Science Advisory Board Meeting
(August 12-13, 2008)
August 12, 2008:
The meeting was called to order by the Chair of the Science Advisory Board (SAB), Dr. James A. Popp, DVM, Ph.D., Stratoxon LLC. He welcomed the following Board members:
· Dr. Cynthia A. Afshari, Ph.D., DABT, Director, Investigative Toxicology Dept., Amgen Inc.
Michael Aschner, Ph.D., Professor, Department of Pediatrics,
· Dr. James S. Bus, Ph.D., DABT, Director of External Technology, Toxicology and Environmental Research & Consulting, The Dow Chemical Company
M. Ordovas, Ph.D., Director, Nutrition and Genomics,
· Dr. Timothy P. Pastoor, Ph.D., DABT, Head, NAFTA Human Safety Department, Syngenta Crop Protection Inc.
· Dr. Anthony L. Pometto, Ph.D., Chairman, Department of Food Science & Human Nutrition, Clemson University
Stephen M. Roberts, Ph.D., Professor and Director, Center for Environmental
and Human Toxicology, University of
Also present were representatives from the
· Norris Alderson – Associate Commissioner, Office of Science & Health Coordination, FDA/OC
· Joseph Hanig – Research Pharmacologist, FDA/CDER
· Subhas G. Malghan – Supervisory Physicist, FDA/CDRH
· Atin R. Datta, Ph.D. – Supervisory Research Microbiologist, FDA/CFSAN
· Richard Diamond – Medical Officer, FDA/CBER
· Kathleen Uhl, M.D. – Medical Officer, FDA/OC/OSHC/OWH
· Emmanuel Fadiran – Pharmacologist, FDA/OC/OSHC/OWH
· Erik Mettler – Policy Analyst, FDA/OC/OPP
· Paul Norris – Director, ARL, Supervisory Microbiologist, FDA/ORA
· Wendy Sanhai – Senior Scientific Advisor, FDA/OC/Critical Path
Martin Philbert, Ph.D. - Professor of Toxicology
and Senior Associate Dean for Research,
· Daniel A. Casciano, Ph.D - Senior Science Advisor, Department of Applied Science University of Arkansas at Little Rock, AR 72204 Representative for University of Arkansas Little Rock
· Sunny Anand, M.D., Representative for Arkansas Children’s Hospital, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital Research Institute.
Dr. Miller read a statement for the record to confirm that no NCTR Science Advisory Board Member had any financial or other conflicts of interest with any of the topics listed in the meeting agenda. All participants were given the opportunity to comment and were instructed to preclude themselves from further participation if the discussions turned to any topic that would be considered a conflict of interest.
Dr. Slikker, Director of NCTR, presented a brief overview of NCTR’s vision, facilities, personnel changes, and visitors to the Center during the past year. He noted that NCTR’s mission is to conduct peer-reviewed scientific research and to provide information vital to the FDA’s ability to make sound scientific decisions on regulatory issues. The input by NCTR’s Science Board is valuable in helping NCTR’s fulfill its mission.
The Board next heard presentations from each of the research divisions within NCTR focusing on the major research finding of the past year, why this finding was important to the FDA and major issues with current research.
Dr. William Allaben, Director of NCTR’s Office of Scientific Coordination and FDA’s Liaison to the National Toxicology Program, discussed leveraging and the establishment of a science-based partnership between the FDA/NCTR and the National Toxicology Program (NTP)/National Institute for Environmental Health Studies (NIEHS). An interagency agreement (IAG) between the FDA/NCTR and the NIEHS/NTP was established to provide the agency, in a timely manner, with the comprehensive toxicology information to enhance regulatory decision-making and risk management decisions. Utilizing a formal nomination process, agents are selected for research and testing by FDA’s Chemical Selection Working Group (CSWG) which has representation from across the Agency. All studies conducted under the FDA/NCTR-NIEHS/NTP IAG are peer-reviewed by a Toxicology Study Selection and Review Committee comprised of NCTR Principal Investigators, FDA and NIEHS scientists, representatives from other federals agencies, from academia and from industry. Forty-two agents have been, or are, being tested through this IAG.
Division of Biochemical Toxicology- Dr. Frederick A. Beland presented preliminary results from carcinogenicity bioassays being conducted on the dietary contaminant acrylamide and indicated how these data were being combined with pharmacokinetic data to develop risk estimations regarding human exposure. He then showed preliminary results from bioassays in which the carcinogenicity of Aloe vera is being assessed after topical and oral administration to rodents. He showed data that demonstrated that genestein, a component of soy, inhibited the ability of tamoxifen to prevent the growth of human breast cancer cells in an animal model. He next outlined ongoing studies with melamine and cyanuric acids, the agents considered to be responsible for a recent pet food recall. Finally, he compared and contrasted genetic and epigenetic mechanisms of carcinogenesis in a rodent model using the genotoxic liver carcinogen 2-acetylaminofluorene.
Division of Genetic and Reproductive Toxicology – Dr. Martha Moore presented the results of Pig-A assay, which is showing promise as a biomarker for in vivo gene mutations. Studies in rodents showed a good dose-response relationship and that mutations are stable. Studies are continuing to determine the frequency of Pig-A mutations in humans expected to have elevated mutation frequencies.
Division of Neurotoxicology – Dr. Merle Paule provided an update on the studies investigating the developmental exposure to commonly used anesthetic agents. The results of these studies showed that anesthetic agents that block the N-methyl-D-aspartate (NMDA) receptors increase apoptotic cell death during development. Results in rodents and primates suggest that this anesthetic-induced cell death results in functional deficits. Follow-up studies will investigate the threshold of exposure needed to cause this effect.
Division of Systems Toxicology – Dr. Weida Tong reviewed the progress on the Voluntary Genomics Data Submissions (VGDS), Array Track and the Microarray Quality Control (MAQC) project. The VGDS project has lead to the development of a Guidance for Industry on Pharmacogenomics data submissions. Array Track is a bioinformatics tool developed by NCTR to provide an integrated solution for microarray data management, analysis, and interpretation. It is freely available to the public and was recently evaluated and adopted by Eli Lilly. The MAQC project is continuing with MAQC-II which is designed to validate molecular signatures for risk assessment and clinical applications. Future activities in the area of bioinformatics are focusing on support the electronic submission of preclinical data.
Division of Personalized Nutrition and Medicine – Dr. James Kaput explained that this was a new division and is currently designing experiments aimed at helping to understand the effect of both genotype and environment on human health and disease. Using this approach the division will address questions for personalizing healthcare. The research activities are clustered into four areas: biostatics, biology, genome core laboratory, and economics. The division has recently initiated a study to measure the impact of more nutritious food on vitamin levels in children as part of the Obesity Prevention Program.
Division of Microbiology – Dr. Cerniglia explained that the research program focuses on five areas: antimicrobial resistance, gastrointestinal and host interaction, microbiology surveillance and diagnostic support, environmental biotechnology, and food safety and biosecurity. For each of these areas the research contributes to FDA guidelines and regulations, enhancing FDA research interactions and strengthening research program management.
Division of Veterinary Services – Dr. Jeff Carraway explained the role of this division in maintaining animal care, diet preparation, veterinary care, and pathology. The NCTR is a longstanding member of the American Association for Laboratory Animal Science and has been AAALAC accredited since 1977.
All attendees had an opportunity to ask further questions and discuss the projects in more detail.
Dr. Wendy Sanhai, Senior Science Advisor from the Critical Path Program, spoke about the Critical Path and FDA's Public/Private Partnership Program. The Critical Path Program is working to facilitate product safety and efficacy review. The FDA is using various mechanisms to obtain the information needed to facilitate the availability of safe and effective medical products. Public/Private Partnerships are one of the mechanisms that FDA is using to foster the development of research in the area of drug safety. Dr. Sanhai presented the Safekids activity as an example of how these partnerships are working.
The SAB took a short break for lunch when SAB members and guests had the opportunity to tour the NCTR/Jefferson Labs.
Dr. Popp reconvened the meeting by opening a discussion on Public/Private Partnerships. The Board generally agreed that this was an interesting approach for the agency. The Board questioned how the projects were selected and how the method of partnership was determined. Dr. Sanhai explained that the projects came out of the Critical Path Initiative and the means of support was decided on case-by-case basis.
Dr Popp, Chair of the Division of Biochemical Toxicology Site Visit Subcommittee, presented the report of the subcommittee. He stated that overall the Site Visit Subcommittee was uniformly positive about the research being conducted by the Division. He pointed out that the Division had not been reviewed in 10 years. This added to the complexity to this review because many things had changed since the last review. He strongly recommended that the reviews occur on a more regular basis.
He next presented the ten recommendations of the Subcommittee. These recommendations were:
1) The leadership of NCTR and the Division should provide more guidance for the strategic direction of the research program.
2) The presentation of the scientific research should focus on projects rather than investigators.
3) There should be more inclusion of pharmacokinetics and toxicokinetics in the research.
4) Professionals in the area of immunology, experimental pathology, synthetic chemistry, and electron microscopy should be hired.
5) The Division should re-evaluate the “promote from within” policy.
6) Analytical instrumentation should be upgraded.
7) The IAG with the NTP should include monies to purchase equipment.
8) The mass spectrometry and analytical chemistry resources should be combined.
9) Some research conducted in the Division of Biochemical Toxicology was in competition with academic research and more effort should be made to prevent duplication.
10) Professional interaction with
Following this presentation the SAB discussed the subcommittee report in detail. Members of the SAB suggested that the ninth recommendation be re-worded to clarify that the concern for duplicative research was limited. A Committee Member proposed a wording change to the report. The proposal was seconded and agreed to by the full Board. The Full Board then unanimously voted to accept the report with the wording change.
Dr. Beland responded to the recommendations made in the
report. Dr. Beland started his presentation by thanking the Site Visit
Subcommittee for their review and acknowledged that there have been many
changes in the Division over the past ten year. With respect to recommendations,
Dr. Beland noted that currently all new projects are subject to Division-level
and Center-Level review. The Center-level review includes the solicitation of
comments from the appropriate Product Centers. This process is designed to ensure
that research at the NCTR is mission relevant and an agency priority. Dr. Beland
also noted that the decision on how to present the information for the Site
Visit rests with the Division Director and he believes that principal
investigators should have an opportunity to present their own work. He agreed
to incorporate pharmacokinetic and toxicokinetic analyses in to studies as
appropriate and for the need to add an immunologist and electron microscopist.
He explained that the Division has not adopted a “promote from within policy”,
but has experienced limited hiring due to budgetary problems. Dr. Beland felt that some of the concern regarding
instrumentation, expertise and the IAG with the NTP was due to confusion during
the presentation. He decided not to cover all the instrumentation or expertise
available but to provide more detailed information on the ongoing research. Dr.
Beland also noted that his Division has a long history of collaborating with
academic researchers and will make every effort to continue to do so. Similarly
he stated his desire to continue interactions with the
Dr. Popp then called on Dr. Pometto to present the report from the program review of the Division of Microbiology which occurred July 23 to 25, 2007. Dr. Pometto noted that the Division Director, Dr. Cerniglia has built a comprehensive team of scientist to address many important topics relevant to both the FDA and the American public. The Microbiology Division has 13 Principal Investigators that publish 19 to 24 journals articles annually. The research activities are relevant to the FDA and there is good interaction between the Division and other agency scientists. The Subcommittee recommendations were to
1) Fill the vacant position of surveillance support scientist,
2) Provide more discretionary funds to each principal investigator,
3) Add permanent staff to support the high-impact research areas,
4) Create and fill a Deputy Director position,
5) Move the research away from “possible” hazard and toward “relevant” risk for each project,
6) Encourage scientific exchange with the other FDA Centers.
In addition to these recommendations, the Subcommittee outlined some future directions for the division including developing and validating standardized methods, food safety research of fresh produce, recruiting a senior enterovirologist, develop a seminar series among the Centers, focus on risk assessment to decide on high priority projects.
Following a discussion of the report, the SAB voted and the report was unanimously adopted. (Note: Dr. Bus was not present for the vote).
Dr. Cerniglia, Director of the Division of Microbiology was invited to respond to the recommendations made by the Site Visit Review Subcommittee. Dr. Cerniglia began his presentation by thanking Dr. Pometto and the other members of the Science Advisory Board Subcommittee for the thorough review of the research and surveillance diagnostic program. Dr. Cerniglia noted that the Center had recently received Food Protection Plan monies and with the advent of these funds he was able to move forward on many of the recommendations made in the report. For example, the funding for investigators has increased, and the division is hiring postdocs and a virologist. He also stated that he did not intend to hire a Deputy Director since this is not supported by FDA’s administrative structure and he does not believe it is necessary. The Food Protection Plan is also providing more opportunity for interaction among microbiologists in the different Centers. Dr. Cerniglia also mentioned that the plan to fill the vacancies in the Surveillance Program has been presented to Dr. Slikker, Director of NCTR and Ms. Jeanne Anson, NCTR Executive Officer.
Following these discussions, Dr. Popp adjourned the meeting.
August 13, 2008:
The meeting was called to order by the Chair, Dr. Jim Popp. Dr. Popp introduced Dr. William Slikker, Director of NCTR to present NCTR’s Research Strategy and Alignment. Dr. Slikker began his presentation by reviewing the current approaches the Center uses to focus and prioritize research resources on issues of high importance to the FDA. The approaches include product selection boards, responding to requests for proposals, regulator initiated requests and research initiated concept papers. Dr. Slikker invited comment on additional ways for NCTR to ensure that it engages in priority research.
Dr. Slikker went on to explain several of the priority research areas at the NCTR including the Food Protection Plan, Critical Path, Imaging, Nutrition and Obesity and Nanotechnology. NCTR is participating in many research efforts as part of the agency’s food protection plan. At a recent meeting of NCTR researchers involved in food safety, the researchers were able to identify current and future research areas that could be expanded to support this program.
Dr. Slikker then explained how NCTR’s Array Track, liver toxicity knowledge base project, electronic data submission studies, MAQC, and the Pig-A project were integrated into the Agency’s Critical Path Program.
Dr. Slikker went on to describe two new research initiatives, bio-imaging and nanotechnology, which will provide the agency with the tools needed to approach regulatory problems across all the product centers. The nanotechnology effort is designed in collaboration with the Office of Regulatory Affairs so that methods developed to detect nanotech materials can be readily integrated into field operations. Next, Dr. Slikker discussed NCTR’s activities in the area of personalized nutrition and medicine. This is a new area for the Center which promises to dramatically change the way Nutrition is viewed and regulated.
Dr. Slikker closed his presentation by
stressing NCTR’s commitment to training scientists and described the Science
Training and Exchange Professional (STEP) Training Program. This program provides
an opportunity for scientists from any
Dr. Popp complemented Dr. Slikker on the progress he has made in focusing the NCTR research on FDA related issues. He noted that there would be time to discuss prioritization during the later discussions. Dr. Popp then requested that each of the FDA representatives provide a brief statement of their research needs and opportunities for collaboration.
Dr. Nelson of the Office of Food Protection noted that the agency was promoting food protection through the Food Protection Plan. The plan is an integrated strategy for protecting the nation’s food supply by prevention, intervention and response. In support of this plan, researchers from CFSAN, CVM, ORA and NCTR are working to develop a coordinated research agenda.
Dr. Uhl noted that the Office of Woman’s Health (OWH) had a long and successful collaboration with NCTR. She thanked the NCTR researchers for their continued interest in conducting women’s health research and noted that OWH is particularly interested in the predictability of animal models.
Dr. Diamond of CBER stated that there was a need to strengthen CBER’s interactions with NCTR. CBER has many safety issues related to vaccine use in children. The adverse events involve mitochondrial disorders and the new technology used at NCTR could provide a way to investigate these adverse events.
Dr. Malgras noted that the research program at CDRH focused on short-term research projects that lead to guidances or standards that support the review process. He saw a need to strengthen the interactions with NCTR to encourage long-term research that supports devise issues particularly in the areas of biocompatibility and nanotechnology. He also noted a concern that the mechanistic research directed at device issues may not be being addressed.
Dr. Hanig said that the CDER researchers had a very good working relationship with the NCTR. He noted that the current issues being identified in postmarketing surveillance and drug quality represent two important areas for future research.
Dr. Atin Datta of CFSAN noted that this was his first visit to NCTR and while there have been many examples of successful collaborations between CFSAN and NCTR there were many opportunities to expand this interaction. He noted that detection of food borne pathogens continues to be a challenge for the agency. A better understanding of ecophysiology of bacteria will provide insight into how to make appropriate interventions under the food protection plan. He also agreed that the area of nanotechnology represented a serious challenge for CSFAN and he welcomed the interest and expertise from NCTR.
Dr. Popp opened the discussion by noting that postmarketing adverse events is an emerging discipline which requires definition, e.g., what is it? How do we study it? What are the predisposing conditions? Since toxicology is a predictive science there is a need to take the field observations of adverse events back into the laboratory for further study. Other participants agreed that understanding adverse events had links to genomics and personalized medicine, i.e., why is this person different? Transgenic animals may provide a model system to study these events. Dr. Popp summarized comments from the discussion noting that transgenic animals and stem cells might be important model systems for the NCTR to pursue.
Dr. Diamond noted the CBER was experiencing decreases in their research budget and that they can not afford to develop transgenic animal models. He also noted that there was a need to assess stems cells and that CBER was trying to determine how best to do this.
Dr. Afshari noted the
Dr. Slikker noted that if NCTR was to move forward in this arena the tools of nanotechnology and bio-imaging could help determine the fate of stem cells in the body.
The Committee took a short break
Dr. Popp reconvened the meeting and opened a discussion on the organization of the SAB, Site Visits and SAB assignments. He noted that he would like to hear from all participants on ideas for improving the process as well as hearing from the NCTR participants to determine if the SAB was meeting NCTR’s needs.
Dr. Pometto noted that SAB presentations should focus on measures of success. These measures of success should not be limited to number of publications but consider the impact of the research. During the planning stage, investigators should consider what is going to be done, in what amount of time, and what is the impact. The presentation to the SAB should then focus on what is accomplished compared to this plan.
Other participants agreed that this approach will focus the research, aid in priority setting and help the SAB provide definitive comments. Dr. Kaput noted that the impact of science is often difficult to measure.
The discussion continued with a general agreement that the Site Visits provided an opportunity for an in depth review of the programs. In response to a question from Dr. Slikker to determine if the SAB members had the information they needed to make recommendations, there was general agreement that the SAB would like to have more information before the meeting. It was recommended that NCTR prepare a guidance to describe on the information that should be provided to the Site Visit Team. This guidance should include the information that should be in the final report as well as specific questions that the Site Visit Team should address. In addition, the guidance needs to outline the scope and structure of the final report. It was also recommended that the Site Visit presentation could be “broadcasted” to the entire SAB and that the final report of the Site Visit be shared with the entire board. The SAB member agreed that these changes would improve the quality of the recommendations that they gave the Center.
The public portion of the meeting concluded and the executive session began at approximately 12:00 PM.