materials (viruses in some cases, lipids and other materials in other cases) with as yet unproven and potentially dangerous effects on the recipient.
  • Some target diseases for early gene therapy experiments are disease of childhood and are inherited; e.g., cystic fibrosis, familial hypercholesterolemia.

Potential risks to subjects in gene modification studies:

Clinical management of subjects: Gene therapy experiments typically bring a basic researcher with expertise in genetic manipulation and gene transfer to developing an interest in treating a clinical disorder. As such, the investigator is making a significant move into clinical research and clinical treatment with often very little training in either domain.

Moreover, gene therapy experiments are often to be conducted in subjects with a rare disorder (e.g., cystic fibrosis, ornithine transcarbamylase deficiency, familial hypercholesterolemia, etc.) where clinical expertise in caring for such patient subjects can be equally rare.

Risk to subjects is created when such subjects with peculiar clinical issues are being treated, followed and managed by clinically naive investigators. IRBs should be thorough in evaluating and requiring the clinical appropriateness of investigators in any gene therapy trial, especially in trials involving rare disorders.

Children as subjects: Some diseases that have been the focus of early gene therapy diseases occur in children and thus have the usual special risk issues of having children as subjects.

Family dynamics: Many early gene therapy experiments have been conducted in disorders caused by faulty single inherited genes.

Changing the blueprint of life? IRBs need to be clear about which types of cells is the target of the gene transfer; germ cells (eggs or sperm) or non-germ cells (all other cells, called somatic cells).

Nongerm cells do not have the potential to be passed on to offspring of subjects who receive a new gene; thus this is not a relevant risk for most protocols. However, IRBs are advised to query investigators about their evidence that germ cells not inadvertently be subject to gene transfer in the proposed experiments.

Pre-clinical studies: Because gene transfer is a relatively new therapeutic method, pre-clinical studies in tissue culture and animals may be difficult to gather with the same depth or rigor that is seen in typical drug trials. Yet there are large potential risks to subjects from the unknown effects of the gene delivery vehicle and the gene drug. Thus, IRBs should obtain consultation on the relevancy and rigor of the pre-clinical studies that support each protocol.

Unavailability of proven therapy: The unavailability of alternative treatments for rare disorders may make potential subjects and their families desperate to volunteer for any experimental trial however novel and unproven.

Special care should be taken to explain to subjects the preliminary nature of such research, the uncertainty of risks and remote possibility of benefit especially to those involved in early trials. Investigators may have to involve third parties in the consent process to guard against the potential for unintended coercion.


1. Excerpted from: The Responsibility of Oversight in Genetics Research: Issues for Institutional Review Boards in Reviewing Genetics Protocols, Part II: Triage for IRB Review of Genetics Protocols. Developed by Barbara L. Handelin, PhD, and Susan Katz, JD. Supported by a grant from the U.S. Department of Energy Human Genome Project Grant #DE-FG02-98ER6245.