NATIONAL ADVISORY CHILD HEALTH AND HUMAN DEVELOPMENT
 COUNCIL

MINUTES OF MEETING

June 11, 2009

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
June 11, 2009

The National Advisory Child Health and Human Development (NACHHD) Council convened its
one-hundred-thirty-eighth meeting at 8:05 a.m., Thursday, June 11, 2009, Building 31, Conference
Room 6, National Institutes of Health, Bethesda, Maryland. The meeting was open to the public from 8:07 a.m. to 12:40 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 1:40 p.m. until 5:05 p.m.

Dr. Duane Alexander, Chair, NACHHD Council, and Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), presided.

Council members present:

Council members absent:
Dr. Jonathan Gitlin    Dr. Joseph Zanga
Dr. Vivian Lewis       Dr. Steven Wolf, NABMRR
Dr. Gail Martin             Liaison Member

Ex Officio members present:
Dr. David Heppel, Maternal and Child Health Bureau, Health Resources and Services Administration
Dr. Lynn Cates, Department of Veterans Affairs, Veterans Administration
Dr. David S. Louder, III, Air Force Medical Operations Agency, Department of Defense

Council Roster (Attachment I)

1Members 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. Matthew Gillman, Professor and Director, Obesity Prevention Program, Department of Ambulatory
Care and Prevention, Harvard Medical School, Boston, Massachusetts.
Dr. Ardythe Morrow, Professor and Director, Center for Epidemiology and Biostatistics, Cincinnati                                                                   
Children=s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio  
Dr. Alan Willard, Chief, Scientific Review Branch and Referral Officer, National Institute of   
Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, Maryland.

Others present were:

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, June 11, and would be closed to the public in the afternoon for the consideration of grant applications.

Dr. Alexander stated that the January 2009 pilot study of Avirtual attendance@ as an alternative to attending meetings in Bethesda, Maryland, was a success.  He further noted that the Institute will continue to allow members to participate in the meeting through electronic means via Adobe Connect technology. In addition to allowing Council members to participate in the meeting through Adobe Connect, the general public was also invited to attend the Open session from remote sites via NIH Videocast.  Dr. Alexander reviewed the virtual meeting guidelines to facilitate remote participation and to assure that remote Council member attendees will be fully engaged in the discussion and deliberations of the Council meeting.

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 - January 22, 2009, Meeting

The minutes were approved as written.

Future Meeting Dates

The following future meeting dates were agreed to:

September 21, 2009   (Monday)
January 28, 2010        (Thursday)
June 3, 2010               (Thursday)
September 20, 2010   (Monday)
January 20, 2011        (Thursday)
June 2, 2011               (Thursday)
September 22, 2011   (Thursday)

II. NICHD DIRECTOR'S REPORT AND DISCUSSION

The Report of the Director, NICHD, (electronically posted on the Council Member 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.

Dr. Alexander noted with sadness the passing away of Dr. Gabriel (Gabe) Bialy, former Deputy Director, Center for Population Research (CPR) and summarized some of his achievements.  Dr. Richard Tasca, Health Scientist Administrator, will assume the position of Acting Deputy Director, CPR.  He will continue to maintain his portfolio in the Reproductive Sciences Branch.   

Dr. Alexander thanked Dr. Owen Rennert for his service in the Division of Intramural Research (DIR).
Dr. Rennert recently announced his stepping down as Scientific Director of the Institute to return to his laboratory. Dr. Constantine Stratakis, Senior Investigator, Section on Endocrinology and Genetics, DIR, will be Acting Scientific Director as a search is undertaken.

Dr. Alexander shared a budget update and mentioned the new appointees heading agencies in the Department of Health and Human Services. The NIH budget increase is 1.4 percent over the 2008 level. He mentioned the American Recovery and Reinvestment Act, which will be discussed later in the morning.

A Council member asked if funding for staff was included in the stimulus package. Dr. Alexander said that funding for that purpose is very difficult to get access to. The NICHD has hired a few contractors  to help deal with the burden of the stimulus package, but most of it has fallen to current staff.


III. STATEMENT OF UNDERSTANDING

Bryan Clark, Chief, Grants Management Branch, NICHD, provided an overview of the Statement of
Understanding (Authorities for Administrative Adjustments to Grants and Awards) previously posted on the Council Member Website for Council review. Mr. Clark highlighted for the members the actions that are considered individually by the membership. The Council unanimously endorsed the Statement of Understanding. The Statement of Understanding is attached (Attachment III).

IV. ENDOCRINOLOGY, NUTRITION AND GROWTH BRANCH PRESENTATION

Dr. Gilman Grave, Chief, Endocrinology, Nutrition and Growth Branch (ENGB), and Acting Director of the Center for Research for Mothers and Children, highlighted the progress of the ENGB since the last report and presented the future directions for the Branch.  The goal of the ENGB is to improve growth by better understanding hormones and growth factors acting on nutrients to generate macromolecules. In January 2009, the Branch met with 12 outside experts to discuss future directions for the Branch. Three themes emerged from the discussions: 1) gene-environmental interactions; 2) using systems science to analyze complex biological problems; and 3) decision science to improve diagnostic precision of biomarkers and to guide therapy.  His presentation covered the topics below.

Research Training

The ENGB has a large commitment to training the next generation of pediatric academic scientists, devoting more than one-fifth of its budget to training and career development.  The panelists noted that the Child Health Research Career Development Award program is the “Best thing that’s happened in academic pediatrics in the past 20 years.”  Future directions include:  1) maintain current level of funding; 2) encourage training in transdisciplinary and translational research, with a focus on systems science; 3) increase number of clinical and population science trainees; and 4) increase program flexibility to facilitate women raising a family while pursuing scientific training.

Type 1 Diabetes Mellitus

The Branch supports cutting edge research projects on pathogenesis, biomarkers, prevention and therapy of type 1 diabetes mellitus.  As part of the Diabetes Research in Children Network program, investigators have tested a series of glucose sensing devices, all of which performed poorly in the hypoglycemic range, the very part of the glycemic spectrum where readings need to be most accurate. These results stimulated industry to develop better products.  He also presented recent results of a new treatment for new onset diabetic patients in which treatment with Rituximab produced greater insulin secretion and a reduction in daily insulin dose than in the placebo group. The effect was more pronounced in children than adults and accounted for the entire group effect.  Future directions included:  1) new biomarkers and immunomodulatory therapy for type 1 diabetes mellitus; 2) closed loop systems and development of an ‘artificial pancreas’; 3) glucose sensors for very low birth weight infants and other
newborns with unstable glucose metabolism; and 4) neurocognitive effects of hypo- and hyperglycemia in newborns and in diabetic children.

Childhood Obesity

For several decades the Branch has played a leading role in promoting research on childhood obesity. However, interventions have had little impact on the increased prevalence of obesity, probably because we are using single controlled interventions examined one level at a time.  In actuality, obesity is a systemic problem embedded in Western lifestyle, caused by multiple factors within many levels of the body and society acting simultaneously. The Branch now plans to:  1) frame obesity as a complex systems problem with macro and micro-level factors operating at different points along growth and developmental pathways with recursive feedback loops; 2) study origins of health disparities in mechanistic and intervention studies; 3) develop more accurate methods to assess adiposity in pregnancy and infancy; and 4) establish an NICHD Website for sharing information on obesity research studies and findings.

Major Longitudinal Studies

ENGB-supported research on children’s growth involves several longitudinal studies which involve serial measurements on the same individual, in some cases for a lifetime.  As part of the Child Health and Development Studies, levels of dichloro-diphenyl-trichloroethane (DDT) in the serum collection were used to demonstrate a striking dose-response relationship between aggressive breast cancer prior to age 50 and the amount of DDT that women enrolled in the study were exposed to as young girls. These findings demonstrate the value of a well-documented carefully preserved serum collection. Potential future research directions may include: 1) studying the effects of maternal glycemia levels on programming of carbohydrate metabolism in offspring; 2) elucidating the earliest onset of obesity and diabetes at the molecular/biochemical level and tracking surrogates for cardiovascular risk and bone fracture according to BMI, diet, vitamin D status, race, ethnicity, age and stages of puberty;
3) ascertaining the range of normal and abnormal childhood values in continuously distributed variables of hormones, adipokines, lipids, and anthropometry; and 4) using decision science to improve precision of a biomarker’s predictive power for metabolic and cardiovascular disease later in life.

Nutrition

The Branch is studying the complex relationships between nutrition, health and disease in order to make more definitive statements on what a person’s nutritional needs are throughout the lifecycle.  The Bill and Melinda Gates Foundation has awarded the Institute a $10 million grant in addition to funds received from the Office of Dietary Supplements to study the relationship between iron and malaria.  Future directions include: 1) nutrient requirements before and during pregnancy; 2) improved biomarkers of nutrient intake, status and immune and neurocognitive function; 3) interrelationships between nutrition, disease, and drug metabolism; 4) micronutrient needs during critical windows in brain development, especially in intrauterine growth restriction and very low birth weight infants; 5) systems science approach to gene-environmental interactions and individual nutrient requirements; 6) workshop on epigenetic regulatory control of development and metabolism; and 7) influence of environmental nutrient supply on epigenetic ‘gene sculpting.’

Pediatric Endocrinology

The Branch is partnering with the Lawson Wilkins Pediatric Endocrine Society to establish the Study Network of Pediatric Endocrinology to collect data on rare endocrine disorders and to begin common treatment protocols.  Additional potential areas of focus include:  1) mechanisms and treatments for impaired linear growth and bone accrual in children in states of chronic illness; 2) treatments for rare endocrine disorders; and 3) neuroendocrinology of puberty to address the vexing clinical problems of precocious and delayed pubertal onset.

At the conclusion of the report, Council member Dr. Enriqueta Bond urged the Branch to publicize the ENGB-supported longitudinal studies in the National Children’s Study (NCS) community. Additionally, Dr. Margaret Stineman asked if there are any formal partnerships between the Branch and the National Institute on Aging to examine these longitudinal cohorts in the elderly. Dr. Grave responded that the longitudinal studies supported by the ENGB provide an opportunity to examine the childhood origins of adult disease, since the data banks stem from as long ago as 1929.  Investigators from the NCS used the ENGB-supported longitudinal studies as helpful models in developing the NCS. The Branch also partners with the National Institute on Aging and recently published a joint RFA on juvenile protective factors to delay the onset of aging.

Council member Dr. Sherin Devaskar commented that the training programs have contributed immensely to the field of pediatrics. The Pediatric Scientist Development Program graduates are “truly stars” of any training program she has observed and the Child Health Research Career Development Award teaches trainees “think outside the box.” She urged the Branch to ensure the programs continue to hold the same value amidst future modifications.

Dr. Grave’s overview was followed by presentations by two distinguished investigators with long-standing ENGB support.

Dr. Matthew Gillman, Harvard Medical School and Harvard School of Public Health, discussed his team’s epidemiological findings on early infancy as a critical period for the development of obesity.  He presented evidence that growth during the prenatal period, infancy and early childhood is associated with later obesity and its sequelae.  His research team is examining the determinants that predict later obesity and whether they are modifiable.  They found that while breastfeeding is inversely associated with later obesity, breastfed infants gain more weight.  A phenomenon that appears, partially, to explain the relationship between early growth and obesity is endocrine factors during the prenatal period, especially leptin.  A study from Project Viva found that the higher the leptin level in cord blood, the lower the body mass index at age three.

Dr. Gillman identified several future research imperatives, which include adding current biomarkers to existing studies, developing better measurements of body composition in infants, studying pre and normal term infants, looking at racial and ethnic minorities, and examining countries in transition.  He closed by emphasizing the importance of an interdisciplinary approach to obesity, as well as other topics in the developmental origins of disease.  Council members expressed an interest in many aspects of Dr. Gillman’s presentation, in regard to the different perinatal actions of leptin.

Dr. Grave introduced Dr. Ardythe Morrow, who heads a Program Project supported by the Branch that dates back 32 years, started by Dr. R. Rodney Howell. Dr. Morrow, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, discussed human milk oligosaccharides as a novel class of antimicrobials plus their potential use as a biomarker.  Clinical studies have revealed that breastfeeding offers protection against enteric diseases and necrotizing enterocolitis in very low birth weight infants.  The aim of their Program Project is to understand the mechanisms by which breast milk may offer this protection.  Oligosaccharides are one of the most important and potent antimicrobial components of human milk.  The investigators found high levels of specific alpha 1,2 fucosylglycans in maternal milk associated with a lower risk of diarrhea in infants in the first two years of life.  The pathogens bind to human-milk glycans instead of to the host cell-surface glycans.  The glycans also inhibit pathogens by competitive binding with the host cell-surface receptor. Her research team is beginning pre-clinical efficacy studies using synthetic oligosaccharides as antimicrobials.

Dr. Morrow also discussed the use of glycans as biomarkers to assess risk of enteric diseases and necrotizing enterocolitis.  The glycans in human milk are expressed throughout the tissues of our bodies, particularly in the intestinal tract, and can be measured in saliva or through genetic testing. They have found that using saliva samples pre-term infants can be identified as being a high or low risk of necrotizing enterocolitis. Council members were intrigued by the idea of using human milk glycans as antimicrobial agents and were curious about the stability and shelf-life of these agents. Dr. Morrow indicated that as sugars they are very stable, have a long shelf- life, and no cold-chain requirement. Council members were also interested to learn whether the FDA will consider these human milk glycans as dietary or therapeutic agents.  Dr. Morrow responded that she has initiated discussions with the FDA Center for Food and Safety and Nutrition. At this time they are focusing on gastrointestinal health and safety and potentially at a later date will put forward an antimicrobial claim.

Council discussants Drs. Ralph Kauffman and Perri Klass provided their reactions to the report and the overall ENGB portfolio.

Dr. Kauffman praised the breadth and depth of the Branch portfolio, particularly in view of the modest increase in NIH funding over the past six years.  A theme that permeated the report was an emphasis on early determinants of chronic diseases in childhood that present clinically in adulthood.  This changes the paradigm of medicine from one of acute care and management of chronic conditions in adults to early identification of vulnerable individuals leading to prevention or early treatment. The portfolio is innovative and multidisciplinary and addresses the most current important chronic health issues for children. He encouraged the Branch to look for strategies to expand research in infant feeding and adolescent nutrition.  Dr. Grave thanked Dr. Kauffman for his comments and responded that adolescent nutrition is a very challenging area that the ENGB has been attempting to confront. There are few researchers in this field and adolescents are difficult to capture in studies.

Dr. Klass congratulated the Branch on their strong research portfolio, with a focus on the origins of disease through the lifecycle, and thanked the speakers for their accessible and thought- provoking talks. She was struck by the overarching clinical importance of the scientific areas addressed by the ENGB. Pediatrics is all about growth – growth that happens, growth that doesn’t happen, measuring it, assessing it, and growth gone wrong. The obesity epidemic is a clear and present danger and is a dominant clinical concern.  She commented that she worked in a clinic where the population is at a high economic risk and where health disparities are part of the everyday life of taking care of patients.  When we think about the epidemic of childhood obesity and how we understand it in an appropriately complex, multisystem, multifactorial and cross disciplinary way, it was exciting, inspiring, and somewhat daunting to read about the ways the Branch is trying to integrate fields of research.  For clinicians to promote positive growth in children, it is imperative to better understand prenatal interaction between the mother and fetus, the development of the infant gastrointestinal tract, and early manifestations and markers of chronic disease. Dr. Klass urged the Branch to continue to support research that has practical and clinical implications.

Dr. Grave thanked Dr. Klass for her supportive comments and thanked the other council members for their interesting questions and continued support of the ENG Branch’s research initiatives.

V. REPORT OF THE SUBCOMMITTEE ON PLANNING AND POLICY

Dr. Enriqueta Bond, Chair of the Council’s Subcommittee on Planning and Policy, reported on the
May 14, 2009, teleconference meeting of the Subcommittee.  Meeting topics included the report of
Dr. Alexander on the budget.  Dr. Alexander also summarized the American Recovery and Reinvestment Act (ARRA) and NIH implementation of the Act.  Dr. Yvonne Maddox, Deputy Director, NICHD, reported that an evaluation of the NIH loan repayment programs was quite positive.  The evaluation found that the programs may be contributing to earlier entry of promising individuals into scientific research careers.  However, the evaluation also found that women are dropping out of research careers relatively early, a trend of continuing concern.  Ms. Lisa Kaeser, Senior Program Analyst, Office of Program and Public Liaison, NICHD, reported that members of Congress are increasingly interested in legislation to promote cures.  Subcommittee members were concerned that policy-makers may need a better understanding of the NIH, including explanations of the full NIH research portfolio.  Dr. Margaret Stineman, a member of the Subcommittee, stressed to the full Council that the NIH should also continue to emphasize research that would help people with conditions for which there are not yet, and may never be, cures.  This emphasis will be increasingly important as the population ages and more individuals are living with disabling conditions and chronic diseases, Dr. Stineman noted.  Dr. Bond concluded her report by thanking the Institute staff for its outstanding work on processing the very large volume of ARRA funding applications under significant time pressures.

VI. PEDIATRIC ADOLESCENT AND MATERNAL AIDS BRANCH TWO-YEAR UPDATE        

Dr. Lynne Mofenson, Chief, Pediatric, Adolescent and Maternal AIDS Branch (PAMAB) presented a two-year update on activities of the Branch.  The mission of PAMAB is to support and conduct domestic and international research into the epidemiology, natural history, pathogenesis, treatment and prevention of HIV infection and its complications in infants, children, adolescents, women, and families. The branch has a long history of successful collaborations with multiple groups.  Within NIH, collaborating Institutes include the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Mental Health (NIMH), National Institute of Deafness and Communication Disorders (NIDCD), National Heart Lung and Blood Institute (NHLBI) and National Institute on Drug Abuse (NIDA), and new collaborations are under discussion for fiscal year (FY) 2011 with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA).  In addition, PAMAB has ongoing collaborations with the Centers for Disease Control and Prevention (CDC), President’s Emergency Plan for AIDS Relief (PEPFAR), Pediatric European Network for Treatment of AIDS (PENTA), and the World Health Organization (WHO).

In 2007, in addition to a portfolio of investigator-initiated research grants, projects funded by the PAMAB included the NICHD Domestic and International Pediatric and Maternal HIV Clinical Studies Coordinating Center contract, which funds the NICHD pediatric and maternal trials network that collaborates with the NIAID networks, the NICHD Latin American International Site Development Initiative (NISDI), and a trial of infant prophylaxis to prevent transmission in South America and Africa. PAMAB provides cofunding to NIAID for four projects:  the Women’s Interagency HIV Study (WIHS),  the NIAID-funded pediatric International Maternal Pediatric and Adolescent Clinical Trials (IMPAACT) Network and Microbicide Trials Network (MTN) Leadership Groups, and the International Epidemiologic Database for Evaluation of AIDS (IeDEA), which provides regional datacenters around the world to collect data from HIV patient clinic records.  NICHD funding ensures pediatric data collection is included. The Branch collaboratively funds two trials with the CDC regarding breast milk transmission. Finally, NICHD is the lead Institute for the Adolescent Trials Network for HIV/AIDS Interventions (ATN) and the Pediatric HIV/AIDS Cohort Study ( PHACS). A number of new activities have occurred since 2007.  The Branch has expanded new grants in the areas of pediatric TB, malaria, and rectal microbicides. Microbicide clinical trials are underway in adolescent girls and pregnant women. New results are available from clinical trials on prevention of breastfeeding transmission and pediatric drug trials, and a large new perinatal prevention trial PROMISE is about to start.  Expansion of surveillance for late effects of in utero antiretroviral drug exposure internationally through our NISDI project in Latin America and the IeDEA project in Africa is planned. Finally, there is a new collaboration of the ATN and CDC on adolescent identification and care.

Dr. Mofenson then reviewed the future research directions plan from the June 2007 Council report and provided updates on progress in these areas.  In the perinatal area, a critical priority was research to prevent mother to child transmission, particularly focused on breast milk transmission.  Important results from two studies funded by NICHD were published in 2008. The Zambia Exclusive Breastfeeding Study enrolled breastfeeding HIV-infected women who were counseled to exclusively breastfeed and were randomized at age 4 months to rapidly wean versus continue breastfeeding.  Early weaning at age 4 months did not improve HIV-free survival, demonstrating the importance of breastfeeding to infant survival in Africa. Thus, interventions to permit safer breastfeeding are critically needed.  The PEPI-Malawi clinical trial was funded by NICHD and CDC, and found that extended infant prophylaxis with daily nevirapine or nevirapine and zidovudine for 14 weeks reduced breast milk transmission by over 50 percent at age 9 months, for the first time identifying an intervention that allows safer prolonged breastfeeding. Building on the result of this study, the NICHD and NIAID-funded IMPAACT group is planning a large 8,000 patient clinical trial designed to answer multiple questions within the context of a single trial, with the overall goal of maximizing both maternal and infant long-term health and survival called PROMISE – Promoting Maternal Infant Survival Everywhere.

In the perinatal area, another priority was research on effects of in utero exposure to antiretroviral drugs during pregnancy on uninfected infants. In the United States there has been a dramatic reduction in new perinatal infections with current prophylaxis regimens; however, there are now thousands of uninfected infants with in utero exposure to multiple drugs with limited data on long-term safety. The Pediatric HIV/AIDS Cohort Study (PHACS) is designed to evaluate this. The study is led by NICHD and cosponsored by NIAID, NIMH, NIDA, NHLBI, and NIDCD. The PHACS consists of two studies. The Surveillance Monitoring for Antiretroviral Toxicity (SMARTT) study is a prospective study designed to estimate the incidence of abnormalities associated with in utero and postnatal exposure to antiretrovirals among uninfected infants, while the Adolescent Master Protocol (AMP) study is evaluating the effect of HIV infection and its treatments on children infected perinatally but now surviving into adolescence and beyond. As of June 2009, the SMARTT study has enrolled almost 1,700 uninfected children and the AMP study nearly 400 perinatally infected youth and over 160 control uninfected children. The project will be re-competed in FY 2010. 

As use of antiretroviral drugs in pregnant women increases in developing countries, where high rates of underlying comoribidities might affect infant risk, it is critical to also have surveillance for effects of such exposure in these settings. The PAMAB has modified the NISDI in Latin America to include surveillance of uninfected HIV-exposed infants similar to SMARTT to allow potential combined analyses. Additionally, with the recompetition of IeDEA by NIAID, NICHD proposes providing additional funding to support follow-up of uninfected children with antiretroviral exposure in Africa. Finally, the MTN has developed a protocol to follow infants exposed to drugs as part of microbicide clinical trials.

Another priority perinatal topic was research on the effect of antiretroviral drugs used solely for prevention of transmission on the health of infected mothers and infected infants. A specific focus was the effect of development of NVP resistance following exposure to sdNVP for preventing transmission on subsequent response to therapy in mothers and in infants who become infected despite prophylaxis. The NICHD and NIAID IMPAACT Network are conducting a clinical trial to address this question in children. HIV-infected infants with sdNVP exposure (Cohort 1) and without such exposure (Cohort 2) who need treatment are randomized to receive either a NVP-based or protease inhibitor-based regimen. Last month, the DSMB stopped enrollment into the sdNVP exposed Cohort 1 due to finding higher rates of viral failure or death in infants exposed to sdNVP who received NVP-based therapy compared to those who received protease inhibitors.  These findings have important implications for international recommendations for the treatment of children.

A priority focus was research on obstacles to implementation of prevention programs, which has been more difficult to address.  Operational research generally has not scored well on review and has not had high priority for research funding at NIH.  The Office of AIDS Research is holding a meeting of outside
experts in July to obtain recommendations about the NIH role in such HIV research. The PAMAB staff work with PEPFAR on evaluation of proposed public health evaluation projects, and staff are involved with a number of organizations which are developing a catalogue of implementation research and gaps.

In terms of pediatric HIV research, an important priority was research on the management and treatment of HIV and its complications in children. Much of this research is done collaboratively between the NICHD Network and the NIAID-funded IMPAACT clinical trials group. The NICHD funds 21 domestic and 10 international clinical trials sites that collaboratively develop and participate in trials with NIAID-funded sites. The NICHD also co-funds the IMPAACT leadership group that develops the scientific agenda. In the past 2 years, there have been pediatric approvals for three new protease inhibitors as a result of the NICHD/NIAID IMPAACT Network pediatric trials.

Another priority was research evaluating the impact of HIV and effects of chronic therapy on children as they age.  HIV-infected children are now aging into adolescence and young adulthood and HIV has become a chronic disease with all its challenges. Life-prolonging therapy is also associated with newly recognized late complications. The PHACS Adolescent Master Protocol (AMP) is designed to assess these issues domestically.  Some of the findings to date from PHACS include: 1) HIV-infected children have elevated biomarkers of vascular inflammation and echocardiographic alterations in left ventricular size and function and aortic valve dimension, suggesting possible subclinical cardiovascular disease;
2) 20 percent of HIV-infected children had low bone mineral density and 13 percent had insulin resistance at baseline; and 3) 35 percent of HIV-infected children have either primary or secondary language impairment compared to an expected 16 percent in the general population. As pediatric treatment in developing countries increases, the benefits and adverse outcomes of treatment need to be evaluated in these settings as well.  In Latin America, the NISDI project in infected children has been modified to be more like AMP to allow potential combined analysis.  Also, NICHD co-funds the IeDEA regions in Africa and Asia for inclusion of pediatric patients, and to date, 28,000 HIV-infected children are included in the databases from these five regions.

An additional priority was research on important co-infections that are prevalent in developing countries in children and pregnant women. In 2008, PAMAB issued an RFA to solicit grants dealing with pediatric HIV and TB coinfection; three grants have been funded and there are plans to reissue the RFA.  Also in late 2008, PAMA funded a program project in Kenya that will address the effect of antiretroviral treatment on malaria in HIV-infected pregnant women and children and also assess the efficacy of three different malaria prophylaxis regimens in children.

In the area of adolescent research, the mission of the ATN is to study treatment, adherence, and clinical management in HIV-infected youth and primary prevention including HIV vaccines and microbicides in at-risk youth, often in collaboration with other Networks. Since the inception of the ATN in 2002, over 13,000 subjects have enrolled into a variety of therapeutic, behavioral and community-based protocols.

The number of protocols has increased over time; currently there are 14 open studies and 24 in development. In the current ATN cycle since 2004, there have been 51 papers published or under review.

The ATN and CDC have developed a joint initiative, called the SMILE for CARING for YOUTH - Strategic Multisite Initiative for the Identification, Linkage and Engagement in Care of Youth with Undiagnosed HIV Infection. Specific objectives include development of interventions to improve identification of youth with undiagnosed HIV infection through CDC/local health department testing programs, facilitate linkage of newly identified youth to care at ATN sites and maintain them in care, and to conduct evaluation to determine effectiveness of the program. Currently pilot sites are being selected and protocol implementation is anticipated in the fall.

Another priority was the conduct of adolescent behavioral research. The ATN has developed two protocols studying innovative strategies to identify minority youth with undiagnosed HIV infection in the US through use of their social networks. Additionally, some innovative interventions to improve adherence to therapy in HIV-infected youth are under study in the ATN, using technology familiar to youth, including:  1) a computerized adherence intervention; 2) use of cell phone support for adherence; and 3) text messaging to improve adherence.

In terms of women’s HIV research, a priority was research to evaluate the natural history of HIV disease in women in the antiretroviral era. The Institute co-funds the WHIS, which is the largest and longest cohort of HIV-infected and at-risk women in the US. The study covers multiple scientific domains, ranging from behavioral studies to organ system disorders, genetics, and metabolic studies. Recent findings from WHIS include the following. In the treatment era, non-AIDS conditions have replaced AIDS as the major cause of death in HIV-infected women. While survival is improved, an increasing number of metabolic and organ system dysfunctions are being observed: low bone mineral density is four-times more common in infected than uninfected women, dyslipidemia is associated with both HIV infection and use of protease inhibitor drugs, and risk of insulin resistance and diabetes mellitus increases
significantly with prolonged exposure to nucleoside drugs. Anal intraepithelial neoplasia is present in nearly a quarter of HIV-infected women suggesting a potential increased risk for anal cancer.

Another priority was research on gender-specific aspects of HIV and treatment. For example, there are potential interactions between hormonal contraceptives and some of the drugs used for HIV treatment which could compromise the efficacy of the contraceptive or of the anti-HIV drugs, and it is critical to define these interactions. One trial did not find a significant interaction with three antiretroviral anti-HIV drugs and depo-provera, but another trial found changes in both hormonal levels as well as decreased anti-HIV drug levels in women using Ortho Evra.  Additional studies are ongoing.  In terms of coinfections, there is a study that is about to start to evaluate isoniazid prophylaxis of tuberculosis in HIV-infected pregnant women in developing countries and another assessing response of HIV-infected women to human papillomavirus vaccine.

The PAMAB focus in the MTN is to promote evaluation of microbicides in adolescents and in pregnant women.  MTN 004 is a study developed jointly by the MTN and the ATN to evaluate the safety of a new microbicide, Vivagel, in young, at-risk adolescent women.  Two studies are evaluating an antiretroviral
microbicide, tenofovir gel, in pregnancy – first in women undergoing cesarean section delivery, and then administration in the third trimester. 

The Branch held a Strategic Planning meeting on May 18 to evaluate progress and future plans. In addition to current activities, the Branch staff identified several high priority areas and research gaps. Studies using animal models to better understand mother to child transmission and mucosal immunopathogenesis of HIV are needed. International expansion of ATN behavioral and community studies is highly desirable, and is under discussion with NIAID collaboration.  Stimulation of international implementation research on prevention of mother to child transmission is desirable, as is expanded focus on neglected coinfections such as TB, malaria, hepatitis, and CMV in children and pregnant women. The Branch would like to encourage outside investigators to use the NICHD sample repository from studies such as NISDI and PHACS. Finally, the PAMAB discussed a potential meeting in the fall with other branches at NICHD to discuss the PAMAB research agenda and how inter-Branch collaboration might be enhanced. Dr. Mofenson then acknowledged the exemplary Branch staff for their dedicated work on these projects.

VII. AMERICAN RECOVERY AND REINVESTMENT ACT (ARRA) PRESENTATION

Dr. Eugene Hayunga, Director, Office of Extramural Policy, NICHD, provided an overview of the NIH
implementation of the American Recovery and Reinvestment Act (ARRA), which Congress passed in February.  He explained that of the $10B allocation of ARRA funds to the NIH, the NICHD has been allocated $327M for extramural scientific research.

The approach for use of these funds is two-fold, Dr. Hayunga said.  The first is stimulating and accelerating biomedical research with existing research projects that are “shovel-ready.” This means funding additional meritorious proposals that have already been reviewed and been through Council. They are two-year projects. Because of that, R01s need fine tuning because they tend to be five-year projects. The NICHD also can give administrative supplements to accelerate ongoing research.

The second approach is expanding science with new programs. These are competitive supplements, beyond the scope of the original grant. There are institute-specific programs as well as NIH-wide programs. Both approaches will move science forward, stimulate the economy, and create or preserve jobs.

Dr. Hayunga gave an example of an institute-specific RFA - an initiative cosponsored with NIMH on autism.  The NICHD is providing $20M over two years. He also gave examples of some NIH-wide ARRA programs, including Challenge Grants, which cover specific topic areas, are limited to $500,000 total costs per year, and must be completed in two years, and Grand Opportunity Grants, which focus on large scale research areas with budgets of at least $500,000 total costs.

Another ARRA program provides summer jobs in research labs for high school and college students and teachers. These supplements have been reviewed by staff and most have been awarded. The NICHD has provided opportunities for students and teachers in 37 states.

Dr. Hayunga also mentioned another ARRA program on Comparative Effectiveness Research which is an initiative designed for comparing different options that are available for treating a given medical
condition.

The Challenge Grants and Grand Opportunity grants received an overwhelming response from grant-seekers, Dr. Hayunga said. Of 20,000 proposals for Challenge Grants, 1,000 were assigned to the NICHD. The CSR is reviewing the Challenge Grants and the Grand Opportunity grants will be reviewed by the individual institutes and centers.

Dr. Hayunga described challenges in making award decisions. The competitive awards will undergo peer review as usual.  Administrative supplements require strong staff justification and thorough documentation. Dr. Hayunga described an internal review committee formed to look at those
recommendations independently and impartially. All decisions would be subject to approval by senior leadership.

Selection factors include meeting the goals and requirements of ARRA, Dr. Hayunga said. What kind of research will move science forward? How many jobs will be created or preserved?  Can the work generate significant results in two years? How do the two-year aims of R01s relate to the original aims? Is acceleration of the study reasonable? Are there other applications with better scores, and if so, why are we choosing this one?

Dr. Hayunga described grantees’ reporting requirements as above and beyond what is typically done.  They will include quarterly reports that summarize the funds that were received, how they were expended, what activities were undertaken, and how many jobs were created or maintained. The NICHD and the NIH will have to meet other reporting requirements that are still being developed. Reports will be posted to Recovery.org.

A Council member asked what will happen to grant applications if this high budget isn’t continued past two years. Dr. Hayunga said the massive response to ARRA was a surprise and may mean a high tide of applications in two years. Dr. Alexander pointed out that 20,000 Challenge Grant applications that do not get funded this year will probably get resubmitted next year. The success rate will likely be low in
2010 and 2011. A lot will depend on what happens with the overall NIH budget, he said. We have heard that the 2009 and 2010 appropriations weren’t higher because of NIH’s large ARRA budget. It may be that NIH will get a higher increase in 2011, when ARRA is over.

A Council member asked how the Council is involved in the review of ARRA grants. Dr. Alexander said that there may have to be a virtual meeting or mail ballot before the September Council meeting to deal with applications that require funding this fiscal year. Only a small number of applications have to go to Council; the supplements, for example, do not require Council approval, and the R01s that meet the criteria and were between the 10th and 25th percentile, but weren’t funded in the last round, have already had Council review.

A Council member asked if there were limitations about the money staying within the United States.
Dr. Hayunga said that the NICHD has taken an even stronger position than NIH overall and will not support anything with a foreign component.

A Council member asked if it was true that most of ARRA money would not affect NICHD programs.  She also asked how ARRA funds will affect K awards. Dr. Maddox reiterated that each of the institutes was allowed to decide how to spend their ARRA funds. NIH requested that the Institutes put at least 40 to 50 percent of ARRA research dollars into research-project grants (RPGs). The NICHD felt that to give relief to some of the applications that were at the cusp of funding, the majority of funding should go into RPGs.  Because of the two-year length, the NICHD also thought ARRA funds would be less useful for K awards. Also, significant amounts will be added to the NICHD administrative supplements to RPGs.

Dr. Alexander added that several topics for the Challenge Grants RFA came from the NICHD. The Institute elected not to participate in some programs, including the new-faculty recruitment program and the competitive supplements program, but did go in with NIMH on the autism RFA.

A Council member asked about compliance of faculty and of the NICHD to the reporting component.  She suggested that the academic community work closely with the NICHD to get the story told.
Dr. Hayunga responded that several NICHD offices are working closely on the reporting aspect of ARRA.

A Council member said that it would be helpful for researchers to know what specific things should be emphasized in their reports.

A Council member asked how much of the $327M will be spent on administrative supplements.
Dr. Hayunga said the target goal is $15M per year. Supplement requests are due to the NICHD on June 30th, and then the Institute will begin review. Dr. Alexander noted that it will depend on how much the NICHD invests in other ARRA grants.

A Council member asked if investigators who receive R01 funding for two years instead of five can come back to the regular R01 process. Dr. Hayunga said that it is not permitted to mix ARRA and non-ARRA funds in a single award.  A grant can not receive ARRA dollars and regular dollars. The investigator would have to complete the study and then can apply for an R01 under the regular process.

VIII. ENHANCING PEER REVIEW AT THE NIH: UPDATE

Dr. Alan Willard, Chief of Review and Referral Officer at the NINDS, provided an update to the NICHD Council on the status of Enhancing Peer Review at the NIH.  Dr. Willard identified the four goals of this effort as:  1) identify and encourage new and early stage investigators; 2) improve clarity of feedback;
3) ease burden on research enterprise; and 4) fund the best science, by the best scientists with the least
amount of administrative burden.   He provided a history and background of the status of this effort that included a diagnostic phase, a design implementation plan, and a phased implementation description which included an implementation timeline that showed changes made so far, changes occurring now, and future changes. 

Current changes include the use of Enhanced Review Criteria; use of Critique Templates; Scoring of Individual Core Review Criteria; and use of a new Nine Point Scoring System.  Dr. Willard presented examples of new critique templates and described various review criterion descriptions that reviewers are asked to use in preparing their critiques, including guidance on Overall Impact and scoring using both scores and matching descriptors.  Dr. Willard concluded his presentation with a description of future peer review changes which include restructuring of applications for FY 2011 funding; shorter research plans; and alignment of application sections with the review criteria.  Council members had several questions regarding the use of “triage”, which Dr. Willard clarified as no longer using the terms “streamlining” or “triage” but, rather, “Discussed” versus “Not Discussed”.  Council members also asked how review criteria are weighted.  Dr. Willard responded that they are not weighted but take into account the nature of the strengths and weaknesses identified in terms of their effect on overall impact as determined by each individual reviewer.

IX. CONCEPT CLEARANCE REVIEW AND DISCUSSION

The following three concepts were discussed.

• Pharmacokinetic Research and Optimization of Treatment in Pediatric HIV/TB Co-Infection

The purpose of this RFA is to stimulate research to evaluate the pharmacokinetics of anti-TB drugs and pharmacokinetic drug interactions of clinical significance between anti-TB drugs and anti-HIV medications in children with HIV-TB co-infection. The proposed RFA will also solicit research examining the relationship between pharmacokinetics and treatment outcomes. Pediatric HIV and TB co-infection is a significant problem in resource-poor populations in international settings which has for the most part remained unaddressed. The proposed project will support investigator-initiated grants to increase knowledge of how to optimize the treatment of TB/HIV in children. This initiative is part of a
research agenda that will help to reduce health disparities among children by generating data upon which future clinical trials of HIV/TB co-infection may be based.

The concept was unanimously endorsed by the Council.

• Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN)

The proposed RFA is a competing renewal, using the U01 mechanism, to provide for continuing support for a multi-center basic science and clinical research network with 15 clinical sites across the U.S. and Puerto Rico. Their scientific mission is to conduct independent and collaborative research that evaluates interventions for treatment and management of HIV infection and its complications among youth.  It also addresses the prevention of HIV transmission and explores promising behavioral, microbicidal, prophylactic, therapeutic, and vaccine modalities in HIV-infected and HIV at-risk adolescents, ages 12 through 24 years. The proposed initiative calls for the continuation and further expansion of a broad array of interventional studies aimed at the primary, secondary, and tertiary prevention of HIV infection and its consequences. The RFA objective is to continue the infrastructure required for a network of 15 clinical sites, one data and operations center and one scientific leadership group with discipline-specific
subgroups to expand research capacity and be able to increase enrollment of a much needed and underrepresented ethnic minority population.

The concept was unanimously endorsed by the Council.   

• The Role of Human-Animal Interaction in Child Health and Development

Nearly 75 percent of U.S. households have pets, and decreasing family size, with the disappearance of younger siblings, babies, and elderly from family homes, means that many children may be more likely to grow-up with an animal than with a younger sibling or grandparent in the home. The purpose of this RFA is to build the field of human-animal interaction (HAI) research and is intended to encourage interdisciplinary studies of HAI broadly, both in terms of the (positive and negative) impact of pets in the home on child and adolescent health and development, and therapeutically, through experimental trials of
the use of HAI in treatment of behavioral problems, stress and anxiety, emotional difficulties, and social development problems.

A Council member questioned if children with disabilities would be included in the research. The program officer responded that although not stated in the concept, children with disabilities will be included in the RFA and that HAI and pregnancy, gestational diabetes, and teen/early pregnancy studies would be included in the RFA solicitation.

With slight modification, the concept was unanimously endorsed by the Council.

REVIEW OF APPLICATIONS

A total of 1302 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 508 applications requesting $239,767,135 in total costs.  Council favorably recommended 508 new, renewal, supplemental research and training grant applications with requested total costs of $239,767,135.

XI. ADJOURNMENT

There being no further business, the meeting was adjourned at 5:05 p.m. on Thursday,
June 11, 2009. The next meeting is scheduled for September 21, 2009.

Attachments: 

Council Roster (Attachment I)
Report of the Director (Attachment II)
Statement of Understanding (Attachment III)

Mary Plummer
Committee Management Officer, NICHD

²These minutes will be formally considered by the Council at its next meeting, and any corrections or notations will be incorporated in the minutes of that meeting.