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Science Management Issues at the NIH


House Subcommittee on Labor-HHS-Education Appropriations
Statement by Story C. Landis, Ph.D., Director, National Institute of Neurological Disorders and Stroke

House Date: April 22, 2004

William Beldon, Acting Deputy Assistant Secretary, Budget

Mr. Chairman and Members of the Committee:
I am pleased to testify at today's hearing focused on science management issues at the National Institutes of Health (NIH). The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to reduce the burden of neurological disorders by finding ways to prevent or to treat these diseases. Several hundred diseases affect the nervous system. Some, such as stroke and epilepsy, are among the most common causes of death and disability, while others, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy, are individually rare, but collectively are an enormous burden for patients and their families. Progress against the many neurological diseases requires a broad spectrum of research from laboratory studies of cells and animals to clinical studies that involve human subjects. Therefore, to carry out our mission effectively and efficiently, the NINDS has to balance many competing priorities in utilizing the funds with which the Congress has entrusted us. For Fiscal Year 2004, the enacted level for NINDS was $1,500,693,000.

Managing Science

The NINDS has in place a series of mechanisms to ensure that we fund the most promising research relevant to our mission. Much of the clinical and basic science that the NINDS supports is initiated by investigators at universities and medical schools, who are stimulating innovation and harnessing the collective ingenuity of the scientific community. Proposals are assigned to NINDS according to mission-defined referral guidelines, assessed by NIH peer review groups, and funded by NINDS according to scientific merit and impact. The NINDS also supports targeted, centrally-coordinated efforts, when appropriate to stimulate a research area that is critical for progress. One example is a recent solicitation for studies to elucidate the blood-brain barrier that protects the brain from toxic compounds in the blood, but also prevents many promising medicines from reaching the brain. The NINDS also has an intramural research program on the Bethesda campus that complements efforts in the extramural community, with a particular focus on integrating laboratory and clinical neuroscience.

In addition to the NIH peer review system, which ensures the significance and scientific quality of individual research projects conducted in both the extramural and intramural programs, the NINDS receives guidance on several levels about how best to allocate its resources among the many, competing priorities. The Congressionally mandated National Advisory Neurological Disorders and Stroke Council, with representation of scientists, physicians, and the public, provides policy advice and additional review to help ensure that resources are allocated effectively with respect to the Institute's mission. The Council assesses ongoing activities and new programs; has working groups on topics such as training, infrastructure, and clinical trials; and gives special consideration to grant proposals that address high program priorities. Periodically, the NINDS undertakes strategic planning efforts, which engage the scientific community, to highlight emerging research opportunities that may have an important impact on many diseases, and follows up with focused scientific workshops to further guide our actions. Central to its mission, the NINDS also carries out planning tailored to the specific needs of individual diseases. In recent years, these have included research plans for Parkinson's disease, brain tumor, stroke, epilepsy, the muscular dystrophies, and tuberous sclerosis, and workshops on several rare disorders.

Today, I will focus on Parkinson's disease to illustrate the comprehensive and inclusive planning and management efforts that guide NIH disease research. I will also use the example of neuroscience research more generally to illustrate how the parts of NIH work together toward common goals.

Parkinson's Disease Research

Just as the NIDDK and NHLBI lead the NIH efforts against obesity, the NINDS leads NIH Parkinson's disease (PD) research, and I will explain how we set goals and manage our resources to achieve them in this particular area. PD is a devastating and complex neurodegenerative disorder, caused by the gradual death of nerve cells, that progressively affects the control of purposeful movement. PD research has been a high priority at the NIH for decades. We are fortunate that initially patients can be treated successfully with the drug L‑dopa, one of the most effective treatments available for any neurological disorder. However, this drug does not slow the loss of brain cells that underlies the inexorable deterioration of movement control in PD. As the disease progresses, the increasingly higher doses required become less effective and lead to disabling side effects. In recent years, advances in basic neuroscience, in areas such as genetics, stem cells, natural growth factors, and brain circuits, have opened new opportunities to understand what causes PD and to develop improved treatments even for people with advanced PD. To create a plan for accelerating PD research and therapeutics and ensure that the NIH was fully exploiting these scientific opportunities, the NINDS developed the Parkinson's Disease Research Agenda.

The first step was to bring together the people who knew the most about the disease, ongoing research, and what was needed to develop more effective treatments. To that end, the NINDS convened a workshop in January 2000, involving intramural, extramural, and industry scientists and clinicians; representatives from several PD voluntary health organizations; and bioethicists. The intensive discussions of that group formed the basis of the NIH PD Research Agenda ‑ a comprehensive description of the research needed to understand the genetic and environmental factors that cause PD; to determine what goes wrong at the level of molecules, cells, and brain circuits; and most importantly, to develop new therapies using drugs, surgery, gene transfer, and stem cells. Following the development of the Agenda, the NINDS assessed the portfolio of ongoing NIH‑funded research. It is testimony to the effectiveness of the investigator‑initiated, peer reviewed research system that the NIH at that time was already supporting research in every broad domain highlighted by the Agenda.

However, the Agenda identified additional opportunities for the NIH to accelerate progress by focusing on particular scientific areas. The NIH has been aggressively implementing the PD Agenda since its inception, with dozens of targeted grant and contract solicitations, supplements to currently funded investigators, scientific workshops, and an active intramural research program. These efforts, in aggregate, address every aspect of the Agenda in depth, from basic questions about understanding PD to clinical trials of therapies. I will focus on just a few examples.

One Agenda priority is to increase early phase clinical testing of therapies. To address this priority, the NINDS developed a new clinical trial paradigm, the PD Neuroprotection Trial, or NET‑PD, which will expedite the selection and testing of drugs that might slow or stop the progression of PD. In most clinical trials funded by the NINDS, applicants select the drugs and design the trial. In contrast, for NET‑PD, we first solicited suggestions for promising drug candidates from academia, industry, and voluntary health organizations, both here and abroad. Then, a team of clinicians, pharmacologists, and clinical trial experts, including NINDS scientific staff, evaluated the 59 compounds that were nominated. While the drug selection process was underway, the NINDS created a network of 42 (now 51) clinical sites around the country; set up independent coordination and statistical centers; and designed the early phase clinical trials. The trial sites have already completed recruitment of people with early, untreated PD to participate in phase II clinical trials of the first two drugs selected by this process. Enrollment for trials of the next two agents is underway.

Gene therapy is another promising approach to treating PD that the Agenda highlighted, and we are committed to moving as rapidly as is prudent toward human testing. In October 2000, the NINDS sponsored a scientific workshop on "Gene Therapy for Neurological Disorders". As a consequence of this meeting, several researchers formed a consortium to address PD gene therapy in a concerted fashion, and are conducting extensive development and testing of gene therapy strategies in animal models of PD. The NINDS oversight of this project uses milestone driven funding, as is common in industry, and the first‑year milestones were accomplished on schedule.

The Morris K. Udall Parkinson's Disease Research Centers of Excellence are another important component of the PD research effort. Each Center brings together teams of researchers from different disciplines to address key scientific questions identified by the Agenda. The NINDS facilitates interactions among the Centers through regular meetings of the Centers network, supplements for collaborative efforts, and the creation of shared resources, such as a data coordinating center. In keeping with Agenda goals, the Institute also worked with the extramural community to develop guidelines for consistent clinical data collection and brain banking. The activities of the Udall Centers are complemented by a consortium program funded by the National Institute of Environmental Health Sciences (NIEHS). The NIEHS centers are joined in a collaborative network focused on understanding the role of gene‑environment interactions in the developmental of PD, a research priority highlighted by the Agenda.

Scientific opportunities and obstacles can emerge unpredictably, so effective science management requires continuous monitoring and adaptation. Initially we tracked only the NIH portfolio of PD research, but we have added PD research funded by the Department of Defense, the Department of Veterans Affairs, and private foundations, so that currently we monitor more than 1000 PD research projects. To ensure that the Agenda goals reflect the rapid advances in PD research, the NIH has convened two major meetings to assess progress and identify new opportunities. At the more recent meeting, in July 2002, the NIH director convened a "Summit" with a small group of outstanding scientists to gain a better sense of where the field of PD research stood at the global level, and to identify "roadblocks" that might be impeding progress. The NIH developed the recommendations from the Summit into a Matrix (http://www.ninds.nih.gov/research/parkinsonsweb/PD_Plan_2006.htm) of short‑to‑long range, and low‑to‑high risk goals that address these roadblocks. This Matrix is a management tool that will evolve in response to scientific progress. The Summit also helped to crystallize the opportunities for voluntary PD groups to expedite the Agenda, such as through funding of pilot projects and recruiting participants for clinical trials.

Parkinson's disease research also provides a useful illustration of how various parts of the NIH work together. The NINDS leads NIH efforts on PD, but 15 other components of NIH support research relevant to this disease. For example, the National Institute of Mental Health (NIMH) supports research on depression in PD, the NIEHS on the possible role of environmental toxicants in PD, and the National Human Genome Research Institute (NHGRI) and National Institute on Aging (NIA) on genes in PD. The NIH coordinates these efforts through extensive interactions among scientific program directors and through the PD Coordinating Committee (PDCC). In addition to NIH members, the PDCC includes representatives of the Department of Defense and the Department of Veterans Affairs, which also support programs of PD research.

From the beginning, we have worked to ensure that the development of the Agenda, its implementation, and the evaluation of progress are transparent. The NIH publicly disseminates the Agenda and Matrix, detailed information on implementation, scientific advances, and other PD‑related information through the NINDS Parkinson's Disease Research Web (http://www.ninds.nih.gov/parkinsonsweb/index.htm ), meetings with the scientific community and voluntary health organizations, and frequent informal interactions with scientists and the public. The NIH has also presented updates of Agenda related activities in Congressional hearings, reports, and briefings. In addition to these mechanisms of accountability, components of the Government Performance and Results Act (GPRA) process are directly relevant to PD. Specifically, one GPRA goal focuses on developing improved animal models that best recapitulate PD, using scientific findings of genetic or environmental influences. Another goal focuses on identifying small molecules that are active in models of nervous system function or disease, and show promise as drugs, diagnostic agents, or research tools. For each GPRA goal, the NIH annually provides detailed implementation strategies and progress reports. We believe our planning and management for PD are, in fact, accelerating progress against this disease.

Cooperation Among the Brain Institutes

The NINDS is only one of several NIH Institutes that support brain research. At least six other Institutes have a primary focus on basic and clinical neuroscience, including the NIMH, the National Institute on Drug Abuse (NIDA), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and Other Communication Disorders (NIDCD), and the National Eye Institute (NEI). We all share the common goal of understanding how the brain develops, how it functions normally, how function is perturbed in disease, and how dysfunction and/or damage can be repaired. Each Institute also has a distinct mission to prevent, treat, or repair different types or aspects of brain disorders. Other institutes whose missions involve significant attention to the brain and nervous system include the NIA, the National Institute of Dental and Craniofacial Research (NIDCR), and the National Institute of Child Health and Human Development (NICHD).

Before taking my present position as the NINDS Director, I was the Scientific Director of the Institute's intramural research program, and worked with my counterparts at other neuroscience institutes to integrate our respective intramural research programs through a common seminar series, a shared website, shared resources, and joint recruitment of outstanding scientists. The emergence of an inter-institute and multidisciplinary community of intramural neuroscientists led to the development of the concept for the new Porter Neuroscience Research Center (PNRC) on the NIH Bethesda campus. Scientific Directors from seven intramural programs worked together to select cross cutting neuroscience research themes with potential relevance to many disorders and researchers whose approaches to those themes complemented one another. Laboratory space in the Center is assigned according to the potential for catalyzing scientific interactions rather than by institute affiliation. Beginning later this year, when the first phase of the PNRC opens, investigators from each of the participating NIH institutes will be joining in this effort to "put the brain back together" and set the standard for collaborative research in neuroscience.

In the extramural programs, the neuroscience Institutes took a major step forward in coordinating efforts with the development of a combined neuroscience training program for graduate students. Training the next generation of basic and clinical neuroscientists is a priority for all of the NIH institutes that share an interest in the brain. This program has worked extraordinarily well. It has catalyzed the creation of cross‑cutting and interdepartmental neuroscience graduate programs in many universities that will bring together diverse lines of research with a bearing on specific neurological disorders such as Parkinson's disease, Alzheimer's Disease and schizophrenia.

Cross‑institute cooperation is quite frequent. As one illustration, the brain research Institutes have issued more than 60 joint grant and contract solicitations over the last three years. One recent example, supported by NINDS, NIMH, NICHD, and NIDA, is a detailed MRI brain imaging database of the developing human brain that can serve as a baseline for studies of abnormal development and pediatric diseases. Other important collaborative programs have focused on mouse genetics, autism, and the development of chemical compound libraries to expedite the development of therapeutics to treat diseases, and of reagents and assays to study them. In each case, it is evident that it would have been very difficult for any one institute to support activity alone.

These examples underscore the enormous benefit that could accrue from additional coordination of our efforts in infrastructure support, tool and technology development, and training in neuroscience research. In addition, we all share the need to understand neural development, neurodegeneration and repair, and neuroplasticity. In the coming year, the directors of the NIH neuroscience institutes will develop a "blueprint for the brain" to direct our common efforts, so that we can accelerate progress against brain disorders, and enhance our understanding of how brain and behavior are interrelated.

As described above, the NINDS has in place a series of mechanisms to guide our decisions on investments in research that will contribute to reducing the burden of neurological disorders. We have planning processes and rigorous scientific review that inform our funding decisions, and we engage in portfolio management within our institute, between institutes, and among other federal and private organizations. As we do this, we are mindful that the NINDS must focus resources on diseases for which the science seems close to helping people, without abandoning problems about which we have, as yet, few clues. Likewise, the Institute must expedite even incremental improvements in the quality of life for people now confronting neurological problems, while continuing long-term efforts toward cures and prevention. Because diseases do not recognize organizational boundaries, the NINDS must remain cognizant of the broader research and health care context, recognizing what government can do best, what is in the province of the private sector, and how public and private organizations can work together. Finally, the Institute must support today's research, while training the next generation of investigators and attending to the high-technology infrastructure that will accelerate future discoveries.

Thank you. I would be pleased to answer any questions.

Last Modified February 4, 2011