June 4, 2003
Holiday Inn Select
Bethesda, MD
This meeting was held in conjunction with the National Children’s Study, which is led by a consortium of federal agency partners: the U.S. Department of Health and Human Services (including the National Institute of Child Health and Human Development [NICHD] and the National Institute of Environmental Health Sciences [NIEHS], two parts of the National Institutes of Health, and the Centers for Disease Control and Prevention [CDC]) and the U.S. Environmental Protection Agency (EPA).
Workshop moderators were Jeffrey Botkin, M.D., M.P.H., University of Utah School of Medicine, and Benjamin S. Wilfond, M.D., National Human Genome Research Institute, NIH, DHHS. They summarized the purposes of the workshop and reviewed the activity of the Ethics Working Group that led to the planning of this workshop. The agenda included segments on three focus areas: recruitment, retention, and consent; confidentiality and information sharing; and interventions and interaction with communities.
Workshop objectives were:
- To gain the experience and advice of investigators who have conducted longitudinal studies similar in size, scope, length of follow-up period, or target populations of pregnant women, mothers, and children about the ethical issues they encountered and how they resolved them
- To anticipate how to address such issues for the National Children’s Study (Study)
- To try to apply these experiences to the Study.
Donald Mattison, M.D., Federal Advisory Committee Chair, NICHD, NIH, DHHS, and Marshalyn Yeargin-Allsopp, M.D., Interagency Coordinating Committee Member, CDC, DHHS, provided an overview of the Study.
Focus Area: Recruitment, Retention, and Consent
Project Viva
Matthew W. Gillman, M.D., S.M., Harvard Medical School/Harvard Pilgrim Health Care, presented information about this Boston area cohort study of more than 2,000 pregnant women and their offspring to examine the roles of prenatal and perinatal factors in outcomes of pregnancy, infancy, and childhood. The study focuses on maternal diet during pregnancy and its relation to outcomes of pregnancy, infancy, and early childhood. Dr. Gillman discussed the study goal and aims, study design and operations, lessons learned, recruitment and retention strategies, study experience to date, and challenges related to the use of human subjects.
Recruitment strategies involved publicity at early prenatal visits and classes. Interested women were referred to a research assistant for more information and enrollment. Clinicians were minimally involved in recruitment but did have veto power if they felt that a subject was not appropriate for the study.
Retention strategies during the childhood phase include:
- Signing up participants early for the long term
- Home visits
- Appropriately large incentives but not too large to be "coercive"
- Minimizing participant burden.
Prenatal enrollment, home visits, and larger incentives would have helped in recruitment and retention. The best incentive is cash offered for completion of visits, for coming in to the clinic instead of requiring home visits, and for collection of specimens.
Human subject challenges relate to informed consent for mother and child. The study has had only one withdrawal of consent. Health Insurance Portability and Accountability Act (HIPAA) regulations will make consent and authorization more difficult.
Questions and comments following Dr. Gillman’s presentation concerned the consent process at later stages, representativeness, and the impact of certain study features.
Tucson Children’s Respiratory Study
Anne L. Wright, Ph.D., University of Arizona, Tucson, described this longitudinal study, which is investigating the natural history of asthma from birth into early adult life. A total of 1,246 healthy newborns were enrolled between 1980 and 1984. In-depth evaluations are performed periodically, and questionnaires are administered in between. Health maintenance organization (HMO) pediatricians enrolled the participants, and consent was obtained via HMO nurses. Loss to follow-up has occurred, with slightly more than 60 percent retained by age 16. Dr. Wright discussed strategies used to minimize loss of participants, including obtaining detailed contact information on the families using a "family tree" and sending newsletters and address confirmation cards. She had particular praise for the role of the study nurses in relating to and retaining participants.
Incentives were modest, mainly directed to the child, and were given for any level of participation. Consent was obtained at enrollment and at each in-depth evaluation. The first consent covered to age 5. From about age 6, an assent form was used for the child. A child’s consent early on is largely parental permission and depends on how the parent presents it. Participants were allowed to refuse any specific aspect of the study, for example, blood draws. This is a good approach from an ethical standpoint, but obviously has its drawbacks. Overall, 21 percent withdrew from the study for reasons such as being too busy or no longer interested. There have been no requests to withdraw specimens. Consent forms have gotten much more detailed with regard to genetic material.
Questions asked by participants related to whether the institutional review board (IRB) considered this a minimal risk study, collaboration with the HMO, and the age at which the methylcholine challenge was done. Dr. Wright responded that a full IRB review was needed due to the methylcholine challenge test. The test began at age 11, and extensive exclusion criteria were used. There were no data sharing issues with the HMO.
Avon Longitudinal Study of Parents and Children
Karen Birmingham, University of Bristol, UK, presented this study, which was designed to understand the ways in which the physical and social environments interact over time with the genotype to affect health, behavior, and development. Participants were enrolled as early in pregnancy as possible. Ms. Birmingham discussed study objectives, inclusion criteria, and data collection. The study has used very detailed questionnaires (assessing health, diet, lifestyle, social factors, and environmental information), some of which were child-based questionnaires. About 700,000 questionnaires have been sent and about 500,000 have been returned.
Data collection involved direct measures, biological samples, health records, environmental measures, and educational data. A law and ethics committee deals with consent, assent, and confidentiality issues as well as with substudies. Some variables must ethically be fed back to the participants, such as visual and hearing problems, low hemoglobin, and high blood pressure.
Recruitment methods included use of mass publicity, posters, and media in different languages. No incentives were given to the midwives involved in the study, but the midwives were very helpful. Enrollment cards were short and had very little data. An introductory brochure stated that there were no benefits for mothers and the children, but the study would benefit future generations. The brochure emphasized that participants could opt out at any point and guaranteed not to link names to any of the data, which may have increased retention rates. Placentas and cord blood were collected without many mothers’ knowledge, but these samples have not been analyzed without getting written consent.
The study has a family liaison team and a communications team. The family liaison team uses telephone and home visits and is very sensitive in dealing with families. Team members work hard to retain participants and offer various options to try to keep them in the study. The communications team deals with the media.
Focus Area: General Discussion
Topics addressed included use of the word "coercion," enrolling and obtaining consent from pregnant adolescents, assent of children, questionnaires, opt-out methods, and responsibility of investigators to communicate public health or medical warnings or new relevant health information. There was some discussion about the importance of addressing positive as well as negative aspects of a child’s environment. Other questions and comments related to the "family tree" and contact process, IRBs and minor consent and teen births, adolescents and state laws, subject understanding of informed consent materials, and alternatives to the word "coercion."
There was also discussion about collection of sensitive information, such as sexual history, pregnancy terminations, and drug use.
Focus Area: Confidentiality and Information Sharing
Wisconsin Cystic Fibrosis Newborn Screening Study
Norman C. Fost, M.D, M.P.H., University of Wisconsin Medical School, discussed this large study, now in its 18th year, which is assessing the benefits and risks of newborn screening and presymptomatic treatment for cystic fibrosis. More than 600,000 children were randomized in the study, which has extremely complex ethical issues. The unusual study design that was finally developed involved the screening all 60,000 newborns (using blood spots) each year for 10 years and randomizing them into the study group or the control group. The study group data were decoded immediately, and parental consent was sought for further testing and early treatment of infants with cystic fibrosis (100 percent compliance was achieved). The remaining data were sealed following the initial test and not decoded until four years later, when the families were contacted and consent was requested for further testing.
Justification for this unique study design was based on the facts that risks and benefits of screening and early treatment were unknown and that there is a long history of serious harm from newborn screenings in the past. Routine screening was unjustified, so withholding screening was appropriate. There was wide consensus for this point of view.
Lessons learned related to several issues: waiver of informed consent for control group, nondisclosure of genetic information, community consultation, anticipation of and preparation for public attacks, and anticipation of and preparation for defending litigation.
The study used a variety of public disclosure methods—lectures, articles, and various public forums including TV and radio—to ensure that people knew about the study.
Dr. Fost discussed several issues of possible relevance to the Study, including:
- Waiver of consent can be justified for reasons other than emergencies.
- Withholding genetic testing results can be justified based on an uncertain risk/benefit ratio and the standard of care, supported by reviewers, consultants, and parents.
- Researchers can anticipate and prepare for attacks on the Study by groups, individuals, and the press and can also expect litigation.
Questions and comments by participants related to the study design and deferred consent.
Pregnancy, Infection, and Nutrition (PIN) Study
Nancy Dole, Ph.D, University of North Carolina at Chapel Hill, described this ongoing cohort study that began in 1995 to collect data throughout pregnancy to measure behavioral and biological antecedents of preterm birth (the researchers expected it to be multifactorial). More than 4,100 women have been recruited into two protocols, PIN 1 and PIN 2. The goal is to enroll about 1,800 women in the study. Recruitment is from prenatal clinics. The current protocol calls for enrollment earlier in pregnancy than the first protocol; enrollment now is prior to 20 weeks gestation.
Incentives included cash as the primary incentive for completing study components, gift certificates for substance abusers (as requested by clinic staff), ultrasound photos and videos, and gift bags for mother or baby.
The results are given to the participants. In addition to the ultrasound images at two visits, they receive other measures, including height, weight, and percentage of body fat measures, and they will be given a summary report from the dietary assessments. Some participants have asked for additional information, which is provided when possible. The ultrasound video is a strong incentive for women to participate.
A newsletter is sent to the women with some study results, and statistics and a list of publications are posted on the study Web site. Data are shared with the women’s care providers, for example, abnormal ultrasound and suicide ideation in the postpartum period.
Consent forms can be very complex with new HIPAA requirements. The study’s form is 14 pages long, and women do not understand it. The study recruiters go over details with the women. Substudies about consent procedures are needed to find ways to do this better.
Comments and questions from participants related to disclosure, the distinction between waiving consent and waiving documentation of consent, and efforts to educate participants and obtain participant feedback through various means.
Focus Area: Interventions and Interaction with Communities
Early Childhood Longitudinal Study, Birth Cohort
Jerry West, Ph.D., National Center for Education Statistics, U.S. Department of Education, discussed this study, which is one of two studies designed to provide information on how children are prepared for schools and how schools’ early childhood programs affect children. These national studies track children’s transition from home to school and development over time. The studies also provide data (their basic mission) and release databases for others to mine.
The program includes two studies, the birth cohort study (B) and kindergarten study (K), which follows children through fifth grade. The birth cohort study is mainly home-based and follows 10,700 births with data collection at age 9 months, 2 years, 4 years, the fall of kindergarten, and the fall of first grade (overlapping with the K study). The study collects data on physical and cognitive development, academic achievement, and literacy. Data are obtained from parents and teachers. The K study is another nationally representative sample, mostly school-based, and 22,000 children were enrolled in the fall of 1998. There are multiple data collection points, and the last scheduled visit is at fifth grade in the spring of 2004. The study is an assessment of academic achievement and the school and home environments.
Dr. West described communities of interest, including gatekeepers and special populations. Approaches include working through other groups and forming ad hoc groups as needed. The researchers look for ways to better design studies to be sensitive to the needs of special groups through input from experts.
Effective approaches identified by Dr. West were:
- Start early
- Identify the right groups and individuals to engage
- Communicate regularly (the study uses newsletters for different audiences with relevant information)
- Provide opportunities to influence study design (not just notification)
- Provide feedback on outcomes.
Questions and comments related to state IRBs, the definition of passive consent, local influence on design, how representative their samples have continued to be over time, and how many different language groups they follow.
Michigan Children for Environmental and Children’s Health (MCECH)
Edith Ann Parker, Dr.P.H., University of Michigan School of Public Health, and Wilma Brakefield-Caldwell, B.S.N., Community Action Against Asthma, described this example of community-based participatory research (CBPR). The MCECH is an EPA-NIEHS Children’s Center in existence since 1998. Ms. Brakefield-Caldwell provided background on the study, the decision to focus on asthma, and the organization of the Community Action Against Asthma group. It took about a year to gain trust, organize the group, and get them on board with the project.
Dr. Parker discussed CBPR and research principles the study adopted:
- Involve all partners in research as appropriate in all major phases of process.
- Enhance understanding of issues affecting community, which will lead to developing, implementing, and evaluating plans of action to address community needs. Tangible benefits for the community are needed for epidemiological or other types of research.
- Ensure that findings are produced, interpreted, and disseminated in clear and respectful language to the community.
Ms. Brakefield-Caldwell discussed advantages of community participation and described the role and contributions of the steering committee to the process. Community participation can help raise community self-esteem and strengthen relationships between communities and researchers and their institutions.
The challenges of CBPR included achieving a balance between the research and intervention aspects of the study, the time lag in getting to the intervention, and taking enough time to build trust in the community. Recognizing the context of communities can limit use of standardized instruments across sites.
The study population was drawn from two areas in Detroit, and 300 families with children with probable or known asthma were recruited. About 9,000 questionnaires were mailed, perhaps another 1,000 distributed through schools, and about 3,000 were returned. About 450 children had asthma, 30 percent of which had moderate to severe asthma, and of these about 30 percent were previously undiagnosed. Data collection involved in-house questionnaires plus household walkthrough and dust sampling. Seasonal assessments were done along with a log of symptoms for 11 consecutive seasons. Outdoor/indoor sampling was done in a subset of the population, using backpacks on children. Incentives used were primarily cash.
Questions and comments by participants related to the process to identify who should be a part of the community partnership, access to care issues, the responsibility to intervene if there is, for example, inadequate medication use or some other problem is found, and issues concerning community representatives.
The National Children’s Study: Anticipating the Ethical Issues
Alan Fleischman, M.D., New York Academy of Medicine, moderated the final session of the day, a general discussion of the ethical issues that were brought up during the course of the workshop and their relevance to the Study. A formal ethics advisory committee has been proposed for the Study, in which difficult issues can be discussed.
Following general discussion, each participant made final comments about ethical issues for the Study.
Discussion Moderators and Presenters
Jeffrey R. Botkin, M.D., M.P.H., University of Utah School of Medicine
Wilma Brakefield-Caldwell, B.S.N., Community Action Against Asthma
Karen Birmingham, University of Bristol, UK
Nancy Dole, Ph.D., University of North Carolina at Chapel Hill
Alan R. Fleischman, M.D., New York Academy of Medicine
Norman C. Fost, M.D., M.P.H., University of Wisconsin Medical School
Matthew W. Gillman, M.D., S.M., Harvard Medical School/Harvard Pilgrim Health Care
Peter J. Gergen, M.D., M.P.H., National Institute of Allergy and Infectious Diseases, NIH, DHHS
Donald Mattison, M.D., NICHD, NIH, DHHS
Edith Ann Parker, Dr.P.H., University of Michigan School of Public Health
William J. Rodriguez, M.D., Ph.D., Center for Drug Evaluation and Research, U.S. Food and Drug Administration
Jerry West, Ph.D., National Center for Education Statistics, U.S. Department of Education
Benjamin S. Wilfond, M.D., National Human Genome Research Institute, NIH, DHHS
Anne L. Wright, Ph.D., Medical College Library, University of Arizona, Tucson
Marshalyn Yeargin-Allsopp, M.D., National Center on Birth Defects and Developmental Disabilities, CDC, DHHS
Other Participants
Christine Bachrach, Ph.D.
Marion Balsam, M.D.
Art Bennett, M.E.A., B.E.E.
Melissa Boychak
Arturo Brito, M.D.
Donna T. Chen, M.D., M.P.H.
Linda L. Dimitropoulos, Ph.D.
Vivian B. Faden, Ph.D.
Michael P. Firestone, Ph.D.
Celia B. Fisher, Ph.D.
Mary Foulkes, Ph.D.
Jonathan Francis
Alexa Fraser, Ph.D.
Gail Geller, Sc.D.
Doris Haire
Christine Cole Johnson, Ph.D., M.P.H.
Charles Kaelber, M.D., Dr.P.H.
Sarah A. Keim, M.A.
Woodie Kessel, M.D., M.P.H.
Carole A. Kimmel, Ph.D.
Tamar Lasky, Ph.D.
Jan L. Leahey
Grace K. LeMasters, Ph.D.
Stephen Marcus, Ph.D.
Pauline Mendola, Ph.D.
Victoria Moceri, Ph.D.
James J. Quackenboss, M.S.
William J. Rodriguez, M.D., Ph.D.
John S. Santelli, M.D., M.P.H.
Sherry Selevan, Ph.D.
Peter C. Scheidt, M.D., M.P.H.
Richard Sharp, Ph.D.
Rebecca Sokol, M.D.