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Title. Title. Biodefense research: oversight of safety, oversight of security, and oversight of dual-use implications. Richard H. Ebright Howard Hughes Medical Institute, Waksman Institute, Department of Chemistry Rutgers University. safety-background.

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  1. Title Title Biodefense research: oversight of safety, oversight of security, and oversight of dual-use implications Richard H. Ebright Howard Hughes Medical Institute, Waksman Institute, Department of Chemistry Rutgers University

  2. safety-background Biodefense research: oversight of safety background • 20-fold increase in number of institutions with bioweapons agents • (>300 registered institutions) • 20-fold increase in number of individuals with bioweapons agents (>16,000 registered individuals) • institutions without prior experience • individuals without prior experience increased risk of accidental release recent precedents: 5/2004, Boston University Medical Center, tularemia exposures, infections 6/2004, Oakland Children's Hospital Research Institute, anthrax exposures 8/2004, Boston University Medical Center, tularemia exposures, infection 2/2005, Rocky Mountain Laboratory, Q-fever exposures 9/2005, Public Health Research Institute, missing plague-infected mice

  3. safety-current regulatory status Biodefense research: oversight of safety current regulatory status • no applicable federal laws or regulations • no universally applicable federal guidelines • for most institutions: no coverage • for institutions that both (1) receive NIH support and (2) perform recombinant-DNA research: coverage under voluntary guidelines • (NIH Guidelines for Research Involving Recombinant DNA Molecules)

  4. safety-current regulatory status, IBC system Biodefense research: oversight of safety Institutional Biosafety Committee (IBC) system • created under NIH Guidelines for Research Involving Recombinant DNA Molecules (for subset of institutions subject to NIH Guidelines) • charged with reviewing protocols for safety • local, intra-institution review panels • often ineffective • large-scale violations • institutions without IBCs • institutions with non-functioning IBCs • limited specified practices and procedures • limited or no monitoring • limited or no enforcement

  5. safety-current regulatory status, IRB system Biodefense research: oversight of safety Institutional Review Board (IRB) system • created under federal law (45 CFR part 46) • universally applicable • mandatory • charged with reviewing human-subjects research protocols • local, intra-institution review panels • effective • specified practices and procedures • monitoring • enforcement

  6. safety-required corrective action Biodefense research: oversight of safety required corrective action • legislation to establish universally applicable, mandatory local-level review • (along lines of IRB system)

  7. security-backround 1 Biodefense research: oversight of security background • 20-fold increase in number of institutions with bioweapons agents • (>300 registered institutions) • 20-fold increase in number of individuals with bioweapons agents (>16,000 registered individuals) increased risk of deliberate release In contrast to nuclear or chemical weapons, biological weapons involve propagative, self-replicating materials.  A single viral particle or cell--diversion of which can be neither prevented nor detected--can serve as a seed to produce effectively unlimited quantities and thus can provide the means to mount an attack. 

  8. security-background 2 Biodefense research: oversight of security background • 20-fold increase in number of institutions with bioweapons agents • (>300 registered institutions) • 20-fold increase in number of individuals with bioweapons agents (>11,000 registered individuals) increased risk of deliberate release The simplest, most likely, path for a sub-state adversary, such as AlQaeda, to acquire bioweapons capability is to obtain bioweapons agents and training by penetration of a bioweapons-agents research project in a US laboratory. One well-placed graduate student, post-doctoral fellow, or technician.  No cost (salary being provided courtesy of the US taxpayer).  No risk.  No difficulty. 

  9. security-current regulatory status Biodefense research: oversight of security current regulatory status • Public Health Security and Bioterrorism Preparedness Act of 2002 • (PL 107-188; effective 6/02) • Interim Final Rule on Possession, Use, and Transfer of Select Agents • (CFR 42 part 73; effective 2/03) • Final Rule on Possession, Use, and Transfer of Select Agents • (CFR 42 parts 72-73; effective 4/05)

  10. security-current regulatory status, gaps, security Biodefense research: oversight of security current regulatory status, security gaps • insufficient requirements for physical security • no specific requirements apart from requirement for lock on door • [requirement for locks on storage containers present in Interim Final Rule, but removed from Final Rule] • no specific requirements for multi-level access control, for security personnel, or for video surveillance • insufficient requirements for personnel security • no requirement for exclusion of non-screened persons from laboratory • [requirement for exclusion present in Interim Final Rule, but removed from Final Rule] • de minimis personnel screening (database search only--watch-list, immigration, criminal, mental-health, and military-service records) • insufficient requirements for transportation security • no requirement for enhanced transportation security • no requirement for enhanced transportation monitoring • no requirement for immediate incident reporting

  11. security-current regulatory status, gaps, coverage Biodefense research: oversight of security current regulatory status, coverage gaps • insufficient coverage of select-agent nucleic acids • no coverage of genome segments • [coverage present in Interim Final Rule but removed from Final Rule] • no coverage of gene and genome synthesis technologies • no coverage of gene and genome synthesis services

  12. security-current regulatory status, gaps, coordination • state and local governments cannot know possible threats • state and local governments cannot properly equip first responders • state and local governments cannot properly train first responders Biodefense research: oversight of security current regulatory status, coordination gaps • insufficient coordination with state and local governments • no disclosure of registration information permitted • state and local governments cannot know possible threats • state and local governments cannot properly equip first responders • state and local governments cannot properly train first responders • no disclosure of transfer/transportation information permitted

  13. security-required corrective action Biodefense research: oversight of security required corrective action • rulemaking or legislation to address coverage and security gaps • legislation to address coordination gaps

  14. dual-use implications-background 1 • antibiotic-resistance • vaccine-resistance • increased lethality • increased transmissibility • increased deliverability • increased environmental stability Biodefense research: oversight of dual-use implications background • 20-fold increase in research activities with bioweapons agents • identification of new vulnerabilities--inadvertent or intentional • difficulty of addressing new vulnerabilities net increased vulnerability

  15. dual-use implications-background 2 • Would demonstrate how to render a vaccine ineffective • Would confer resistance to therapeutically useful antibiotics • Would enhance virulence of pathogen or render nonpathogen virulent • Would increase transmissibility of a pathogen • Would alter host range of a pathogen • Would enable evasion of diagnostic/detection modalities • Would enable weaponization of a biological agent or toxin Biodefense research: oversight of dual-use implications background, NAS "experiments of concern" • National Academies of Science report: Biotechnology Research in an Age of Terrorism: Confronting the Dual Use Dilemma (released 10/03) • Seven "experiments of concern"

  16. dual-use implications-current regulatory status 1 • "Experiments utilizing recombinant DNA that involve the deliberate transfer of a drug resistance trait to select agents that are not known to acquire the trait naturally, if such acquisition could compromise the use of the drug to control disease agents in humans, veterinary medicine, or agriculture" • "Experiments involving the deliberate formation of recombinant DNA containing genes for the biosynthesis of select toxins lethal for vertebrates at an LD50 < 100 ng/kg body weight." Biodefense research: oversight of dual-use implications current regulatory status • Final Rule on Possession, Use, and Transfer of Select Agents • (CFR 42 parts 72-73) • requirement for national-level approval for two narrowly defined experiments of concern • possible requirement for national-level approval for other experiments of concern under study • ["Experiments will be proposed for addition to the listing of restricted experiments, as warranted, through the publication of a proposed amendment for public comment."]

  17. dual-use implications-current regulatory status 2 Biodefense research: oversight of dual-use implications current regulatory status • NIH Guidelines for Research Involving Recombinant DNA Molecules • requirement for national-level approval of two narrowly defined experiments of concern • "deliberate transfer of a drug resistance trait to microorganisms that are not known to acquire the trait naturally...if such acquisition could compromise the use of the drug to control disease agents in humans, veterinary medicine, or agriculture" • "deliberate formation of recombinant DNA containing genes for the biosynthesis of toxin molecules lethal for vertebrates at an LD50 less than 100 nanograms per kilogram body weight."

  18. dual-use implications-current regulatory status 3 Biodefense research: oversight of dual-use implications current regulatory status • no other applicable federal laws or regulations • no other applicable federal guidelines

  19. dual-use implications, required corrective action Biodefense research: oversight of dual-use implications required corrective action • rulemaking or legislation to establish mandatory national-level review of NAS experiments of concern involving select agents • (e.g., by adding NAS experiments of concern to list of restricted experiments in amendment to Final Rule on Possession, Use, and Transfer of Select Agents) • legislation to establish mandatory local-level review of NAS experiments of concern involving any biological agent

  20. Title Title Biodefense research: oversight of safety, oversight of security, and oversight of dual-use implications Richard H. Ebright Howard Hughes Medical Institute, Waksman Institute, Department of Chemistry Rutgers University

  21. public-health relevance, bioweapons agents Biodefense research: NIH management public-health relevance, prioritized agents anthrax: average US cases/year: 3* (includes 22 bioterrorism-related cases in 2001) average US deaths/year: 1* (includes 5 bioterrorism-related deaths in 2001)tularemia: average US cases/year: 122 average US deaths/year: 0 plague:average US cases/year: 5 average US deaths/year: 0 data for 1996-2003: http://www.cdc.gov/mmwr/PDF/wk/mm4553.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4654.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4753.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4853.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4953.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm5053.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm5153.pdf; http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5330a6.htm

  22. public-health relevance, bioweapons agents Biodefense research: NIH management public-health relevance, non-prioritized agents tuberculosis: 17,403salmonellosis: 42,457shigellosis: 22,567borreliosis: 17,642legionellosis: 1,334ehrlichiosis: 591pertussis: 8,252syphilis: 38,007gonorrhea: 346,765chlamydia: 685,508meningococcal infection: 2,290streptococcal infection, invasive: 4,371streptococcal infection, invasive, drug-resistant S. pneumoniae: 3,083 average US cases per year; data for 1996-2003: http://www.cdc.gov/mmwr/PDF/wk/mm4553.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4654.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4753.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4853.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm4953.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm5053.pdf; http://www.cdc.gov/mmwr/PDF/wk/mm5153.pdf; http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5330a6.htm

  23. NIH role-overview Biodefense research: NIH role overview • NIH has the potential to make critical contributions to biodefense. • NIH has the potential to make unique contributions to biodefense.

  24. NIH role-potential strengths Biodefense research: NIH role potential strengths • basic research • peer-review process

  25. NIH role-potential strengths, basic research Biodefense research: NIH role potential strengths, basic research (bacteriology) • research on pathogenic microorganisms • research on model microorganisms • model microorganisms • standard experimental workhorses (E. coli, B. subtilis) • exceptionally well-characterized • exceptionally well-developed experimental tools • nonpathogenic, or minimally pathogenic • advantages • cost-effective • rapid • raise no safety issues • raise no security issues • outputs origin of recombinant DNA technology and biotechnology industry • detection systems • diagnostic systems origin of current detection systems, diagnostic systems, and antibiotics • countermeasures • all R&D up to final testing

  26. NIH role-potential strengths, peer review Biodefense research: NIH role potential strengths, peer-review process • ensures quality • effective

  27. NIH management-overview Biodefense research: NIH management overview • has not exploited potential strengths in basic research and peer review • has had negative impact on basic research and peer review

  28. NIH management-management errors Biodefense research: NIH management management errors (1) Biodefense responsibility was assigned to a single NIH institute (NIAID).More than half of NIH bacteriology research is carried out by other NIH institutes. This research inappropriately has been excluded from biodefense planning and support. (2) Biodefense was defined narrowly as work with bioweapons agents.Model-microorganisms research and non-bioweapons-agents-pathogens research inappropriately have been excluded from biodefense planning and support. (3)  The standard peer review process was circumvented.To review biodefense proposals, special review panels were created, with special review procedures and special, generous review standards.  As a result, sub-par research has been funded.  As a further result, an incentive structure has been created that has diverted scientists out of highly promising, biodefense-relevant, model-microorganisms and non-bioweapons-agents-pathogens research (where funding is tight and competitive) into less promising bioweapons-agents research (where funding is loose and easy).

  29. NIH management-consequences Biodefense research: NIH management consequences • massive inflow of funding, institutions, and investigators into work on category-A bacterial bioweapons agents--i.e., the agents that cause anthrax, plague, and tularemia • 1400% increase in number of grant awards • (from 32 in 1996-2000 to 465 in 2001-Jan 2005) • massive outflow of funding, institutions, and investigators from work on non-bioweapons-agents basic bacteriology • 41% decrease in number of grant awards for laboratory research on • model microorganisms (Microbial Physiology and Genetics 1 and 2) • (from 490 in 1996-2000 to 289 in 2001-Jan 2005) • 27% decrease in number of grant awards for laboratory research on • non-bioweapons-agents pathogenic microorganisms • (Bacteriology and Mycology 1 and 2) • (from 627 in 1996-2000 to 457 in 2001-Jan 2005)

  30. NIH management-negative impacts Biodefense research: NIH management negative impacts • negative impacts on biodefense • ineffective (minimal biodefense bang for biodefense buck) • funding of subpar research • failure to exploit existing strengths • erosion of existing strengths • counterproductive • 20-fold increase in number of institutions with bioweapons agents • 20-fold increase in number of individuals with bioweapons agents • 20-fold increase in safety, security, and dual-use concerns • negative impacts on public health • negative impacts on science

  31. NIH management-requests for corrective action Biodefense research: NIH management requests for corrective action • In February 2005, a letter requesting corrective action was submitted to the NIH Director by 758 researchers who have served on, or received grants reviewed by, the NIH Microbial Physiology and Genetics and NIH Bacteriology and Mycology Initial Review Groups. • Signers included nearly two-thirds of researchers who have served on, or received grants reviewed by, the NIH Microbial Physiology and Genetics and NIH Bacteriology and Mycology Initial Review Groups in 1996-2005. • Signers included the president-elect and seven past presidents of the American Society for Microbiology. • In March 2005, a letter requesting corrective action was submitted to the NIH Director by 76 intramural-NIH bacteriology researchers. Signers included nearly nine-tenths of intramural-NIH bacteriology researchers.

  32. NIH management-required corrective action Biodefense research: NIH management required corrective action • Re-assign authority for NIH biodefense from NIAID to inter-Institute office. • Broaden NIH-Institute participation in biodefense research. • Broaden NIH definition of biodefense research. • Consolidate all bioweapons-agents review panels with • non-bioweapons-agents review panels. • Seek, and accept, input from scientific community.

  33. NIH management-NIAID statements-prioritization 1 Biodefense research: NIH management NIAID statements "There is a dearth of investigators involved in research on some of the most important pathogens that could potentially be used in a bioterrorist attack. For example, relatively few bench scientists in the country are currently working on the bacterium that causes tularemia, Francisella tularensis, one of the six Class A agents.  There are several reasons behind the shortage of biodefense research personnel. First, substantial research funding targeted to these pathogens became available only in the past 5 years. Relatively little attention was paid to these uncommon infections until the mid-1990s, when officials became concerned about the possible dispersal of biological agents from the former Soviet Union weapons program. Prior to that, greater funding urgency was deservedly assigned to widespread emerging infections, such as HIV/AIDS, tuberculosis, and malaria. The number of Americans living with HIV/AIDS is approaching 1 million; the number reported to be infected with plague in 1999 was only 9."[Tara Palmore, Greg Folkers, Carole Heilman, John La Montagne, and Anthony S. Fauci, The NIAID Research Agenda on Biodefense, ASM News, August 2002 (http://www.niaid.nih.gov/director/pdf/biod_agenda.pdf)]

  34. NIH management-NIAID statements-prioritization 2 Biodefense research: NIH management NIAID statements "This funding is the largest single increase of any disease of any institute in the history of the NIH, and that includes the war on cancer. It includes all of the acceleration with HIV/AIDS. That is really really quite impressive, and it's going to be sustained, I can assure you." [Anthony S. Fauci, AEI Newsletter, August 2002 (http://www.aei.org/news/newsID.15154/news_detail.asp)]  "Investigators should not hesitate to put in applications for grants or respond to RFPs and contracts....You'd be making a big mistake because you may miss a grant or contract cycle if you do that....This will be the largest single increase of any discipline, in any institute, for any disease in the history of NIH." [Anthony S. Fauci, The Scientist, December 5, 2002 (http://www.biomedcentral.com/news/20021205/04/)]

  35. NIH management-NIAID response 1a Biodefense research: NIH management requests for corrective action, NIAID response NIAID has asserted that non-bioweapons-agents microbial research has remained "rock-solid." • There has been a 40% reduction in number of competing awards, and a 40% reduction in inflation-adjusted dollar volume of competing awards, for NIH extramural laboratory research in non-bioweapons-agents microbial physiology, genetics, and pathogenesis.  • The crash in number and inflation-adjusted dollar volume of awards occurred in a single one-year interval: between FY2002 and FY2003 (i.e., in the same one-year interval corresponding to the prioritization of bioweapons-agents research). • There has been no, zero, recovery from the crash.

  36. NIH management-NIAID response 1b Biodefense research: NIH management requests for corrective action, NIAID response • NIH Microbial Physiology and Genetics 1 and 2 and NIH Bacteriology and Mycology 1 and 2 study sections (new or competing awards, inflation-adjusted first-year costs): • before prioritization of bioweapons-agent research:FY1999: 216 awards, $64.3 MFY2000: 221 awards, $68.5 MFY2001: 226 awards, $66.5 MFY2002: 222 awards, $66.7 M • after prioritization of bioweapons-agent research:FY 2003: 138 awards, $40.2 MFY 2004: 116 awards, $38.1 M

  37. NIH management-NIAID response 2 Biodefense research: NIH management requests for corrective action, NIAID response NIAID has asserted that "support for basic bacterial physiology research has increased substantially." • NIAID includes as "basic bacterial physiology research" not only non-bioweapons-agents laboratory research, but also bioweapons-agents laboratory research, epidemiological research, psychosocial research, and other research. [awards under biodefense special emphasis panels, and awards under Epidemiology and Disease Control, Epidemiology of Chronic Diseases, Epidemiology of Clinical Disorders and Aging, Behavioral and Social Consequences of HIV/AIDS, Psychosocial Risk and Disease Prevention, Alcohol and Toxicology, Neurotoxicology and Alcohol, Synapses Cytoskeleton and Trafficking, Human Embryology, Tropical Medicine and Parasitology, Experimental Virology, and Virology study sections] • NIAID omits all non-NIAID research.

  38. NIH management-NIAID response 3 Biodefense research: NIH management requests for corrective action, NIAID response • The president-elect of the American Society for Microbiology has described the NIAID response as a "stubborn reiteration of past statements."  A former president of the American Society for Microbiology has described the NIAID response as "circle-the-wagons" and noted that he was "not persuaded by the argument."  Another former president of the American Society for Microbiology has described the NIAID response as "duplicity."  Other scientists have described the NIAID response as "stonewalling," "damage control," and "sleazy." • The intramural-NIH open letter was circulated after the NIAID response, and signed by 70+ intramural-NIH scientists after the NIAID response. Scientists have not found the NIAID response persuasive.

  39. NIH management-NIAID response 4 Biodefense research: NIH management requests for corrective action, NIAID response • The facts are clear to scientists who have served on study sections in the discipline, submitted proposals to study sections in the discipline, or attended scientific meetings in the discipline.  • The facts are clear to scientists who have examined the award and cost numbers in NIH databases. To scientists, any response that denies those facts must be considered uninformed or untruthful.

  40. NIH management-NIAID response 5a Biodefense research: NIH management requests for corrective action, NIAID response NIAID has asserted that the Microbial Physiology and Genetics 1 and 2 and Bacteriology and Mycology 1 and 2 study sections were responsible only for a small part of non-bioweapons-agents, basic bacterial research in the period under consideration. • The Microbial Physiology and Genetics 1 and 2 and Bacteriology and Mycology 1 and 2 study sections were the only study sections within the Infectious Diseases and Microbiology Integrated Review Group expressly related to laboratory research on bacterial physiology, genetics, and pathogenesis in the period under consideration. • The Microbial Physiology and Genetics 1 and 2 and Bacteriology and Mycology 1 and 2 study sections were the only study sections, barring special circumstances, to which proposals with primary focus on laboratory research on bacterial physiology, genetics, and pathogenesis were referred by the NIH Center for Scientific Review-Office of Referral and Review).

  41. NIH management-NIAID response 5b Biodefense research: NIH management requests for corrective action, NIAID response bb

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