Special Considerations in Genetic Research Delia Wolf, MD, JD, MSCI Assistant Dean, Regulatory Affairs & Research Compliance Harvard School of Public Health dywolf@hsph.harvard.edu

What is Genetic Research Research involving the use and analysis of DNA, RNA, genes and/or chromosomes in order to detect an inherited or acquired alteration that might increase the risk of a particular disease or condition pedigree studies (to discover the pattern of inheritance of a disease and to catalog the range of symptoms involved); positional cloning studies (to localize and identify specific genes); DNA diagnostic studies (to develop techniques for determining the presence of specific DNA mutations); and gene therapy research (to develop treatments for genetic disease at the DNA level) 2 2

Definitions Genetic testing: The analysis of human DNA, RNA, chromosomes, proteins or other gene products to detect a person’s genetic profile, inherited or acquired mutations, physical characteristics or chromosomal profile. Four basic categories: Testing newborns (e.g., PKU) Testing for carrier status Prenatal testing Risk assessment testing (e.g., BRCA1 or BRCA2 genetic test) 3 3

Definitions (cont.) Genotype: A person’s particular collection of genes, which cannot be discerned from outward traits. Phenotype: The physical characteristic resulting from expression of a particular gene. Proband: An individual, who is the first affected family member who seeks medical attention (or enrolled in a genetic study) for a genetic disorder. 4 4

Definitions (cont.) Repository (tissue bank): Prospective collection of samples stored for an extended period for research use. A repository may be comprised of samples which are originally removed from patients as a part of their clinical care, or from subjects as part of study procedure. A repository may reside in one geographic location or may be a virtual collection of biologic specimens from many locations. 5 5

Definitions (cont.) Sample: In the context of genetic research, a sample is any human biological material. This includes, but is not limited to: molecular material such as DNA, cells, tissues (blood, bone, muscle, etc.), organs (liver, bladder, heart, etc.), gametes, embryos, fetal tissue, waste (hair, nail clippings, urine, feces, etc.) and other materials of human origin. Secondary Use of Samples/Data: Research that uses samples or data that were collected or generated from the original IRB/IEC-approved study. 6 6

Types of Samples/Data Anonymous: Samples or data that were obtained and stored without any identification that may link to a specific individual. Anonymous samples may have population information (e.g., the samples may come from patients with diabetes) Anonymized: Samples or data that may have been acquired from identified humans subjects, but all identifiers or codes have been removed and destroyed. An investigator would not be able to link anonymized/de-identified samples or data back to a specific individual. 7 7

Types of Samples/Data (cont.) Coded: Samples labeled with a code (e.g., a number, a bar code), rather than a person’s name or other personal identifier. Such code can be traced or linked back to sample donor by an investigator, who usually keeps the key to the code. As long as a link exists, data are considered indirectly identifiable and therefore, not anonymous or anonymized. Identified: Samples or data labeled with the name of the subject or other personal identifying information that would be sufficient to allow person who provided the sample to be identified. 8 8

Genetic Research-Associated Risks psychological risks social risks family discord stigmatization employment discrimination insurance discrimination breach of confidentiality limitations of genetic testing 9 9

Important/Special Considerations Research using prospectively collected samples Research using existing samples Tissue repository/bank for future genetic research Secondary use of existing samples Recruitment of family members Inclusion of children Disclosure of research results to subjects 10 10

Prospectively Collected Samples Unless the samples are collected anonymously, research involving the prospective collection of coded or identified samples requires participants’ consent The investigators has the obligation to maintain confidentiality to the extent permitted by local law

Prospectively Collected Samples In addition to the required elements, a consent form should include: What information will result from the research What the implications and limitations are Unexpected findings may result What follow-up information subjects will receive How samples are to be disposed How to withdraw from the study List of regulatory agencies/parties that may review study results Steps that will be taken to ensure subjects confidentiality

Prospectively Collected Samples If a study asks to storage of samples for future research, subjects need to be informed: Where and how long their samples will be stored; Once the sample is provided, if samples are stored in the anonymous fashion, remove one’s samples from further testing is not possible; and They have the option of being re-contacted to consider use of their samples in future studies.

Using Existing Samples When retrospective research is to be conducted using anonymous or anonymized samples, consent from participants is not necessary For research using samples that are identifiable, consent must be obtained. In certain cases, where the informed consent process that was in place when the samples were taken does not meet current consent standards for genetic studies, the investigator may seek a waiver of written informed consent and authorization

Tissue Repository/Bank All tissue repositories, whether they focus on specific types of diseases, or they serve as a resource for research on any diseases, require IRB/IEC review and approval if the repository retains any identifiers. The investigator is required to provide the following information to the IRB/IEC: How will samples be obtained How the repository will handle the samples How confidentiality will be protected; and How tissue samples will be made available to other researchers

Tissue Repository/Bank (cont.) Investigators must seek informed consent from individuals who are asked to provide sample(s) to a tissue repository. The consent document must include: A description of the repository and how it is operated A description of what type(s) of research the tissue will be used for A list of conditions under which samples and data will be released to recipient-investigators Procedures for protecting the privacy of subjects and maintaining the confidentiality of data.

Tissue Repository/Bank (cont.) For recipient-investigator, if one requests unidentifiable or coded samples from the repository and the code is kept by the repository, then that investigator most likely does not need to have an approval from IRB/IEC If the investigator requests samples with identifiers, then the recipient investigator must submit the proposed research protocol to the IRB/IEC, and the IRB/IEC will determine whether obtaining consent from the tissue donor is required, or whether the requirement of informed consent can be waived

Secondary Use Secondary use of existing samples or data must fall within the research scope described in the IRB/IEC-approved consent form for the original study If such use was not stated in the original consent document, IRB/IEC review and approval is required The IRB/IEC may grant a waiver if all of the elements specified in federal regulations are met

Secondary Use (cont.) The investigator, who intends to use the original sample/data, is required to provide the following information/documents to the IRB/IEC: A description of the original study, under which the samples were collected A copy of the original consent form A description of the study population When did the original study start Number of subjects/samples were enrolled/collected under the original study Justification for a waiver of written informed consent, if any

Recruitment of Family Members Investigator may not directly contact any family members from a list provided by a proband. Instead, investigator must ask probands to initiate contact with family members about research studies To help the probands communicate effectively, investigator should prepare an information sheet that is similar to a recruitment letter. Family members could then contact researchers directly if they are interested in participating in the study

Recruitment of Family Members Deciding whether family members are subjects: What is collected for research? Subjects? What is required? Tissue or blood sample from family members Yes Informed consent Review of family members’ medical records Data obtained from identifiable proband Usually waiver of informed consent Data from de-identified proband No Nothing

Inclusion of Children While the requirements to include children as subjects in genetic studies, in which these children display the phenotype under the study, are similar to these in other studies in which children may be asked to participate, special issues should be considered when children are enrolled not as the direct subjects of investigation, but to provide information necessary to analysis of the family

Inclusion of Children (cont.) Following issues should be addressed in the protocol: Is there a possibility that information would be discovered as a consequence of the study that may impact the health or future family planning of the child? If the child does not display the phenotype under study, what is the likelihood that he/she will eventually develop this phenotype? If there is a reasonable possibility that the phenotype will eventually appear, follow-up genetic counseling and psychological counseling should be made readily available. If the child does not display the phenotype, and is believed to be unaffected, provide justification as to why it is necessary to include the child in this family study. Is there any potential benefit to the family unit by having the child participate? If so, specify. What types of tissue samples would be collected for the study. What efforts will be made to obtain the child’s assent to participate in the study?

Disclosure of Research Results In general, should not disclose genetic research results to a research subject. Disclosure may be approved by the IRB/IEC if all of the following conditions are met: The research results are scientifically valid and are performed by a certified laboratory Research results have significant implications for the subject’s or the public’s health A course of action to ameliorate or treat the subject’s or the public’s health concerns is readily available

Specific Information included in Protocol and Consent Form Purpose of Study Duration Control and Ownership of Specimens/Materials Subject Access to Genetic Information Secondary Use Risks