Continuing Assistance to the National Institutes of Health on Preparation of Additional Risk Assessments for the Boston University NEIDL, Phase 1

Committee on Continuing Assistance to the National Institutes of Health on Preparation of Additional Risk Assessments for the Boston University NEIDL

Board on Life Sciences

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
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Continuing Assistance to the National Institutes of Health on Preparation of Additional Risk Assessments for the Boston University NEIDL, Phase 1 Committee on Continuing Assistance to the National Institutes of Health on Preparation of Additional Risk Assessments for the Boston University NEIDL Board on Life Sciences Division on Earth and Life Studies THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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National Research Council 500 Fifth Street, NW Division on Earth and Life Studies Washington, DC 20001 Board on Life Sciences Phone: 202 334 2187 Fax: 202 334 1289 April 20, 2010 Francis Collins, M.D., Ph.D. Director National Institutes of Health Building 1 9000 Rockville Pike Bethesda, Maryland 20892 Dear Dr. Collins: At your request, the National Research Council (NRC)1 reconvened its Committee on Technical Input on Any Additional Studies to Assess Risk Associated with Operation of the National Emerging Infectious Diseases Laboratory (NEIDL), Boston University2 to provide you and your Blue Ribbon Panel with further technical input on the scope and design of any additional studies that may be needed to assess the risks associated with the siting and operation of the NEIDL. In particular, you asked the NRC committee to meet with the NIH Blue Ribbon Panel in public at key milestones in the development of the draft risk assessment. To this end, the NRC committee met in open session with the Blue Ribbon Panel on March 19, 2010 to hear presentations by NIH’s contractors on the approaches they intend to take in conducting the risk assessment. Following the open meeting, the NRC committee met in closed session to prepare this brief letter report on the plan for the supplementary risk analyses, focusing on whether the analyses are scientifically and technically sound in general and whether they address the concerns raised by the NRC in its first two letter reports. The committee’s full statement of task, as developed with your office, is provided in the main body of this report. The committee heard plans, but not yet results. In general, the NRC committee finds the proposed approaches to conducting the risk assessment suitable and well planned. The agents selected for analysis are appropriate and comprehensive, and the expertise available on and to the assessment team is strong. NIH and its contractor (Tetra Tech) appear to recognize data 1 The principal operating arm of the National Academy of Sciences and the National Academy of Engineering. 2 A list of committee members and their biographies is included as Attachment A. 2

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limitations and the need for flexibility in study design. The committee encourages NIH and Tetra Tech to develop qualitative analyses (an explanation of the safety and risk profile) of all 13 pathogens on the list in a manner that is clear and accessible to the public. For example, the qualitative analyses in the body of the assessment could be supplemented with results of quantitative modeling planned for five pathogens, with details provided in appendices. Further, the committee encourages NIH and Tetra Tech to rely on data that are available from existing case studies, public health surveillance of the surrounding communities, and incidents, not only to support its models but also to provide a complete and understandable picture for the public. The final risk assessment must also be able to serve as an effective risk communication tool. More detailed observations on these points appear in the body of the report. This report reflects the consensus of the committee and has been reviewed in accordance with standard NRC procedures. The work was supported by Frances Sharples, Director of the NRC’s Board on Life Sciences, Panola Golson of the Board on Environmental Studies and Toxicology, and Kathi Hanna, our professional science writer. The committee thanks NIH for seeking its input as it works to develop resources for advancing the national capacity to protect and improve health. The committee hopes that its suggestions will be useful in this regard. Sincerely, John F. Ahearne, Chair Committee on Continuing Assistance to the National Institutes of Health on Preparation of Additional Risk Assessments for the Boston University NEIDL cc: Amy Patterson, M.D. 3

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BACKGROUND AND INTRODUCTION In 2003, the Boston University Medical Center (BUMC) was awarded a $128 million grant from the National Institutes of Health (NIH) to build one of two national high- and maximum- containment laboratory facilities for research on biological pathogens. The National Emerging Infectious Diseases Laboratories (NEIDL) are meant to support the National Institute of Allergy and Infectious Diseases’ biodefense research agenda, conducting research to develop new approaches to treating, preventing, and diagnosing a variety of bacterial and viral diseases. Diseases and agents to be studied include viruses (e.g., Ebola, Marburg, dengue fever, Lassa fever, and highly pathogenic influenza) and bacteria (e.g., Shigella and plague) that occur naturally and cause infections or that could be used in deliberate attacks. The facility includes a biosafety level 4 (BSL-4) containment laboratory housed in a 192,000 square foot building. Although the NEIDL BSL-4 laboratory space accounts for only 13 percent of the building’s total space, it has been the source of virtually all of the community concern surrounding this project. The location of the facility on Albany Street in Boston’s South End (an environmental justice community) has been controversial, and there have been numerous public meetings over the plans for the facility as well as three legal actions that challenge the project. Construction of the laboratory building is now complete although commissioning of the laboratory facilities has not been completed. A remaining issue is whether the BSL-4 component will become operational. The building, including the BSL-4 laboratory, is part of the BioSquare Phase II project. Under the Massachusetts Environmental Policy Act (MEPA), the Secretary of the Commonwealth of Massachusetts’s Executive Office of Environmental Affairs issued a certificate stating that the BioSquare II project required the preparation of an Environmental Impact Report. In August 2004, the Massachusetts Secretary of Environmental Affairs issued a certificate stating that the final Environmental Impact Report adequately and properly complied with MEPA. This determination was challenged in court, and in July 2006 the Superior Court of Massachusetts vacated Massachusetts’ certification of the Environmental Impact Report and remanded the matter to the Secretary of Environmental Affairs for further administrative action. NIH prepared a document, “Draft Supplementary Risk Assessment and Site Suitability Analyses” (DSRASSA), regarding the siting and operation of the NEIDL in response to comments from the federal court presiding over another lawsuit under the National Environmental Policy Act (NEPA) and to supplement NIH’s previous assessments of the potential risks posed by the NEIDL at its current location in Boston. 2007 NRC Letter Report In 2007, the Massachusetts Executive Office of Energy and Environmental Affairs (MEOEEA) asked the National Research Council (NRC) to establish a committee to provide technical input to the MEOEEA on the NIH DSRASSA. Although the DSRASSA was prepared in response to comments that arose in federal litigation pursuant to the NEPA process, the MEOEEA requested a review because it expected the DSRASSA to be an integral part of the material that would be submitted to it by Boston University in fulfillment of MEPA requirements. 4

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NRC’s Committee on Technical Input on the NIH Draft Supplementary Risk Assessment and Site Suitability Analyses was convened to review the DSRASSA and discuss its methods and analyses in response to specific questions posed by the MEOEEA. In November 2007, the committee released its letter report answering these questions.3 The committee’s assessment was critical of the DSRASSA, finding that it was not sound and credible, did not adequately identify and thoroughly develop worst-case scenarios, and did not contain the appropriate level of information to compare the risks associated with alternative locations. The report also raised specific concerns about agent selection, scenario development, modeling methodology, environmental justice issues, and risk communication. In March 2008, NIH announced that additional steps would be taken to address the NRC committee’s comments on the DSRASSA as well as the comments and concerns expressed by the courts, the local community, and the general public regarding the construction and operation of the NEIDL. Specifically, NIH established an independent Blue Ribbon Panel (BRP) to advise the agency in responding to these comments and concerns. The BRP was established as a Working Group of the Advisory Committee to the NIH Director and is comprised of experts in infectious diseases, public health and epidemiology, risk assessment, environmental justice, risk communication, biodefense, biosafety, and infectious disease modeling.4 NIH initiated the development of a draft supplementary risk assessment and sought additional input from the NRC committee on this project. The MEOEEA informed NIH that it views the NRC’s additional input on the supplemental assessment being conducted by NIH as an important part of the review process. 2008 NRC Letter Report In 2008, the reconvened NRC committee released its second letter report.5 As in its first report, in addressing its charge from NIH, the committee did not review the content of previous documents (such as the original environmental impact statement or environmental impact report) or the scope of what had already been done to address risk and community concerns. The committee restricted its comments to suggestions based only on its review of the DSRASSA and on improving the risk assessments presented therein as input to any additional studies that may be needed to assess risk associated with the siting and operation of the NEIDL. The committee prepared its second letter report largely on the basis of the analysis and discussions that went into the preparation of its November 2007 report and discussions that were expanded by a series of conference calls held in April 2008. As noted in its 2007 report, the committee acknowledged and emphasized the need for biocontainment laboratories, including BSL-4 laboratories. The committee also recognized that BSL-4 facilities are being operated safely in both urban and rural areas. However, the committee’s view remained that the selection of sites for high-containment laboratories should be supported by detailed analyses and transparent communication of the 3 NRC. Technical Input on the National Institutes of Health’s Draft Supplemental Risk Assessments and Site Suitability Analyses for the National Emerging Infectious Diseases Laboratory, Boston University: A Letter Report (2007). Available at: http://www.nap.edu/catalog/12073.html. 4 See http://nihblueribbonpanel-bumc-neidl.od.nih.gov/roster.htm. 5 NRC. Technical Input on Any Additional Studies to Assess Risk Associated with Operation of the National Emerging Infectious Diseases Laboratory, Boston University: A Letter Report (2008). Available at: http://www.nap.edu/catalog/12208.html. 5

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available scientific information regarding possible risks. The committee refrained from prescribing specific methods and other details, electing instead to structure its suggestions to the NIH BRP around a few overarching questions that should be addressed in future impact reports about the risks associated with operating the NEIDL. The NRC committee offered a series of suggestions and recommendations to NIH and the BRP for consideration in its development of any additional risk assessment studies, loosely organized around the following three domains: What Could Go Wrong? — Scenarios of Release of an Infectious Agent — Agents to Consider for Risk Assessment What Are the Probabilities? What Would Be the Consequences? Finally, the committee also recommended that NIH use the accumulated wisdom in the published literature on how to achieve effective risk communication. Statement of Task for This Letter Report This report again involved reconvening the NRC committee, consistent with NIH’s intention to engage the committee at key milestones during the development of a draft supplementary risk assessment. The statement of task is as follows: The NIH will engage the Committee on Technical Input on the NIH’s DSRASSA for the Boston University NEIDL at key milestones during the development of a draft supplementary risk assessment. The NRC and the NIH Blue Ribbon Panel (BRP) will meet together in public to discuss the developing draft report. Information contained in the draft risk assessment may include data on agents, models, and scenarios; preliminary modeling results; and quantitative and qualitative assessments. Documents reviewed and discussed at these meetings will be made available to the public. Following each meeting with the BRP, the NRC Committee in closed session will prepare brief letter reports on the preliminary results of the supplementary risk analyses, focusing on whether the analyses are scientifically and technically sound in general and whether they address the public health concerns previously raised by the NRC in its review of the July 2007 DSRASSA. These letter reports will be made available to the public. The committee will also provide written comments on the draft supplementary risk assessment when that document is made available for formal public comment. The Committee will submit their findings in the form of a final letter report that will also be made available to the public. The NRC committee and the BRP met by conference call (which was open to the public) in April 2009 and in person in March 2010 to discuss the developing draft report. At the March 19, 2010 joint meeting of the NIH BRP and the NRC committee, the two groups selected by NIH to complete the supplemental risk assessment—Tetra Tech and its subcontractors from the 6

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University of Utah—made presentations on the proposed approach for the supplemental risk assessment. At NIH’s request, the committee focused its discussions of the proposed approach on the following questions: 1. Is the range of agents being studied appropriate? 2. Is the approach to event sequence analysis appropriate? — Will the method result in an adequate range of scenarios being considered and selected for analysis? — Are the plans for analysis and expression of results appropriate? 3. Is the modeling approach appropriate? — Is the approach to initial infection sound? — Are the criteria for and selection of models sound? — Are the uses of the hybrid branching-compartment models and the extreme values analysis sound? This letter report is a response to the committee’s charge to provide input on key milestones (as presented at the March 2010 meeting) in the development of the supplementary risk assessment. COMMITTEE RESPONSE AND RECOMMENDATIONS In reviewing the proposed risk assessment plan, the committee took into account the discussions with the BRP in evaluating whether the proposed risk assessment is proceeding in the right direction, with appropriate choices being made regarding agents to be assessed, scenarios, event sequence analysis, and qualitative and quantitative methodologies. The committee was pleased to see that NIH and its contractors seriously considered and responded to the NRC committee’s findings and the suggestions presented in its second letter report. The material presented provides a range of scenarios that meet the criteria the committee recommended be examined. The contractor appears to be cognizant of data limitations and has accommodated those limits in its proposed methodology. In addition, the contractor appears to have followed the three classic risk triplet questions: What can go wrong? How likely is that? And what would be the consequences? This was recommended in the committee’s 2008 letter report. Selection of Agents: The committee finds the range of the 13 agents to be studied appropriate and comprehensive. Although Ebola virus has relatively low transmissibility, its inclusion in the assessment is appropriate given its associated high case fatality rate, public concern about this agent, and its status as a BSL-4 agent. The risk assessment, however, should take special care in explaining that Ebola virus has limited transmissibility (by contact with blood or body fluids of infected people, not by aerosol transmission). In general, NIH and its contractors should not attempt to push modeling further than data for the agents being studied allow. For example, although the Rift Valley Fever (RVF) literature contains good examples of forecasting models in which the incidence of RVF is rendered as a function of weather indices, these are not the kind of data needed for the NEIDL risk assessment. The combination of compartmental and vector borne models outlined by Tetra Tech will require estimating coefficients for both horizontal 7

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transmission (animal-human, animal-animal) and, in the vector borne component (animal- animal), biting rates, and insect abundance for the Boston area. This is a challenge even when describing what happens in those countries where RVF is endemic, and is not likely to be less challenging here. Also, the likelihood of asymptomatic infections and incubation period variability should be acknowledged as important epidemiological characteristics directly associated with the success of containment strategies. Finally, the committee strongly supports conducting a qualitative assessment for all 13 pathogens and quantitative analyses for five of the pathogens. Modeling: The committee finds that the proposed use of both the branching process and compartmental modeling approaches is appropriate, rational, and straightforward. These strategies individually and sequentially can facilitate the modeling of both small and large transmission events, accommodate common laboratory events, and can most likely be completed within the project’s timeframe (i.e., by the end of calendar year 2010). There is evidence that well-designed models—even those for which there are limited datasets—have significant value. Such models contribute information to support decision making, policy development, and designing intervention options to mitigate risk (e.g., training, security issues, vaccination strategy), and to identify areas of uncertainty or data gaps. Nevertheless, modeling results should be augmented by case studies based on actual occurrences of laboratory or natural infections (e.g., Burkholderia mallei, Sabia virus, Francisella tularensis, Yersinia pestis). For this reason, the committee cautions that it will be critical to complement transmission modeling with the qualitative methodologies being used in the assessment. Such case studies can serve to illustrate actual risks and minimize misconceptions and misinformation. To the extent possible, the models should take into account environmental justice issues as well as health disparities in terms of access to and quality of care. The committee recognizes that much of the required data will be difficult to find but notes that the compartmental models proposed by the contractors can easily accommodate demographic characteristics such as age, pre-existing conditions, and even access to care should such data be available. Finally, the committee is skeptical about the plans for using extreme value analysis. The statistical methods of extreme value analysis require great care about underlying assumptions (e.g., the assumptions underlying the use of a Gaussian [normal] probability distribution) in the estimation of parameters and selection of probabilities to be used in the risk analysis. Without such care, the risk analysis could ignore important issues of dependence versus independence in the sequence of events leading to exposure and subsequent infection. Rather, it is the committee’s view that the emphasis should be on sensitivity analysis and carefully examining scenarios (e.g., event sequences) with low probability (rare occurrence) but high consequence, using data when available and well-documented judgment from experts when data are not available to estimate event probabilities. While statistical techniques in extreme value analysis may be helpful, these methods must be checked to be consistent with expert judgment regarding the probabilities of unlikely, but possible, high-consequence events. In addition, uncertainty analyses, which differ from sensitivity analyses and are generally more qualitative, should be included. Some input data may be highly uncertain, yet this uncertainty may have minimal impact on overall risk. 8

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Expertise and Capabilities: The committee was critical of the previous team contracted by NIH. The committee was encouraged to see the inclusion of personnel with experience in hospital infection control and infectious disease research, theory, and public health on the new team, as well as personnel who are already in touch with the Boston area public health surveillance system. The new team is also well connected to other networks of expertise that can be consulted if needed and has been working with NIH on developing a plan for identifying additional expertise should this be required. The presentations of the new team suggested that they understand the issues. However, the committee is concerned that the project staff is small and the schedule is tight. It will be important to provide the contractors with adequate resources to complete their work in the time proposed. Qualitative Issues: The committee identified a few issues that it urges be considered in the qualitative assessments, and to the extent possible, in the models. The first is the need to focus on vulnerable populations where transmissibility and/or susceptibility may be higher, for example, among immunocompromised individuals. The second is the benefit of using a curve for infectious dose-response relationships, rather than relying solely on ID50 calculations. The limitations of use of points on the dose-response curve (e.g., ID50, ID10, ID1) should be clearly articulated. Risk Communication: The committee continues to urge that the supplemental risk assessment be developed in recognition of the inevitable use of the document as a risk communication tool. To this end, it should be clear, accessible, and transparent to non-scientists, or be accompanied by a summary version that is comprehensive and easily accessible to the lay reader. In addition, the committee recommends that whenever possible, the final risk assessment clarify which findings are generalizable to other high-containment laboratories and those findings that are specific to the NEIDL, and why. Doing so could be valuable in informing future risk assessments for other facilities. While pleased that the plans presented are consistent with the committee’s recommendations, the committee notes that these are plans. We await the results. Finally, although the plans for analysis look appropriate, it is important that the assessors are flexible in applying and modifying their methods as any new information as well as analytical results become available. Attachments: A Committee Membership and Biographies B March 19, 2010 Open Session Public Agenda 9