National Institute of
General Medical Sciences

• Executive Summary
• Background
• Scientific Presentations
• Pharmacogenetics Initiatives
• Open Discussion and Advice
  • Advice for Researchers
  • Advice for NIGMS
• Specific Recommendations for NIGMS
• Conclusions
• Follow-up Activities
• Resource Materials
• Agenda

Executive Summary

The Populations Advisory Group meeting was convened on May 27, 1999 with nine consultants in attendance, including members with basic and clinical scientific expertise, historical knowledge, social policy perspective, genetic counseling experience, and involvement with outreach activities. A representative of the patient community was also present. Their goal was to consider the possible ramifications of future research in the area of pharmacogenetics. The pharmacogenetics initiatives invite applications addressing the genetic basis for individual differences in therapeutic medication responses. The initiatives are intended to stimulate research activities in this field, and to encourage the creation of a public pharmacogenetic database. Because research may be conducted with human subjects, possibly as members of identified groups, the National Institute of General Medical Sciences (NIGMS) asked the Populations Advisory Group to provide advice regarding the views of, and potential areas of misunderstanding for, individuals and communities who might participate in these studies. Advice was compiled both for the research community and for NIGMS, along with specific recommendations. Members of the Populations Advisory Group emphasized that they support pharmacogenetics research, and will aid in anticipation of the issues and assist in implementation of the recommendations.

Background

A meeting of the Populations Advisory Group, a sub-group of the National Advisory General Medical Sciences Council, was convened on May 27, 1999. Nine consultants were in attendance, including members with basic and clinical scientific expertise, historical knowledge, social policy perspective, genetic counseling experience, and involvement with outreach activities. A representative of the patient community was also in attendance.

The charge to the committee was to consider the possible ramifications of future research that will be conducted in the area of pharmacogenetics (for an overview, see http://www.nigms.nih.gov/Research/SpecificAreas/PGRN). NIGMS anticipated the receipt in late July 1999 of applications responding to the pharmacogenetics initiatives. The initiatives include the program announcement PA-99-016, "Mechanisms Underlying Individual Variations in Drug Responses," and the request for applications RFA GM-99-004, "Pharmacogenetic Research Network and Database." Both of the initiatives invite applications from investigators interested in determining the genetic basis for individual differences in responses to therapeutic drugs. They are intended to stimulate research activities in this field, and to encourage the design of a public pharmacogenetic database.

Through these efforts, NIGMS and other institutes of the National Institutes of Health (NIH) intend to foster collaborative, multi-disciplinary approaches to translating DNA sequence differences into scientific and medical information. This information has the potential to be used to predict people's individual variations in response to medications. In order to accomplish this goal, the research may need to be conducted with human subjects, and possibly with subjects who are members of identified groups. NIGMS asked the Advisory Group to provide advice regarding the views and potential areas of misunderstanding of individuals and communities who might participate in these studies. NIGMS is aware of the sensitive nature of this research, and seeks to be proactive in establishing a process to address these concerns prior to funding research in this area. The meeting agenda included both formal presentations and an open discussion period.

Scientific Presentations

First, an overview of pharmacogenetics research was presented, ranging from basic research through clinical significance. The presentation included descriptions of the scientific approaches used, and was illustrated with examples of genetic variants that are known to influence drug responses. One well-established example cited was treatment of acute lymphoblastic leukemia (ALL), a childhood cancer, for which patients receive a drug (6-mercapto-purine) that has a very narrow therapeutic index and can produce severe bone marrow suppression. The disease can be fatal if undertreated, and the drug can be fatal given in excess. Therefore, it is extremely important to dose a patient correctly. The proper dosing level can be ascertained at the outset through an individual analysis of genotype for the enzyme thiopurine methyltransferase (TMPT), allowing prediction of the drug metabolism rate in that person. Other examples were also described ( e.g. , cytochrome P450, form 2D6), and it was pointed out that in some cases there is a pronounced difference in the frequency of alleles among ethnic groups. Knowledge of this heterogeneity can aid in guiding medical practice and public screening decisions. However, non-genetic factors must also always be considered ( e.g. , environment, age, overall health status).

Next, the use of identified populations in research was discussed. Because human genetic variation is not distributed randomly, but reflects local evolutionary history and common ancestry, mathematical analysis can demonstrate the association between genetic variation and populations. An example of the aldehyde dehydrogenase locus (ALDH2) was described, where the dominant ALDH2*2 allele is correlated with the alcohol response in different populations. Research with other candidate genes was described (gamma-amino butyric acid (GABA) and dopamine (DRD4) receptor genes), but direct correlations have not been demonstrated. The lack of direct correlation could suggest that these genes are unrelated to alcohol's effects, or that there is an interplay of genes and the environment, or a multi-gene effect. No existing population is genetically homogeneous. While populations are a research tool, one cannot superimpose the results of one grouping onto another. It was cautioned that symmetric relationships do not exist; while a gene is diagnostic of a population, a population is not diagnostic of a gene.

Pharmacogenetics Initiatives

The scope and specific objectives of the NIGMS pharmacogenetics initiatives ( PA-99-016 and RFA GM-99-004 ) were reviewed, against the backdrop of the scientific presentations. The construction of a public pharmacogenetic database to be used by scientists is a specific goal. The database will likely contain and organize information about common genetic variants, their biochemical and biological functions, as well as their possible clinical and medical significance. This will involve the definition and standardization of descriptions of phenotype, and linking this information to genotype. Phenotypes will be defined differently depending upon the situations, based upon both objective measurements ( e.g. , a measurement of an enzyme activity in a blood sample) and subjective determinations ( e.g. , behavioral or disease progression scoring). It is anticipated that the database will store information that is no longer associated with identifiable human subjects, and that there will be no way to associate the data back to the particular study participants. A Steering Committee will be established that meets regularly, to guide and evaluate development of the pharmacogenetic database. This committee will discuss both scientific content and issues surrounding the database and the research network. The Steering Committee will exist on an ongoing basis to allow the two-way exchange of information between investigators and the NIH.

Open Discussion and Advice

One member of the Populations Advisory Group who has had a personal brush with adverse drug reactions of a pharmacogenetic basis described the experiences. In this particular circumstance, the understanding that came from learning the genetic basis for the adverse reactions was empowering, because the negative experiences were explained and future situations could be avoided. In addition, genetic testing now makes it possible to learn which other members of this patient's family might be affected. It was emphasized that gaining the information was a very positive experience for this person, but it was acknowledged that the outcome could be different were a stigmatizing disease involved. The group noted that when describing future research results, care should be taken to avoid the use of stigmatizing words such as "mutant gene." It was also mentioned that those involved in health care delivery, especially physicians, need to be educated to recognize the impact of pharmacogenetics ( e.g. , drug sensitivities are not the same as drug allergies).

The members of the Advisory Group engaged in an open discussion, asked questions of each other around the table, and considered possible answers. They shared their initial thoughts and provided advice, both for individual investigators conducting the research studies, and for NIGMS as the organizer of the overall research effort. The group's recommendations are listed below:

Advice for Researchers:

• Researchers must have a defensible rationale for constructing hypotheses based on ethnicity for a particular study ( e.g. , not rely on "convenience sampling").
• Researchers must consider how ethnicity is defined for a study, and where the biological and social bases might not be in concordance.
• Researchers should clearly articulate specific expected benefits of the research, as well as possible negative consequences of conducting the research.
• Researchers should anticipate the perceptions and apprehensions of those who might be involved in the research.
• Researchers should utilize community outreach representatives to establish truly accessible personal contacts for participants in studies.
• Researchers should understand the profound impact of educational level and economics upon the communities with which they interact.
• Researchers must recognize that there should be no coercion, and allow participants to "opt out" at any time.
• Researchers must communicate the final results of a study to participants, when desired, in a way they can understand.
• Researchers should work to establish trust, and recognize that this takes time.
• Researchers must make consistent efforts to include people who are underrepresented in medical research.
• Researchers must evaluate whether the study design introduces intentional or unintentional biases.
• Researchers should reflect diversity in the research team itself.
• Researchers must consider whether there is potential for group stigmatization.
• Researchers should consider whether possible group harms remain even after individuals die, and are no longer covered by human subjects protections.
• Researchers should accept feedback from a group or community when study results are shared.
• Researchers should be aware of relevant developments in the social policy field ( e.g. , potential for insurance discrimination).
• Researchers must consider any other moral responsibilities that could arise from conducting the research.
• Researchers should address these issues thoughtfully before experiments begin, although the responsibility continues as research is ongoing and thereafter.
• Researchers must adequately prepare to educate the media and try to prevent miscommunication of results.

Advice for NIGMS:

• NIGMS should consider the apparent paradox for this research area, in which identified groups may be studied, yet it is individuals (not groups) who will be treated with therapeutic medications.
• NIGMS needs to educate people, beyond those directly participating in studies, about the purpose of pharmacogenetics research.
• NIGMS should communicate realistically what to expect from the research--and in what time frame--when it is conducted.
• NIGMS should anticipate wide ranging objections to this research, which may differ for particular groups and research findings.
• NIGMS must promote culturally competent research and educate researchers, so they recognize this is an ongoing and bi-directional participatory process.
• NIGMS should engage in a sustained dialogue with community leaders as true consultants at every level in the research funding process.
• NIGMS should also seek input from many group members, and recognize that not all people's feelings or opinions can be represented by a few leaders
• NIGMS must be as visibly open as possible in its deliberations and not exclude anyone from the process.
• NIGMS should be aware there is distrust from the past, and choose words accordingly ( e.g. , the word "diversity" now carries negative connotations).
• NIGMS must accept what people are willing to allow; its goal should be to permit people to make informed, reasoned decisions.
• NIGMS should support improvement of consent forms through the Steering Committee ( e.g. , it may take time for participants to decide).
• NIGMS needs to participate in the process of educating the media, but with caution, because a little information can be problematic if misconstrued.
• NIGMS should be aware that views and needs will change, and be prepared to track future issues as they develop ( e.g. , with new legislation).

Specific Recommendations for NIGMS

• Add educated lay people and representation of other disciplines as appropriate ( e.g. , social scientists, genetic counselors) to all stages of the NIH review and granting process.
  • Add representation to the peer review committee(s)
  • Add representation to the National Advisory Council(s)
  • Add representation to the Steering Committee for the Pharmacogenetic Research Network and Database
• Design a truly informative brochure for the lay community.
  • Avoid technical jargon like the term "pharmacogenetics"
  • Present both the potential positives and potential negatives of the research
  • The brochure should be culturally sensitive, but not necessarily targeted, and should have broad, simple explanations of individual differences
  • Acknowledge that people's perceptions and fears are real
• Continue updating members of this group and having further meetings as needed.

Conclusions

The Advisory Group members stated clearly that they view their role in supporting biomedical research in the area of pharmacogenetics. Their concern is to ensure that this research will go forward. However, they did caution that any negative social effects must be anticipated. There is a balance to be achieved, or the process will become self-defeating. The members of the group pledged to continue to work with NIGMS and offered to make their expertise available to comment upon, and possibly even assist in distributing, careful and thoughtful materials developed for the public.

Follow-up Activities (as of September, 1999)

NIGMS is currently working with a professional facilitator to convene focus group meetings in which the concepts underlying pharmacogenetics are being tested in various audiences. The feedback on public knowledge and opinions should aid in developing an informative brochure. Additionally, the Center for Scientific Review has assured NIGMS that lay (non-Ph.D., non-researcher) member(s) will be added to the peer review group(s). NIGMS also plans to add such members to other committees at all steps in the funding and oversight processes.

Resource Materials

(intended to assist the reader in gaining a background in the subjects discussed; this is a sampling and is not an all-inclusive listing)

• Identified at the Meeting:

Understanding genetic research and population-based research. National Cancer Institute 1999 Publication No. 99-4364.

Rothenberg KH, Rutkin AB. Toward a framework of mutualism: The Jewish community in genetics research. Community Genet 1998, 1:148-53.

Freeman WL. Making research consent forms informative and understandable: The experience of the Indian Health Service. Camb. Q. Health Ethics 1994, 3:510-21.

• Assembled after the Meeting:

Mittman IS, Secundy MG. A national dialogue on genetics and minority issues. Community Genet .1998, 1:190-200.

Foster MS et al . Communal discourse as a supplement to informed consent for genetic research. Nature Genetics 1997, 17:277-9.

Juengst ET. Group identity and human diversity: Keeping biology straight from culture. Am. J. Hum. Genetics 1998, 63:673-7.

Freeman HP. The meaning of race in science--Considerations for cancer research. Cancer 1998, 82:219-25.

Jackson F. Concerns and priorities in genetic studies: Insights from recent African American biohistory. Seton Hall Law Review 1997, 27:951-70.

Rothenberg KH. Genetic information and health insurance: State legislative approaches. Journal of Law, Medicine, and Ethics 1995, 23:312-19.

Marshall A. Laying the foundations for personalized medicines. Nature Biotech . 1997, 15:954-7.

Weber W. Pharmacogenetics 1997, Oxford University Press, New York.

• Related NIH Initiatives in which NIGMS is Participating:

RFA HG-99-002, "Studies of the Ethical, Legal and Social Implications of Research Into Human Genetic Variation," http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-99-002.html

PA-99-079, "Research on Ethical Issues in Human Studies," http://grants.nih.gov/grants/guide/pa-files/PA-99-079.html

Agenda