NICHD ADVISORY COUNCIL
BETHESDA, MARYLAND

DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
NATIONAL ADVISORY CHILD HEALTH AND HUMAN DEVELOPMENT COUNCIL
SUMMARY MINUTES
January 24, 2008¹

The National Advisory Child Health and Human Development Council convened its one-hundred-thirty-second meeting at 8:10 a.m., Monday, September 10, 2007, Building 31, Conference Room 6, National Institutes of Health, Bethesda, Maryland. The meeting was open to the public from 8:10 a.m. to 12:35 p.m. As provided in Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S.C., and Section 10(d) of Public Law 92-463, for the review, discussion, and evaluation of grant applications and related information, the meeting was closed to the public from 1:35 p.m. until 3:50 p.m. Dr. Duane Alexander, Chair, National Advisory Child Health and Human Development Council, and Director, National Institute of Child Health and Human Development, presided.

Council members present:

Council members absent:
Dr. Donald Stein
Dr. Perri Klass

Ex Officio members present:
Colonel Martin G. Ottolini, Defense Threat Reduction Agency, Department of Defense
Dr. Robert Ruff, Department of Veterans Affairs, Veterans Administration

Ex Officio member absent
Dr. David Heppel, Maternal and Child Health Bureau, Health Resources and Services Administration

¹1Members absent themselves from the meeting when Council discusses applications from their own institutions or when a conflict of interest might occur. The procedure applies only to individual applications discussed, not to en bloc actions.

Invited speakers:
Dr. Mary Hebert, Professor, Department of Pharmacology, University of Washington, Seattle
Dr. James Leeder, Professor of Pediatrics/Pharmacology, Children’s Mercy Hospital, Kansas City, Missouri.
Dr. David Badman, Program Director, NIH Rapid Access to Interventional Development (RAID) Pilot, Office of the Director, NIH, Bethesda, Maryland.

Others present were:
Dr. William Sansalone, Georgetown University Medical Center
Ms. Laura Abulafa, American Association on Intellectual and Developmental Disabilities
Ms. Lily Albert, Senate Office of Senator Hillary Rodham Clinton
Ms. Debra Hawks, American College of Obstetricians and Gynecologists
Ms. Karen Studwell, American Psychological Association
Dr. George Jesien, Association of University Centers on Disabilities
Ms. Krysta Jones, American College of Obstetricians and Gynecologists
Ms. Mary Beth Busby, FRAXA Research Foundation
Mr. Emil Wigode, March of Dimes
Dr. Mary Ann McCabe, Society for Research in Child Development
Ms. Emily Hartford, American Academy of Pediatrics
Ms. Branka Sekis, Social Scientific Systems
Dr. Amy Pollick, Association for Psychological Science
Ms. Jacqueline Roche, American Association of Orthopedic Surgeons
Ms. Loretta Doan, The Endocrine Society
Ms. Pam Moore, LRP Publications
Ms. Michelle Rodrigues, SRI International
Ms. Carolyn Huitema, RTI International
Mr. Kevin Beverly, Social Scientific Systems
Dr. Perry Kirkham, Purdue University
Members of Staff, NICHD
Members of Staff, NIH
Members of Staff, CSR

I. INTRODUCTORY REMARKS

Dr. Alexander welcomed Council members, guests, invited speakers, and staff and announced that the meeting would be open to the public on Thursday morning, January 24, and would be closed to the public in the afternoon for the consideration of grant applications.

Review of Confidentiality and Conflict of Interest

Dr. Alexander reminded Council members that material furnished for review and discussion during the closed portion of the meeting is considered privileged information. Advisors and consultants serving as members of a public health advisory committee may not participate in situations in which any violation of conflict of interest laws and regulations might occur. Responsible staff shall ensure that a Council member does not perform duties or render advice which might have a direct and predictable effect on the interests of an organization or institution in which he/she has a financial interest. In particular, Council members should not participate in the evaluation of grant applications for federal support which will affect the interests of such organizations or institutions. At the end of the closed session of the meeting, all members were required to certify that they had not been involved in any conflict of interest situations during the review of grant applications.

Council Minutes - September 10, 2007, Meeting

The minutes were approved as written.

Future Meeting Dates

The following future meeting dates were agreed to:

June 12, 2008, (Thursday)
September 11, 2008 (Thursday)
January 22, 2009 (Thursday)
June 11, 2009 (Thursday)
September 21, 2009 (Monday)
January 28, 2010 (Thursday)
June 3, 2010 (Thursday)
September 20, 2010 (Monday)

II. NICHD DIRECTOR'S REPORT AND DISCUSSION

Dr. Alexander welcomed new Council members that were in attendance and requested that they introduce themselves. Each new member presented a brief overview of their research interests, expressed their interest in serving on the Council, and their enthusiasm for interactions with present Council members and NICHD staff.

Dr. Sherin Devaskar is Professor, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles (UCLA). Her scientific expertise is in fetal-neonatal nutrition, placental transfer, growth, intrauterine growth retardation, cerebral glucose metabolism, and a variety of topics related to neonatal and perinatal physiology. In 2004 she was selected as the Editor-in-Chief for the prestigious journal Pediatric Research. Additional appointments at UCLA include Executive Vice Chair for the Department of Pediatrics and Director, Neonatology Fellowship Program. Prior to her UCLA appointment, she was Chief of Neonatology and a Pediatrics Professor at the University of Pittsburgh.

Dr. Gail Martin is a Professor in the Department of Anatomy and Division of Genetics, School of Medicine, University of California, San Francisco. As a developmental biologist she has focused her interests in the investigation of molecular and genetic control of embryonic vertebrate development, from early development and gastrulation through organogenesis. She was the first to demonstrate the isolation of pluripotent embryonic stem cells from mouse embryos, which allowed for the development of knockout mice technology.

Dr. Truglio is the Vice President of Research and Education at Sesame Workshop. Dr. Truglio has conducted research on the effects of media on children and the role of television in the socialization and education of children. She is responsible for developing and reviewing the content across all Sesame Street products and programs (e.g. publishing, home videos, and outreach). Her career focus is to ensure that the creative process embraces the major curriculum points in a safe, sensitive, responsible and age-appropriate manner.

New Council member Dr. Perri Klass, Professor of Journalism and Pediatrics, New York University, was not in attendance for the January 2008 session of Council.

III. MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES BRANCH UPDATE PRESENTATION

The Report of the Director, NICHD, (electronically posted on the Council Members Website prior to the meeting) is appended (Attachment II). Dr. Alexander provided a brief overview of personnel changes at NICHD and NIH. He shared with Council a legislative update since the last meeting and provided a summary of current and upcoming Institute conferences and workshops. Members were encouraged to contact the appropriate NICHD staff representatives if they had an interest in attending any of the upcoming conferences and workshops.

Dr. Alexander began with an anecdote about the first Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development—then the National Institute of Child Health and Human Development.

Dr. Alexander related that the search committee charged with finding a director for the new institute unanimously recommended Dr. Robert A. “Bob” Aldrich for the job. However, when then NIH Director Dr. James Shannon offered Dr. Aldrich the position he turned him down. Dr. Aldrich thanked Dr. Shannon, but explained he wasn’t interested, as he was very happy serving as Chair, Department of Pediatrics, University of Washington Medical School. A short time later, Dr. Aldrich’s phone rang. President John F. Kennedy was calling, personally asking him to serve as the NICHD’s first director and to help establish the new institute. Dr. Aldrich thanked President Kennedy for his interest, but again explained that he couldn’t possibly abandon his position at the University of Washington. A few minutes later, the phone rang again. It was the University of Washington’s President informing him that he was fired. Still absorbing the shock of the news,

Dr. Aldrich had barely put the receiver back in its cradle when the phone rang once more. “This is President Kennedy calling again,” said the voice at the other end. “I understand that you’re out of a job. I know of an opening that you might be interested in.”

Dr. Aldrich served as NICHD Director from March 1963 to October 1964 before returning to the University of Washington Medical School.

Dr. Alexander noted that Drs. Richard Blye and H.K. Kim retired in January, too late for their retirements to be included in the Director’s Report. Drs. Blye and Kim served in the NICHD’s Contraception and Reproductive Health Branch, Center for Population Research, where they oversaw animal and biological testing of new products.

Regarding the NICHD’s efforts at safety and efficacy testing for pharmaceuticals and labeling for use in children and pregnant women, a Council member asked if biological differences between men and women, and between children of different ages, would be taken into account. Dr. Alexander replied that such differences were being accounted for in all Institute sponsored efforts.

Dr. Alexander noted that NICHD staff had worked with other program officials at NIH to develop a research plan to capitalize on and expand Down syndrome research funded by the various institutes. He added that the plan would serve as a model for an upcoming plan seeking to accomplish similar goals for NIH-sponsored research on Fragile X syndrome.

A Council member acknowledged Dr. Alexander’s having received the Distinguished Service Award from the American Society of Reproductive Medicine. Dr. Alexander stated that the award was in recognition of the Institute’s role in this field.

Dr. Alexander announced that with the departure of Dr. Anne Willoughby on February 17, Dr. Gilman Grave, Chief, Endocrinology, Nutrition and Growth Branch, Center for Research for Mothers and Children (CRMC) would serve as Acting Director of the CRMC until a permanent director is hired.

IV. NATIONAL CENTER FOR MEDICAL REHABILITATION RESEARCH TWO-YEAR UPDATE

Dr. Michael Weinrich, Director, National Center for Medical Rehabilitation Research (NCMRR), began by noting that previously the NCMRR presented a strategic plan for the next 5 years. He presented the progress of the NCMRR since the last report and the future directions planned for the Center to implement that report’s recommendations.

Dr. Weinrich stated that the number of awards funded by the Center and the dollar amount awarded has leveled off in the last few years, consistent with funding as a whole at the NICHD. The bad news is there are not any increased funds, but the good news is that rehabilitation research has remained competitive. He outlined the areas to promote or further research directions, which included:

1) translational research; 2) basic research to advance rehabilitation; 3) plasticity and adaptation of tissue in response to activity and environment; and 4) reintegration of persons with disabilities into the community.

He identified the cross cutting objectives to develop mechanisms to support new investigators, to enhance consumer input and outreach, and to extend the interdisciplinary model from basic research through applied research and community studies.

Dr. Weinrich provided an example of translational research supported with K series, R Series, and contracts for the last 10 years. He described research on a new way of controlling a powered prosthesis that allows individuals more control following the loss of an upper extremity. For this advanced prosthetic, the median, radial, ulnar, and musculocutaneous nerves of the brachial plexus are dissected and joined to aspects of the pectoralis major and minor muscles, which the patient controls by activation of the servo motors in the prosthesis. Thus, when the patient thinks to flex his elbow, the reimplanted musculocutaneous nerve fires, the pectoralis major contracts, and the detected signal causes the prosthetic elbow to flex. He noted that the patient has vastly more control; the control provided by the powered prosthesis is precise and natural. This is an example of the research funded by the Center, and it is a cornerstone of the 40 million dollar project in rehabilitation research funded by the Defense Advanced Research Projects Agency.

Dr. Weinrich described basic research on mosaic organization of neural stem cells in the adult brain by a group from the Department of Neurosurgery and Developmental and Stem Cell Biology Program, University of California, San Francisco. He noted a fundamental finding by Merkel et. al. (2007) that neuroprogenitor cells are a heterogeneous and not a homogeneous population of neurons. This is a problem for principal investigators (PIs), who are trying to develop/replace tissue following nervous system damage. He mentioned again that plasticity is a major thrust of research at NCMRR. He described the Extremity Constraint Induced Therapy Evaluation (EXCITE) randomized clinical trial led by Advisory Council liaison member Dr. Steven Wolf, Department of Rehabilitation Medicine, Emory University School of Medicine, which is investigating the effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after a stroke. He reported the EXCITE trial has demonstrated that constraint therapy for select patients has added benefits over conventional therapy. Single site studies have suggested that constraint-induced movement therapy (CIMT) for select patients that maintain some hand and wrist movement can improve upper extremity function that persists for at least one year.

Dr. Weinrich next explained that reintegration of persons with disabilities into the community is a really hard area of research. He stated that the Center recently engaged the NCMRR National Advisory Board on Medical Rehabilitation Research on this issue.

Dr. Weinrich also announced an increase in young investigators as a result of extended pay lines for R03, R21 and R01 awards. He drew particular attention to the number of young PIs in FY 2007 (27 new/305 total) which was 5 percent higher than in FY 2006 (25 new/301 total). He added that new K12s were awarded to develop allied health personnel in rehabilitation research at the University of Texas and the University of Kansas. He addressed other new mechanisms for young investigators, including the ERRIS grant writing workshop that advised young PIs by providing extensive hands-on grant writing help. In addition, he noted that the NCMRR biannual training meeting was held as a satellite at the American Congress of Rehabilitation Medicine (ACRM) 2007 annual meeting in Washington, D.C. He stated the training meeting attracted young investigators and provided exposure to mentors and networks. The biannual training meeting was previously a stand alone; however, it will now be rotated to different rehabilitation meetings as a satellite. As a final point in this area, he acknowledged the NCMRR Medical Rehabilitation Infrastructure Centers continue to provide a collaboration and training opportunity for investigators to apply cutting edge technology/resources to rehabilitation.

Finally, Dr. Weinrich discussed the reissue of the Program Announcement Reviewed by an Institution (PAR) for rehabilitation research to improve functional outcomes in individuals with chronic diseases. The PAR was active for 3 years with only 6 of the 87 applications being fundable. He added that the applicants proposed good research problems and formed the required interdisciplinary teams but did not use the team to write the application. As a result, the applications received poor reviews on the methods section. The solution is to reissue the PAR as conference grants to provide support to help generate competitive R01s.

A Council member commented that the prosthetic research presented by Dr. Weinrich was exciting and that the work on the contracture of the pectoralis complements the work being done by Dr. Steve Wolf. Dr. Wolf stated that he looks forward to hearing from the NCMRR in future years.

V. OBSTETRIC AND PEDIATRIC PHARMACOLOGY BRANCH PRESENTATION

Dr. Donald R. Mattison, Chief, Obstetric and Pediatric Pharmacology Branch (OPPB), CRMC, introduced the first Branch Report by providing an overview of the development of the Branch and its mission, which is to “enhance productivity and effectiveness in accomplishing program goals by centralizing research, clinical trials and drug development activities for pediatric and obstetric pharmacology within a single organizational entity in the Center for Research for Mothers and Children (CRMC).” The OPPB was formed in 2004, by combining the Pediatric Pharmacology Research Units (PPRU) Network, the Obstetric-Fetal Pharmacology Research Units Network (OPRU) and the Best Pharmaceuticals for Children Act (BPCA) program to provide an organizational structure that is based on a cross fertilization of science expertise which will improve the safety and effectiveness of pharmaceuticals and promote new research on the safety and efficacy of medications used during pregnancy and in children.

The purpose of the presentation to the NACHHD Council regarding the OPPB was to provide an overview of Branch functions; listen first-hand to Principal Investigators (PIs) actively engaged in OPPB research; reflect on recommendations compiled from the panel of pediatric and obstetric experts convened to evaluate and comment on the draft Branch Report; and to allow reactions from NACHHD Council members about current and future OPPB activities as described in the presentation.

Dr. Mattison’s summary included discussions regarding ongoing BPCA clinical activities awarded via the contract mechanism; future goals of the PPRU in developing characteristics (biomarkers); ongoing projects with the European Union (EU) and the World Health Organization (WHO); plans for developing private/public partnerships; and the challenges faced to-date by the OPPB in creating a vibrant grant portfolio to help satisfy the Branch’s mission and goal.

Dr. Mattison addressed several challenges facing the Branch that also were clearly recognized by the expert panel. In reflecting on the achievements and activities of the Branch, it is apparent that since the Branch inception, OPPB’s focus has been on funding and conducting pediatric research. Dr. Mattison explained that because much of OPPB’s funding is contributed by other NIH Institutes to support BPCA-related activities, the priority has been BPCA and pediatrics. The expert panel recommended that a primary goal of the Branch should be to acquire more funding outside of BPCA that ultimately would allow for a more balanced research agenda between pediatrics and obstetrics.

Another challenge recognized by the expert panel was that most work appears to have been focused on clinical and translational research. The experts encouraged the Branch to consider funding more basic research in the future. Lastly, the expert panel recognized the importance of funding future training opportunities in these disciplines because of the scarcity of researchers in obstetric and pediatric pharmacology.

Dr. Mattison introduced invited speakers Drs. Mary Hebert and Dr. Steve Leeder, both OPPB-funded PIs, who currently are conducting research within the OPRU and PPRU Networks.

Dr. Mary Hebert, Professor, Department of Pharmacology, University of Washington, Seattle, is one of four PIs for the Obstetric Pharmacology Research Units (OPRU) Network. Her presentation reported on one of the collaborative multicenter studies being conducted by the OPRU, Pharmacokinetic-Pharmacodynamic-Pharmacogenomic Study of Glyburide for Treatment of Gestational Diabetes.

The OPRU was created in part to demonstrate that clinical pharmacology studies can be performed in pregnant patients in order to improve treatment for this large but understudied population. Gestational diabetes (diabetes occurring during pregnancy) occurs in 5 percent of pregnancies. Maternal complications include urinary tract infections, wound infections, pregnancy-induced hypertension, preeclampsia, and diabetic ketoacidosis. Fetal complications include increased fetal insulin production and resulting neonatal hypoglycemia and increased neonatal size, cardiac dysfunction, increased neonatal bilirubin levels, and death in-utero.

The OPRU chose to study this disease and one of its treatments, oral glyburide, to determine how drug disposition and response change during the course of pregnancy in comparison to non-pregnant and pregnant control patients (women with Type 2 diabetes taking glyburide and pregnant women without gestational diabetes but who have altered carbohydrate metabolism which occurs during pregnancy). Insulin and glucose concentrations, as well as glyburide (free and protein-bound) and its metabolites, were measured in pregnant women being treated with glyburide. Results of the study indicate that pregnant patients with gestational diabetes had markedly reduced insulin sensitivity, reduced glyburide concentrations over the entire dosage interval associated with increased apparent oral clearance, suggesting either poor oral absorption or rapid hepatic elimination. Glyburide had previously been reported to be metabolized to 3 metabolites; 4 additional metabolites were discovered. Additionally, placental transport and metabolism has now been observed. In some patients, poor response to oral glyburide may be from inadequate dosing in pregnant patients.

The second speaker, Dr. James Leeder, Professor of Pediatrics and Pharmacology, Children’s Mercy Hospital, Kansas City, Missouri, is a member of the PPRU Network whose field of expertise is developmental pharmacology. His research is focused on the genomic changes that occur during development, including those that affect drug disposition and effect. The purpose of Dr. Leeder’s presentation was to provide examples of how characterization of drug biotransformation phenotypes can provide important insights into the interaction between pharmacogenetics/genomics and human development across the age continuum. The first example described a series of studies designed to characterize the metabolism of acetaminophen (APAP), whose use in early pregnancy has been associated with an increased risk of gastroschisis, a rare but serious congenital defect of the abdominal wall. The results of these studies identified four metabolic enzymes (sulfotransferases) expressed in human fetal liver that were capable of catalyzing sulfate conjugation of APAP. One form of this enzyme (1A3) appeared to be the primary determinant of APAP sulfation and future research will study this high priority gene candidate for genetic association studies.

Acquisition of functional drug biotransformation activity after birth and its impact on drug dosing is another issue of importance to pediatric drug therapy. A longitudinal phenotyping study was conducted in infants in the first year of life to characterize the ontogeny of cytochrome P450 2D6 (CYP2D6). The results of this study revealed that CYP2D6 phenotype did not change appreciably throughout the first year of life. However, a secondary pathway of drug metabolism in adults, N-demethylation, increased dramatically over this same period of time. The results have important implications for several drugs/drug classes, including serotonin re-uptake inhibitors, codeine, promethazine, atypical antipsychotics and other medications commonly administered to children.

Finally, preliminary, unpublished data from a study of valproic acid (VPA) metabolism in children were presented. This project is of significance to pediatric pharmacology as the risk of fatal VPA hepatotoxicity is dramatically increased in children less than two years of age receiving concurrent treatment with “enzyme-inducing” antiepileptic drugs (e.g. phenytoin, carbamazepine). This project explores inter-individual variation in urinary valproic acid metabolite excretion with the intent of identifying patterns that may be used to identify patients at increased risk for developing severe liver toxicity, and subsequently the genetic basis of increased risk.

These examples demonstrate that many opportunities exist for developmental pharmacogenetic and pharmacogenomics strategies to be applied to drug therapy problems in children, and will require solutions involving multi-disciplinary teams and multi-center collaborations.

Council discussant Dr. Ralph Kauffman initiated several questions following the presentation by Dr. Hebert. He was interested in knowing if she felt increases in clearance of glyburide were due to decreased absorption or some effect of the markedly increased weight of the subjects. Dr. Hebert said she felt it was difficult to determine, although changes in clearance during pregnancy, and between pregnant and non-pregnant subjects who are of similar weight, indicate that it is likely due to the pregnancy. Dr. Kauffman was also curious whether they were collecting DNA from the mother and father. Dr. Hebert confirmed they were collecting DNA from the mother, but not the father nor the baby, although they were considering a change to the protocol to address this. Council members agreed it was important to collect this information for future work .

A Council member reiterated the difficulty in recruiting patients. Dr. Hebert confirmed this by saying a willingness to participate in studies increased with a patient with an illness versus a pregnant patient who is healthy. Council discussant Dr. Enriqueta Bond inquired about the ability to track ethnicity in this study, and suggested that Dr. Hebert could do sub analysis of the data, if available. Dr. Bond also asked if Dr. Hebert obtained (birth weights) on the mothers, and even though Dr. Hebert confirmed she did not, felt it was a good suggestion in future studies.

Other Council members noted the importance of conducting research in obstetrics and pediatrics. Members emphasized that we cannot lag behind in the genomic approach. Some members felt that insurance companies will ultimately force this approach, but it is important for us to look at the developmental origin of disease. Dr. Kauffman confirmed that the science is moving in that direction, e.g., considering PK data in terms of developmental pharmacogenomics. The area of developmental pharmacology is complex and cross-disciplinary; it exemplifies translational research and also emphasizes biological sciences and applied needs. Council members agreed that we need the translational component to help answer questions about what we’re doing in drug therapy. The Branch shouldn’t necessarily shift to basic research – rather attempt to pursue both approaches to help fill the knowledge gap.

Dr. Kauffman provided his reaction to the report and overall activities of the OPP Branch. He felt the report was thorough and captured the numerous ongoing activities and challenges of the Branch. He is pleased to see the OPRU and PPRU co-existing in the same Branch. Dr. Kauffman emphasized the importance of providing funding for training in these disciplines. Additionally, he stressed the need to change the paradigm from the “silo” approach to a more interdisciplinary model.

Dr. Bond also provided comment to the OPP report and presentation. She echoed Dr. Kauffman’s comment on changing the research approach from organ and disease based to an interdisciplinary model. Dr. Bond recommended that NICHD explore options for using AHRQ’s Center for Education and Research on Therapeutics (CERTs) or the new Clinical and Translational Science Awards (CTSAs) being awarded by the NIH. She also encouraged the use of stored tissue samples to study difficult populations (pregnant women and fetuses).

Other comments by Council included a recommendation that the Branch take on as a future goal obstetric and pediatric involvement in the whole human genome, in order to potentially link obstetric and pediatric disease to adult disease. A Council member noted that the OPPB is the only Branch doing pharmacology work in the orphan population of pregnant women.

Dr. Kauffman completed the summary by stating that the Branch’s complex cross-disciplinary work is valuable, and exemplifies translational research, by impacting patient care and incorporating basic human biological mechanisms. A member echoed Dr. Kaufman’s comments, and emphasized the need to keep translational, clinical, and basic research together, and noted there are many unmet needs in clinical care.

In closing, Council members recommended that the Branch attempt to get funding outside of BPCA for other activities, and congratulated Dr. Mattison on the many successful Branch activities.

VI. REPORT OF THE SUBCOMMITTEE ON PLANNING AND POLICY

The following topics were discussed at the January 7, 2008, Subcommittee on Planning and Policy teleconference meeting.

Budget

Dr. Enriqueta Bond, Subcommittee Chair, reiterated Dr. Alexander’s budget overview and stated that President Bush signed the NIH FY 2008 budget appropriation, on December 26th. The budget measure provides the NIH a 0.5 percent increase. The NICHD budget ($1,255,000) is slightly under $1 million above the 2007 budget. With an expected inflation rate of 3.7 percent, the NIH and the NICHD will have less purchasing power than in 2007. The budget for the NIH Office of the Director contains $110.9 million for the National Children’s Study. The expectation from Congress is that the NIH will be able to continue funding all activities (training, new investigators, number of research grants) at the same level as FY 2007. The NICHD expects to fund to the 15th percentile (compared to 17.5 in FY 2007) for RPGs and continue funding above the 20th percentile for new investigators. At the current budget level, the Institute expects to fund 90 fewer competing RPGs.

National Children’s Study (NCS)

As a show of support for the NCS, Congress raised the FY 2008 appropriation for the NCS from $110.9 million to $112.87 million before rescinding 1.74 percent, returning the appropriation to the original $110.9 million. As noted previously, these funds are in the OD, NIH. This funding will allow adding the next wave of new sites, as well as starting recruitment in the seven vanguard centers. Dr. Peter Scheidt, Study Director, will report on the progress of the NCS at the June Council meeting.

Institute Name Change

On December 13, 2007, a bill was introduced in Congress by Senator Orrin Hatch (R-Utah) to rename the National Institute of Child Health and Human Development as the Eunice Kennedy Shriver National Institute of Child Health and Human Development, in recognition of her advocacy efforts on behalf of children and persons living with intellectual and developmental disabilities. The bill was passed and the name change is official. In addition, the Institute is renaming its Mental Retardation and Developmental Disabilities Research Centers as the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers.

Reengineering Peer Review

The working group on Peer Review of the NIH Advisory Committee to the Director has reviewed all of the comments it received regarding how the NIH conducts the peer review process to evaluate grants for funding. The diagnostic phase is essentially complete and now the committee is reviewing suggestions for improving the process and identifying emerging ideas that can be tested through pilot studies, which are scheduled to start in March 2008. Dr. Lawrence Tabak, Director, National Institute on Dental and Cranial Research, will present an update and status report at the June Council meeting.

NICHD Clinical Research Policy Development

New draft NICHD guidelines for clinical data and safety monitoring and conflict of interest were reviewed. The Clinical Research Monitoring policy was developed to ensure the safety of clinical research studies and protect study participants from unacceptable risk, and to maintain the integrity of the data collected. The Conflict of Interest policy was developed to help in identifying and avoiding real or apparent conflicts of interest in NICHD-supported clinical research. The Subcommittee members were pleased with the overall policies, which they found to be very thorough and complete. Questions concerning specific details in the policies were discussed and answered to the satisfaction of the Subcommittee.

Council of Councils

Dr. Bond updated the Subcommittee on the activities of the Council of Councils (CoC), stating that she and Council member Dr. Sergio Ojeda represent the NICHD. The CoC’s primary concern to date has been Roadmap issues. Its three newly established subcommittees will focus on how research is conducted. The three new subcommittees are: 1) Resource Development and Analysis; 2) Strategic Coordination; and 3) Evaluation and Systematic Assessments.

Agenda for June

Key agenda items for the June Council meeting include:

• CRHB Branch report presentation
• NCS update
• Status report on reengineering the peer review process

VII. NIH RAPID ACCESS TO INTERVENTIONAL DEVELOPMENT (NIH-RAID) PILOT

Dr. David Badman, of the National Institute of Neurological Disorders and Stroke and Program Director, NIH RAID Program, outlined the basics of the NIH’s Rapid Access to Interventional Development (NIH-RAID) Pilot. The RAID program assists researchers at non-profit institutions who have discovered promising candidates for new pharmaceutical agents to develop, test, and prepare those new agents for clinical trials. Such new drug candidates, he said, can span the spectrum of human disease.

Dr. Badman noted that the intent is to reduce some of the common barriers between laboratory discoveries and clinical trials of new therapies.

The NIH-RAID Pilot is not a grant program. Successful projects gain access to the government’s contract resources as well as assistance in establishing and implementing a product development plan. Funding comes from Roadmap funds and from individual Institutes, with Institutes assuming the bulk of support in specific disease areas germane to their mission.

Review of RAID requests involves a two-stage evaluation. The preliminary administrative assessment determines whether the resources requested are appropriate and whether one or more Institutes/Centers (ICs) are prepared to provide co-sponsorship. Individual ICs have established priority areas for the NIH-RAID Pilot. Based on the preliminary evaluation, selected applicants will be invited to submit a full proposal for assessment by a panel of external reviewers. The results of that evaluation will guide final Institute and Roadmap allocation.

VIII. DIVISION OF EPIDEMIOLOGY, STATISTICS AND PREVENTION RESEARCH TWO-YEAR UP-DATE PRESENTATION

Dr. Germaine Buck Louis, Acting Director, Division of Epidemiology, Statistics and Prevention Research (DESPR), provided an update on Division activities since the last Advisory Council review in 2005.

Current composition of DESPR includes 25 FTE staff members divided among three branches, two sections, and the Office of the Director. From 2005-2007, DESPR mentored a total of 78 Intramural Research Training Award (IRTA) fellows and interns (an average of three per investigator). Over that same period of time, DESPR staff has given 138 invited talks, seminars or keynote addresses. Staff members have also been honored with numerous awards.

Dr. Buck Louis then briefly reviewed the research areas of each of three branches. In the Biometry Branch, their areas of methods development include issues related to reproductive health and pregnancy, genetic determinants of birth defects, and growth curve models. In the Prevention Research Branch, research focuses on the family management of diabetes, adolescent health behavior, and studies looking at safety issues for young drivers. In the Epidemiology Branch, work focuses on three main areas: reproductive, perinatal and pediatric epidemiology. Studies range from a randomized clinical trial looking at the efficacy of low-dose aspirin in relation to the prevention of pregnancy loss (EAGeR) to a project looking at neurodevelopment among children born with the help of fertility treatment (Upstate KIDS).

Next, Dr. Buck Louis provided an update on one of the largest studies that the Division currently has in the field, the Longitudinal Investigation of Fertility and the Environment (LIFE) Study. The focus of the Study is the potential reproductive and developmental toxicity of environmental chemicals in the context of lifestyle factors. The goal is to recruit 500 couples. Exposures of interest include: PCBs, PBDEs, PFOS, PFOA, pesticides, metals, cotinine, phytoestrogens, smoking, alcohol, caffeine, vitamins, stress, and exercise. To date, approximately 350 women have been enrolled in the Study. Once enrolled, couples have provided the needed biospecimens per the protocol, even the semen samples.

Following the presentation a Council member asked why the recruitment rate in the LIFE Study is so low? Dr. Louis responded that it is proving very difficult to capture couples at the time they are planning to start trying to become pregnant. The overwhelming majority of women contacted are not planning a pregnancy in the next six months. However, most eligible women do enroll in the Study.

IX. CONCEPT CLEARANCE REVIEW AND DISCUSSION

The following eight concepts were discussed and unanimously endorsed by the Council.

Innovative Statistical and Computational Methods for the Design and Analysis of Multilevel Studies in Childhood Obesity

The purpose of this initiative is to enhance multilevel research in childhood obesity, which involves the simultaneous consideration of the complex socio-environmental and biological factors (e.g., from genetics to food policy), and their interplay, that regulate the dietary and physical activity patterns of children and their families. However, current statistical methods used in obesity research are insufficient to account for more than 2-3 levels of behavioral influences at the same time. Statistical approaches such as Bayesian methods and fractional factorial or adaptive intervention designs, as well as computational techniques such as systems dynamics modeling and agent-based modeling, are promising new approaches that can further enhance the understanding and prevention effort of childhood obesity.

The ultimate objective of this initiative is to lay the methodological foundation for the next frontier of obesity research that can help to quantify and determine the degree of influence of a wide range of factors, from biological to socio-environmental, on the dietary and physical activity behavior of children.

Youth and HIV Risk The purpose of the proposed Request for Applications (RFA) is to stimulate collaborative, multidisciplinary research in an area in which unsolicited applications have been too narrowly focused to advance the science optimally. It will call for research on the interactions among developmental and environmental/cultural/social processes contributing to HIV risk in youth. It will call for studies focusing on HIV risk in specific settings around the globe where HIV prevalence is high or increasing.

The ultimate goal of this RFA is to build the body of basic social science data upon which preventive interventions may profitably be built.

Studies of Antimicrobial and Prebiotic Activity of Oligosaccharides

The purpose of this initiative is to stimulate research on the antimicrobial and prebiotic properties of oligosaccharides. The majority of the world's 10 million children younger than age five who die every year succumb to enteric microbial infections. Therefore, the development of a new class of antimicrobial agents directed at intestinal pathogens would be of great public health importance. After lipids and galactose, oligosaccharides comprise the third most prevalent component of human milk. Oligosaccharides are composed of sugar molecules, such as D-glucose, N-acetyl glucosamine, D-galactose, sialic acid and L-fucose, linked together in short chains in hundreds of combinations. However, oligosaccharides are non-nutritive for human infants. Evidence is accumulating that the reason for the evolutionary persistence of large amounts of oligosaccharides in human milk is because of their antimicrobial properties. This initiative is designed to stimulate research on how various kinds of oligosaccharides and their glycoconjugates prevent enteric infections. This initiative will be aimed at developing specific oligosaccharides and their glycoconjugates as antimicrobial agents to prevent and treat gastrointestinal infections.

The ultimate goal of this RFA is to lead to a better understanding of the how oligosaccharide binding sites for specific enteric pathogens are synthesized, packaged, transported, and incorporated into the cell membrane of the enterocyte to stimulate research on how oligosaccharides prevent enteric infections and to develop a new class of antimicrobial therapy to prevent or treat enteric bacterial or viral infections.

Epigenetic Processes in Development

The purpose of this RFA is to enable scientists to pursue novel, high risk/high-payoff projects in Developmental Epigenetics, complementary to the efforts encouraged in the NIH-wide Epigenomics Roadmap initiatives. Epigenetic marks regulate gene expression, fine-tuning the genetic apparatus of cells. Epigenetic changes can both set in motion a developmental program, and occur in response to it. We hope to encourage scientists to consider both roles of epigenetics in development and to propose projects that are specifically relevant to the NICHD’s interest in epigenetics.

The ultimate objective of this initiative is to encourage researchers to pursue novel and potentially risky, high-payoff projects to break new ground in Developmental Epigenetics, a field that is critical to many of the research areas which NICHD supports.

Using Proven Factors in Risk Prevention to Promote Protection from HIV Transmission

HIV and other sexually transmitted infections (STI) are threats to the health and well-being of youth, with about 25 percent of HIV cases occurring in the under 25 year old population and almost 4 million new cases of STIs occurring annually in American adolescents. Preventing early and unprotected sexual intercourse in adolescents is critical to slow the epidemic of HIV and to reduce the negative consequences of disease. Despite a science base for some effective prevention programs, many communities continue to invest in prevention programs with limited effectiveness.

The ultimate goal of this RFA is to stimulate research that will increase the number of effective HIV prevention programs for high-risk youth and reduce the spread of HIV and other sexually transmitted infections.

Translational Research in Female Pelvic Floor Disorders

The purpose of the proposed RFAs is to address knowledge gaps by soliciting collaborative, multidisciplinary research from basic and clinical researchers in the study of female pelvic floor disorders.

The ultimate goal of the RFA is to attract more basic scientists into the field of female pelvic floor disorders, to establish collaborations between basic scientists and clinical researchers, and to promote research that has the greatest clinical applicability in addressing unknown aspects of physiology and pathophysiology of pelvic function.

Studies of the Interaction Between Iron and Malaria

With this RFA the NICHD will invite new and experienced basic scientists, epidemiologists, and clinical investigators to submit research grant applications to further understand: 1) the relationship between iron status and infection (particularly malaria) from both the host and infectious agent perspective 2) factors affecting the safe and efficacious delivery of iron to prevent and treat nutritional anemia in malarious regions and 3) the best available methods for assessing iron status in women, infants and children living in resource limited settings.

The objectives of this RFA are to facilitate a better understanding of the full interaction between iron nutrition and infection and current pharmacological interventions for prevention and treatment of malaria. This program will also serve as a proof of concept for how best to generate evidence regarding the role of diet and nutrition for populations living in a complex environment of food insecurity, infectious disease, indigenous culture, and limited resources.

Factors Affecting Cognitive Function in Individuals with Down Syndrome During Lifespan Transitions

The purpose of this RFA is to encourage investigator-initiated research that focuses upon the maximization and maintenance of cognitive function in individuals with Down syndrome, particularly during life transitions in adolescence and adulthood. Although some research has focused on transitions in childhood and during the aging process, there is a paucity of biomedical, behavioral, and biobehavioral evidence to inform decisions about medical, educational, psychosocial, and psychiatric issues that arise in adolescents and adults with Down syndrome. Since the average life expectancy now reaches at least 50 years and the population of adults with Down syndrome is expected to increase substantially in the next twenty years, encouragement of such research is needed.

The objective is to create a more substantial base of evidence to inform future research directions in studies of adults with Down syndrome and to better meet the medical, psychosocial, and psychiatric needs of a growing population of adults with Down syndrome in the United States and internationally.

X. REVIEW OF APPLICATIONS

A total of 1092 applications were initially assigned to the Institute. Applications that were transferred out, withdrawn, noncompetitive, unscored, or were not recommended for further consideration by the initial review groups were not considered by the Council. Council reviewed 453 applications requesting

$175,595,989 in total costs. Council favorably recommended 453 new, renewal, and supplemental research and training grant applications with requested total costs of $175,595,989.

XI. ADJOURNMENT

There being no further business, the meeting was adjourned at 3:45 p.m. on Thursday, January 24, 2008. The next meeting is scheduled for June 12, 2008.

Mary Plummer
Committee Management Officer, NICHD