Dr. Gray noted that there are a number of examples of coordinated research in other (non-radiation) fields that can help the radiation research community draw lessons to be learned for organizing a cohesive low dose radiation research program. Four different approaches in two research fields—air pollution and genomic studies—were described in some detail at the symposium.
Experts who helped establish these programs identified dealing with a controversial topic that requires better science to reduce scientific uncertainties as the number one incentive to build a research program in their fields. They observed that a similar incentive also exists within the radiation community.
Mr. Dan Greenbaum (Health Effects Institute [HEI]; see Figure 5.1) provided two examples of coordinated research on the health effects of air pollution. A brief history of the establishment of the programs and lessons learned are described in the following sections.
In 1997, the Environmental Protection Agency (EPA) proposed to establish new national ambient air quality standards for airborne particulate matter (PM) smaller than about 2.5 micrometers in aerodynamic diameter (PM2.5) (EPA, 1997). This proposal was controversial because, at the time,
the scientific understanding of the health effects of PM2.5 was limited. Because of the recognized need to reduce scientific uncertainties, Congress mandated and appropriated substantial funds ($50 million) for EPA to establish a research program on PM2.5. It also directed the EPA administrator to get into an agreement with the National Academies to develop a research agenda for this purpose and to monitor its implementation and research progress. As a result, the National Academies assembled the Committee on Research Priorities for Airborne Particulate Matter,1 which authored four reports to address its task.
The first report (NRC, 1998) proposed a conceptual framework for a national program of PM research; identified 10 high-priority research topics linked to key policy-related scientific uncertainties based on criteria such as scientific value, decision-making value, and feasibility; and presented a 13-year integrated “research investment portfolio” containing recommended
1 The committee was chaired by Dr. Jonathan Samet (Colorado School of Public Health). Mr. Greenbaum also served on the committee.
short- and long-term phasing of research and estimated costs of such research. The second report (NRC, 1999) updated the research portfolio and discussed the criteria and approaches that the committee planned to use in evaluating research progress over the next few years. The third report (NRC, 2001) assessed initial research progress made in addressing key scientific uncertainties for PM regulation. The fourth report (NRC, 2004) further assessed research progress.
Congress, EPA, and the scientific community gave strong support to the National Academies committee’s recommendations. EPA initiated the Particulate Matter Research Program, which largely followed the 13-year research portfolio proposed by the National Academies committee and much of the research called for by the committee has been carried out by EPA and other investigators nationally and internationally. Mr. Greenbaum noted that the National Academies also sought to better integrate the national program across all agencies (e.g., Department of Energy, National Institute of Environmental Health Sciences, National Oceanic and Atmospheric Administration, National Science Foundation, and others) but that effort was not as successful because of the differing priorities across federal agencies.
Mr. Greenbaum noted that strategic plan development and monitoring of progress by a trusted institution such as the National Academies provided an effective management process for the program and enhanced the credibility of the program and its findings. According to Mr. Greenbaum, EPA, until it received guidance from the National Academies, had no experience with managing multi-year programs because of the typical 1-year appropriations cycle within the federal government. Following the National Academies’ guidance, EPA established a National Program Lead for a multi-year program of air pollution research and subsequently did the same for all of its research programs (e.g., on water and chemicals). Also, Mr. Grenbaum commented that the continuing attention of the EPA program to science relevant to regulatory issues has successfully sustained financial support. Funding for PM research continues today within EPA’s Air, Climate, and Energy Research Program and was approximately $95 million in fiscal year 2019.
HEI is an independent, nonprofit corporation specializing in research on the health effects of air pollution. It was formed in 1980 to help resolve the controversy that existed over the regulation of vehicle pollution in the late 1970s following a provision in the 1977 Clean Air Act Amendments that required the EPA administrator to reject the certification of any new vehicles that contribute to an unreasonable risk to public health. Congress gave the vehicle industry the responsibility to demonstrate to the
administrator that an unreasonable risk did not exist. In an atmosphere of distrust between the automobile industry and the regulator, HEI was initiated to produce impartial scientific research to inform the public policy debate concerning the health effects of vehicle emissions (Keating, 2001).
HEI receives joint and balanced funding (about $10 million per year) from EPA and the worldwide motor vehicle industry. In addition, other national and international organizations fund special projects or research programs carried out by HEI.
Since 1996, HEI has expanded its mission beyond the health effects of vehicle emissions to address the health effects of all air pollutants. Since its creation, HEI has funded more than 400 studies on a wide variety of air pollutants. It also periodically performs scientific reviews; currently HEI is undertaking a systematic review of the literature on the health effects of exposure to traffic. HEI-funded results are publicly available.2
Mr. Greenbaum noted that from the beginning of its existence the institute has made an effort to maintain credibility, relevance, and transparency. Its organizational structure and the processes that it uses to manage research activities are designed to achieve that:
- The board of directors, which has to be agreed on by the sponsors but does not include the sponsors, oversees the institute’s staff, appointments to the expert advisory panels, and the selection of members of the research and review committees.
- The research committee is responsible for identifying the institute’s research agenda by providing a 5-year strategic plan, preparing requests for applications, and selecting investigators through a competitive process. It also oversees quality and timeliness of research and provides independent audits and site visits.
- The review committee peer reviews all study results and provides a commentary on the impact of the research in advancing the state of knowledge and its implications for policy and regulations.
HEI’s strategic plan guides the institute’s research and review activities and responds to the needs of its governmental and private sponsors. In addition, it is set to anticipate future technological advances and policies and makes necessary adjustments so that research within the institute remains relevant. Mr. Greenbaum believes that this renewal of the plan every 5 years provides an opportunity to refresh and refocus the research. This HEI structure and plan have led to close to 40 years of sustained funding for air pollution and health research, and a recent analysis suggests a large uptake of HEI’s work in the scientific literature and in regulatory documents.
Dr. Anna Barker (Arizona State University) described two large-scale biology initiatives and discussed the relevance of several lessons learned for setting up a low dose radiation research program in the United States.
TCGA was a joint effort between the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) designed to catalog all of the genetic mutations in a number of different cancers, using genome sequencing, bioinformatics, and a range of analytics. NCI and NHGRI shared the cost of TCGA, estimated to be approximately $375 million.
Dr. Barker noted that the impetus for the initiative was three-fold:
- The increasing burden of cancer diagnosis in the United States and worldwide that comprises a daunting human and economic disease burden;
- The movement in the early 2000s toward precision (or personalized) medicine focused on selecting targeted treatments for complex diseases such as cancer based on the genetic makeup of these diseases; and
- The realization that sequencing of the genomes of different cancers needed to be performed through an integrated network of functions based on the highest quality samples and procedures that adhered to strict scientific, technical, and ethical guidelines.
TCGA was launched as a pilot program in 2005 and scaled up over the next few years. In terms of organization, there were two phases to the program:
- An initial 3-year pilot project was created to identify the genomic alterations in glioblastoma, ovarian, and lung cancers and to establish the project infrastructure and organization including the biobank, data collections, and analytics. The pilot also established the procedures for making the data available through NCI’s Genomic Data Commons, a repository for data sharing across cancer genomic studies. About 100 scientists in 17 institutions were engaged in the pilot.
- The large-scale nearly 13-year project sequenced 33 cancer types and engaged more than 300 scientists, technicians, and cancer advocates (McLendon et al., 2008).
Dr. Barker said that the TCGA project revolutionized cancer research and produced a data set that is fueling new discoveries ranging from molecular classification systems for what heretofore were viewed as single diseases to new targets for therapeutic development. It also provided unprecedented opportunities for biomarker discovery and set the stage for precision medicine. TCGA generated numerous publications and in her view will likely become one of the most cited initiatives in cancer research.
Dr. Barker also reflected on some lessons to be learned for organizing and managing the project. She said that to successfully complete the project there was a need to
- Organize the functions of the project into an integrated whole;
- Obtain high-quality biosamples (which turned out to be a major challenge);
- Integrate different disciplines and technologies into functional teams and results;
- Transition from existing sequencing technologies to more sophisticated approaches;
- Build a new generation of analysis teams to carry out the project;
- Resolve policy issues related to data access and informed consent; and
- Communicate about TCGA to the cancer research community and provide opportunities for comments, input, or questions.
Dr. Barker said that the long and expensive development cycle for new oncology drugs led NCI and the Food and Drug Administration (FDA) to collaborate on the design and development of a next-generation clinical trial named I-SPY 2. The I-SPY 2 trial is a large randomized phase II public–private adaptive platform trial created by an NCI-FDA team and expanded to ultimately become a multi-sector collaborative consortium. It was launched in 2010 through the Foundation for the National Institutes of Health and was subsequently transferred to Quantum Leap Healthcare Collaborative.
The goal of the I-SPY 2 trial was to personalize treatment for high-risk breast cancer patients using biomarkers to determine each patient’s subtype of breast cancer. I-SPY 2 has an innovative adaptive statistical design where every patient’s data contribute to a learning system, which subsequently informs the treatment of future patients and therefore increases
the probability of success for each patient by ensuring that they received therapies shown to be effective for their cancer subtype.
Dr. Barker said that the I-SPY 2 trial, which continues today, leverages the capabilities of many organizations. To date, the trial has brought together breast cancer physicians, translational scientists, pharmaceutical and biotechnology companies, and patient advocates in an unprecedented pre-competitive collaboration. The trial has tested 23 agents and 7 have “graduated” from the trial—meaning that they can move directly into a small phase III trial. Through its efforts, the I-SPY 2 team has also produced sufficient data to establish a surrogate endpoint, pathologic complete response, which was approved by FDA in 2014 for use in breast cancer clinical trials.
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