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2 The Evolving Regulatory Environment for Life Sciences Research in the 2lSt Century INTRODUCTION The regulatory environment for the life sciences has been developed over the course of five decades. Responsibility for regulation in the United States of various aspects of biotechnology research in the life sciences is shared among a number of federal agencies, ranging from the Department of Agriculture (USDA) and the Environmental Protection Agency (EPA) to the Nuclear Regulatory Commission (NRC). The Na- tional Institutes of Health (NIH), for example, sets standards and proce- dures for the research it funds on recombinant DNA (rDNA). Research on human gene therapy is a special case, with both NIH and the Food and Drug Administration (FDA) conducting reviews prior to the initiation of research. While review is mandatory for NIH-funded research, industry often seeks review voluntarily. The Centers for Disease Control and Pre- vention (CDC) sets standards for the handling and transport of some es- pecially dangerous biological pathogens. The NRC has responsibility for regulations to control the receipt, possession, use, transfer, and disposal of radioactive materials by research institutions. The USDA has broad re- sponsibility for biotechnology research related to plants and animals. In- dustries involved in biotechnology research generally have internal pro- cedures to review potential research protocols, although these vary considerably within and between industrial and commercial facilities. Im- portant aspects of their work such as clinical or field trials are also subject to regulation by federal agencies, in particular the FDA and the EPA. Uni- versities have various methods for reviewing and approving potentially 41

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42 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM contentious research. Professional societies address questions of ethics and norms for research. Until the mid-199Os the regulatory environment focused on protect- ing the public health and general environment from biological hazards associated with possible exposures to human pathogens via interstate transport, recombinant organisms, and containment of recombinants and their products so that inadvertent or deliberate releases of these materials to the environment would be within acceptable limits. The regulatory en- vironment for microbial hazards also encompasses the importation of non- native plant and animal pathogens. Following the historic Asilomar Conference in 1975, the NIH, in 1976 published the Guidelines for Research Involving rDNA Molecules (here- inafter referred to as the NIH Guidelines or the Guidelines). The NIH Guidelines described four levels of combinations of laboratory practices, containment equipment, and facility safeguards that were thought to be appropriate for the safe use and physical containment of rDNA molecules in research. The four levels, PI to P4, provide increasing levels of physical protection against personnel contact with or accidental release to the en- vironment of genetically engineered microorganisms. The CDC and the NIH encouraged the life sciences community to participate in a collaborative initiative to develop consensus guidelines to safeguard worker safety and public health from hazards associated with the possession and use of human pathogens in microbiological and bio- medical laboratories. This initiative resulted in the publication by CDC and NIH in 1984 of Biosafety in Microbiological and Biomedical Labora- tories (hereinafter referred to as the BMBL).2 These consensus guidelines also established four ascending levels of physical containment using the terminology Biosafety Level 1-4. The combinations of standard and spe- cial microbiological practices, safety equipment, and facilities for each level are similar to those of the NIH Guidelines. Specific recommenda- tions for appropriate practices, equipment, and facility safeguards are given in the BMBL for pathogens that meet one or more of three criteria: the pathogen is a proven hazard to laboratory personnel working with infectious materials; the potential for laboratory-acquired infection is high even in the absence of previously documented laboratory-associated in- fections; or the consequences of infection are grave. The recommenda- tions are advisory and are intended to provide a voluntary guide or code of practice for investigators who possess and use human pathogens in their research activities. The Recombinant DNA Advisory Committee (RAC) and the BMBL process have been highly successful. Laboratory-acquired infections from exposure to biological agents known to cause disease are infrequent. There are no reports that the possession and use of biological agents and toxins

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THE EVOLVING REGULATORY ENVIRONMENT FOR LIFE SCIENCES 43 for research, education, and other legitimate purposes endangers the pub- lic health. The fourth edition of the BMBL states: "Experience has demon- strated the prudence of the Biosafety Level 1-4 practices, procedures, and facilities described for manipulations of etiologic agents and laboratories settings and animal facilities. Although no national reporting system ex- ists for reporting laboratory-associated infections, anecdotal information suggests that strict adherence to these guidelines does contribute to a healthier and safe work environment for laboratorians, their coworkers, and the surrounding community."3 This experience indicates that com- pliance with voluntary guidelines can achieve safety in research and clini- cal laboratories and protect the public health without significantly restrict- ing the pursuit of science. Spurred by rising concerns about bioterrorism, we are now witness- ing a transition from an environment based upon voluntary compliance with recommended practices to a greater number of statutes and regula- tions, particularly for control of biological materials and personnel. It took the United States three years to ratify the 1972 Biological Weapons Con- vention (BWC) and 17 years for the United States Congress to pass legisla- tion making the provisions of the BWC binding on all Americans.4 Not much changed until 1996 when, with the passage of the Antiterrorism and Effective Death Penalty Act, new regulatory controls were enacted swiftly regarding transfers of dangerous pathogens.5 Less than a year fol- lowing the terrorist attacks on September 11, 2001 and subsequent an- thrax mailings, two major pieces of legislation were passed by Congress and signed into law "The Uniting and Strengthening America by Pro- viding Appropriate Tools Required to Intercept and Obstruct Terrorism of October 2001"6 (hereinafter, the PATRIOT Act), and "The Public Health Security and Bioterrorism Preparedness and Response Act" of tune 20027 (hereinafter, the Bioterrorism Response Act). The PATRIOT Act makes it illegal in the United States for anyone to possess any biological agent, including any genetically engineered organ- ism created by using rDNA technology, for any inappropriate reason. The Act also prohibits the transfer or possession of a listed biological agent or toxin by a "restricted person."8 A "restricted person" is not permitted to ship or transport via interstate or foreign commerce, or possess, or receive any biological agent or toxin that has been shipped or transported in in- terstate or foreign commerce, if the biological agent or toxin is listed as a select agent.9 The Bioterrorism Response Act added new requirements for the sec- retaries of the Departments of Agriculture and Health and Human Ser- vices to consider in listing agents and in preventing unlawful access to agents during transfers.~ The statute also establishes new requirements for registration with the appropriate secretary concerning possession and

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44 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM use of listed agents and toxins, including "information regarding the char- acterization of listed agents and toxins to facilitate their identification, in- cluding their source; and safeguard and security requirements for regis- tered persons." The law also requires the secretary to establish rules that provide appropriate physical security requirements for listed agents and for the Department of Justice through the Federal Bureau of Investiga- tion (FBI) to conduct background investigations on individuals who are permitted access to select agents or who work in a facility where select agents are stored. The security provisions in the Bioterrorism Response Act are radically transforming the life sciences research environment in the United States from one that is basically open to one that excludes, based upon criteria stipulated in the PATRIOT Act, certain individuals from access to and research on certain listed agents. The FBI provisions, which went into force without public notice and comment rulemaking, prescribe the collection of pertinent background information on individu- als; who may access, use, receive or transfer select agents, and the release and disclosure of that information to other entities as described in Section IV in the FBI Information Form (FD-961~.~ These provisions have raised concerns that qualified individuals may be discouraged from conducting biomedical and agricultural research of value to the United States because of the apparent infringement of these rules on individual liberties under the Fourth Amendment. The next section of this report expands on the brief descriptions above to give a more complete picture of the current system of regulations and voluntary practices that govern research in biotechnology. It adds discus- sion of the growing web of controls over foreign nationals seeking to work, study, or participate in scientific activities in the United States and of the various codes of professional conduct that are a fundamental part of the self-governance of scientific practice. As noted at the beginning of this chapter, at present this system is focused on occupational safety and health and on environmental protection, but increasingly, additional ef- forts are being made to control access to biological materials that might be used by terrorists. With the exception of research involving human sub- jects, the system is not intended to provide oversight of research in the sense of making decisions about whether particular projects or experi- ments are appropriate. THE U.S. REGULATORY ENVIRONMENT Oversight of Genetic Engineering Research Chapter 1 mentioned the response of the life sciences community in the mid-1970s to concerns about the potential unknown risks inherent in

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THE EVOLVING REGULATORY ENVIRONMENT FOR LIFE SCIENCES 45 research involving the new field of genetic engineering. The Asilomar pro- cess led to the NIH assuming responsibility for promoting safe conduct of such experiments and to the subsequent publication of the NIH Guide- lines. The Guidelines are designed to address the risks to public health and the environment associated with exposure to either rDNA molecules or organisms or viruses containing such materials. The NIH Guidelines are applicable to all rDNA research within or outside the United States or its territories where the research is conducted at an institution that re- ceives any support for the research from the NIH, including research per- formed directly by NIH. Institutions that are recipients of NIH support for rDNA research must establish an Institutional Biosafety Committee (IBC) as part of their compliance with the NIH Guidelines. Further, as part of documenting that they have established a properly constituted IBC, institutions must register the IBC with the NIH Office of Biotechnology Activities (OBA).~3 IBCs are the cornerstone of institutional oversight of rDNA research. An IBC is a review body appointed by an institution to review and approve potentially biohazardous lines of research relating primarily to rDNA research. IBCs were originally established to provide local, institu- tional oversight of nearly all forms of research utilizing rDNA. On behalf of the institution, IBCs review rDNA research projects for compliance with the NIH Guidelines. Over time, the role of the IBCs at many institutions has been expanded to include review and oversight of a variety of experi- mentation that involves biological materials (e.g., infectious agents) and other potentially hazardous agents (e.g., carcinogens). While an IBC must consist of at least five members there is no upper limit on the number of members. Every IBC is required to have two mem- bers not affiliated with the institution who represent the interests of the surrounding community with respect to health and protection of the en- vironment. These may be officials of state or local public health or envi- ronmental protection agencies, members of other local governmental bod- ies, or persons active in medical, occupational health, or environmental concerns in the community. It is also recommended that IBCs include: experts in biosafety and containment; persons knowledgeable in institu- tional policies and applicable laws; individuals reflecting community atti- tudes; and at least one representative member from the laboratory staff. Committee members cannot review a project in which they have been, or expect to be, involved or have a direct financial interest. Finally, the Guide- lines provide that while opening IBC meetings to the public is suggested but not required, minutes of the meetings and submitted documents must be available to the public on request. Because the NIH Guidelines require establishment of an IBC when research is conducted at or sponsored by an entity receiving any NIH

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46 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM support for rDNA research, even privately funded projects employing rDNA must adhere to the NIH Guidelines if they are being carried out at, or funded by, an organization that has any NIH contracts, grants, or other support for this kind of research. Additionally, some communities and real estate leases require compliance with the NIH Guidelines, making such compliance legally binding even for private companies. Adherence to the NIH Guidelines is mandatory and important because they stipulate biosafety and containment measures for rDNA research. Furthermore, they delineate critical ethical principles and outline key safety reporting requirements for human gene transfer research. Most of the 400 or so IBCs registered with OBA are at institutions that are subject to the NIH Guidelines and for whom IBC registration is man- datory. While most of these institutions are academic, some industry- based IBCs are registered with NIH as a consequence of receiving NIH support for rDNA research (e.g., SBIR grants) and thereby becoming sub- ject to the NIH Guidelines. In other instances, companies voluntarily com- ply with the NIH Guidelines as a means of observing the highest stan- dards for safety practices; as part of that voluntary compliance, they register their IBCs with the NIH. Several federal agencies including the USDA and the Department of Veterans Affairs (VA) have made compli- ance with the NIH Guidelines a condition of their support of intramural and extramural research projects. Furthermore, a number of federal IBCs are registered with NIH, including those at the NIH, the Department of Energy (DOE) laboratories (including the Lawrence Livermore, Los Alamos, Oak Ridge, Sandia National Laboratories) and various VA medi- cal centers and military research institutes such as the Uniformed Services University of Health Sciences, the Walter Reed Army Medical Center, and the U.S. Army's Medical Research Institute for Infectious Diseases. Some of these facilities are registered with NIH because they receive NIH sup- port for their rDNA research and others because it is the policy of the department or agency to comply with the NIH Guidelines. The responsi- bility for the "enforcement" of the Guidelines is shared by the NIH Office of Biotechnology Activities, the Recombinant DNA Advisory Committee (RAC), IBCs at individual institutions, and by the principal investigators (PIs) themselves.~4 FRAMEWORK FOR IMPLEMENTATION OF THE NIH GUIDELINES FOR RDNA RESEARCH The Guidelines provide an administrative framework that specifies the roles and responsibilities of various federal officials, research insti- tutions, and individual scientists. Significant responsibility is shared among the NIH Office of Biotechnology Activities (OBA), the RAC, IBCs

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THE EVOLVING REGULATORY ENVIRONMENT FOR LIFE SCIENCES 47 at individual institutions, the principal investigator (PI), the Biological Safety Officer (BSO) at the institution, and by investigators themselves. Scientific advice on the technical aspects of risk assessment is provided by technical experts on the RAC; public input is provided by experts in nontechnical subjects and by the right of the public to comment on ma- . . Or actions. The system is based upon a tiered set of reviews that encourages ex- perimental design to be well thought out and provides a means for catch- ing potential problems. The Guidelines distinguish among experiments: those needing approval of the IBC as well as the RAC and NIH director before initiation; those involving human testing that need approval of the IBC and the Institutional Review Boards (IRBs) as well as the RAC; those that require approval of the OBA and IBC; those that only require IBC approval; those that merely require notice to the IBC at the initiation of the experiment; and exempt experiments.~5 The RAC is designated to consist of up to 21 voting members, includ- ~ng the chair. A majority of the voting members have to be knowledgeable in relevant scientific fields, such as molecular genetics, molecular biology, or rDNA research, including clinical gene transfer research. At least four members of the RAC have to be knowledgeable in fields such as public health, laboratory safety, occupational health, protection of human sub- jects of research, the environment, ethics, law, public attitudes, or related fields. Representatives of various federal agencies also serve as nonvoting members. Over time, the degree of centralized federal oversight has been substantially reduced. Many of the central functions of the RAC have been delegated to IBCs.~7 Each institution (and the IBC acting on its be- half) has become responsible for ensuring that all rDNA research con- ducted at or sponsored by that institution is conducted in compliance with the NIH Guidelines. The RAC is, however, still responsible for advising the NIH direc- tor on actions such as: (1) adopting changes in the NIH Guidelines; (2) assigning containment levels, changing containment levels, and ap- proving experiments considered "Major Actions" under the NIH Guidelines; (3) promulgating and amending lists of classes of rDNA molecules to be exempt from the Guidelines because they do not present a significant risk to health or the environment; and (4) certify- ing new host vector systems. The RAC is also responsible for: (1) identifying novel human gene transfer experiments deserving of public discussion; (2) transmitting to the NIH director specific comments/recommendations about human gene transfer experiments; (3) publicly reviewing human gene transfer clinical trial data and relevant information evaluated and summarized by the NIH OBA in accordance with the annual data reporting requirements; (4) iden-

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48 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM tifying broad scientific, safety, social, and ethical issues relevant to gene therapy research as potential Gene Therapy Policy Conference topics; (5) identifying novel social, ethical, scientific, and safety issues relevant to specific human applications of gene transfer and providing the necessary guidance. All institutions subject to the NIH Guidelines are required to estab- lish and register an IBC for the review of rDNA research. The IBC is de- signed to provide a quasi-independent review of rDNA work done at an institution. It is responsible for: (1) reviewing all rDNA research con- ducted at or sponsored by the institution and approving those projects in conformity with the Guidelines; (2) periodically reviewing ongoing projects; (3) adopting emergency plans for spills and contamination; (4) lowering containment levels for certain rDNA and recombinant organ- isms in which the absence of harmful sequences has been established; and (5) reporting significant problems, violations, illnesses, or accidents to the NIH OBA.~8 It is also the responsibility of the institution to appoint a Biological Safety Officer if it engages in large-scale research or production activities involving viable organisms containing rDNA molecules. If the institution engages in rDNA research at BL-3 or BL-4 (see below), the officer must be a member of the IBC. The officer's duties include: (1) conducting periodic inspections to ensure laboratory standards are rigorously followed; (2) reporting to the IBC and the institution any significant problems, viola- tions of the Guidelines, and any significant research-related accidents or illnesses; (3) developing emergency plans for handling accidental spills and personnel contamination and investigating laboratory accidents in- volving rDNA research; (4) providing advice on laboratory security; and (5) providing technical advice to the PI and the IBC on research safety procedures. Pre-initiation review of experiments by the RAC has been an impor- tant part of the oversight mechanism. Pre-initiation approval of experi- ments by NIH is required only for: (1) experiments that have not been assigned containment levels by the Guidelines; (2) experiments using new host-vector systems, which must be certified by NIH; (3) certain experi- ments requiring case-by-case approval; and (4) requests for exceptions from Guideline requirements. Prior to the initiation of these experiments the PI must submit a registration document to the IBC containing the fol- lowing information: the Bouncers) of DNA; the nature of the inserted DNA sequences; the hostess and vectors) to be used; whether an attempt will be made to obtain expression of a foreign gene, and if so, the protein that will be produced; and the containment conditions that will be implemented as specified in the NIH Guidelines. The initial RAC review process includes a determination as to

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THE EVOLVING REGULATORY ENVIRONMENT FOR LIFE SCIENCES 49 whether the human gene transfer experiment presents characteristics that warrant public RAC review and discussion. The NIH OBA will notify the PI(s) about the results of the RAC's initial review. Two out- comes are possible: (1) the experiment does not present characteristics that warrant further review and discussion and is therefore exempt from public RAC review and discussion; or (2) the experiment pre- sents characteristics that warrant public RAC review and discussion. Completion of the RAC review process is defined as: (1) receipt by the PI(s) of a letter from the NIH OBA indicating that the submission does not present characteristics that warrant public RAC review and dis- cussion; or (2) receipt by the PI(s) of a letter from the NIH OBA after public RAC review that summarizes the committee's key comments and recommendations (if any). TYPES OF EXPERIMENTS THAT REQUIRE IBC, RAC, AND NIH DIRECTOR REVIEW At this time, only two categories of experiments are considered "ma- jor actions" that require decision by the NIH director after review by the IBC and the RAC. One category includes experiments that propose the "deliberate transfer of a drug resistance trait to microorganisms that are not known to acquire the trait naturally if such acquisition could com- promise the use of the drug to control disease agents in humans, veteri- nary medicine, or agriculture." The second category includes experiments that propose the deliberate formation of rDNA-containing genes for the biosynthesis of toxin molecules lethal for vertebrates at an LD50 of less than 100 nanograms per kilogram of body weight (e.g., microbial toxins such as the botulinum toxins, tetanus toxin, diphtheria toxin, and Shigella dysenteriae neurotoxin). The containment conditions or stipulation require- ments for such experiments must be recommended by the RAC and set by NIH at the time of approval. PHYSICAL AND BIOLOGICAL CONTAINMENT STRATEGIES FOR NIH-FUNDED rDNA RESEARCH ACTIVITIES Regulated experiments must be carried out in accordance with physi- cal and biological containment levels; the degree of containment is based upon the degree of potential hazard. Physical containment requires prac- tices, equipment, and facility safeguards that lessen the chances that a recombinant organism might escape. As discussed above, the NIH first published safety guidelines in 1976, followed by the publication in 1984 of Biosafety in Microbiological and Biomedical Laboratories (BMBL).~9 The BMBL guidelines address laboratory safety procedures for working with and

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50 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM handling infectious disease agents they do not address laboratory secu- rity issues. The BMBL categorizes infectious agents and laboratory activi- ties into four classes or levels (BL-1 to BL-4) and establishes safety re- quirements for each level based upon risk. Factors considered in determining the level of containment include agent factors such as: virulence, pathogenicity, infectious dose, environmental stability, route of spread, communicability, operations, quantity, availability of vac- cine or treatment, and gene product effects such as toxicity, physiological activity, and allergenicity. 20 Table 2-1 summarizes the major require- ments for each of the BMBL biosafety levels. Experiments involving levels 2 through 4 and restricted risk group host organisms require IBC approval before recombinant experiments can be conducted. At the highest level (BL-4), nothing that is created should have any possibility of escape or of coming in direct contact with any laboratory workers. The containment conditions or stipulation require- ments for such experiments must be recommended by the RAC and set by NIH at the time of approval. Containment conditions for experiments involving the introduction of rDNA into restricted agents are set on a case-by-case basis following NIH OBA review. The recommended prac- tices, safety equipment, and facility safeguards in these guidelines estab- lish a code of practice that is complied with voluntarily, one that all mem- bers of a laboratory community can together embrace to safeguard their colleagues and to protect the public. A permit is also required for all facili- ties working with such agents, although clinical laboratories used for re- search, diagnostic, reference, and/or verification purposes need only be certified (but do not require a license. Some organisms, including smallpox (Variola major) may not be stud- ied in the United States except at specified facilities. Smallpox is an acute contagious disease caused by Variola virus, a member of the orthopox vi- rus family. It was one of the world's most feared diseases until it was eradicated by a collaborative global vaccination program led by the World Health Organization (WHO). The last known natural case was in Somalia in 1977. Smallpox was officially declared eradicated in 1980. All research activities, including storage of Variola major are restricted to two interna- tional collaborating centers for smallpox research. The WHO Collaborat- ing Center for Smallpox Research22 in the United States is located at the CDC in Atlanta, Georgia, the other is located at the VECTOR Laboratory in Koltsovo, Russia. Since their initial appearance, the physical biocontainment levels for rDNA experiments have been progressively lowered over time. As expe- rience provided confidence that rDNA technology could be applied with- out creating dangerous organisms that could not be contained, the prohi-

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THE EVOLVING REGULATORY ENVIRONMENT FOR LIFE SCIENCES TABLE 2-1 Summary of Recommended Biosafety Levels (BSL) for Infectious Agents 51 BSL Agents Practices Safety Equipment (Primary Barriers) Facilities (Secondary Barriers) 1 Not known to , . . cause alSeaSe In healthy adults 2 Associated with human disease, hazard = auto- inoculation, . , . Ingestion, mucous membrane exposure Indigenous or exotic agents with potential for aerosol trans- 1 - mlsslon; alsease may have serious or lethal consequences 4 Dangerous/exotic agents which pose high risk of life- threatening disease, aerosol- transmitted lab infections; or related agents with unknown risk of transmission Standard Microbiological Practices BSL-1 practice plus: - Limited access - Biohazard . . warmng signs - 'Sharps' precautions - Biosafety manual defining any needed waste decontamination or medical surveillance 1- - pollcles BSL-2 practice plus: -Controlled access - Decontamination of lab clothing before laundering -Baseline serum BSL-3 practices plus :-Clothing change before entering -Shower on exit -All material decontaminated on exit from facility None required Class I or II BSCs or other physical containment devices used for all manipulations of agents that cause splashes or aerosols of infectious materials; PPEs: laboratory coats; gloves; face protection as needed Class I or II BCSs or other physical containment devices used for all manipulations of agents; PPEs protective lab clothing; gloves; respiratory protection is needed All procedures conducted in Class III BSCs or Class I or II BSCs in combination with full-body, air-supplied, positive pressure personnel suit Open bench top sink required BSL-1 plus: Autoclave available BSL-2 plus: - Physical separation from access corridors - Self-closing, double door access -Exhausted air not recirculated - Negative airflow into laboratory BSL-3 plus: - Separate building or isolated zone - Dedicated supply/exhaust, vacuum, and decon systems - Other require- ments outlined in the text iFrom the CDC/NIH Biosafety Guidelines: Biosafety in Microbiological and Biomedical Laboratories.

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68 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM to the oversight of biotechnology.70 The BWC articulates a widely shared global norm against the weaponization of pathogens and establishes statutory but not regulatory obligations on parties to the Convention. Nor is there any international oversight organization for biology. Efforts to strengthen the BWC by adding provisions for verification and compliance foundered in 2001 on fundamental diplomatic differences of principle and in particular cost-benefit analyses as to the effectiveness of the measures being proposed and whether multilateral versus bilateral approaches were the best way to prevent the development of biological weapons. Multilateral discussions are continuing on ways to strengthen com- pliance with this treaty. At the BWC review conference in November 2002, member states agreed on a U.S. proposal to hold intercessional meetings in each of the next three years (2003-2005) before the 2006 Review Confer- ence to discuss the five voluntary measures put forward by the U.S. to strengthen the BWC.72 With regard to oversight of research, no country has developed guide- lines and practices to address all aspects of biotechnology research. There are a range of norms, standards of conduct for research, regulations, and institutional practices, many of which have been developed to address questions about research involving human subjects or the treatment of laboratory animals. In addition, responsibility for regulation of various aspects of biotechnology research is frequently shared among different departments or agencies. In the United States, the PATRIOT Act and the Bioterrorism Response Act already establish the statutory and regulatory basis for protecting bio- logical materials from inadvertent misuse. Once fully implemented, the mandated registration for possession of select agents, designation of re- stricted individuals who may not possess select agents, and a regulatory system for the physical security of the most dangerous pathogens within the United States will provide a useful accounting of domestic laborato- ries engaged in legitimate research and some reduction in the risk of pathogens acquired from designated facilities falling into the hands of terrorists. The Committee stresses that implementation of current legisla- tion must not be overly restrictive given the critical role that the develop- ment of effective vaccines, diagnostics, therapeutics, and detection sys- tems, along with a responsive public health system, will play in providing protection against bioterrorism and other serious health threats. Other- wise these legislative solutions may unintentionally limit the research on dangerous pathogens by legitimate laboratories and investigators. To be effective, a harmonized, international system for the regulatory oversight of the possession of dangerous pathogens and toxins, comparable to the one being put in place in the United States, is needed. Moreover, the different regulations now on the books do not add up

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THE EVOLVING REGULATORY ENVIRONMENT FOR LIFE SCIENCES 69 to a systematic, generally applicable, means for the United States to re- spond to the challenges posed by research in the life sciences employing advanced biotechnology methods. Nor do they address the issues sur- rounding how to "manage" the knowledge and technologies produced through these research activities. At the moment, "control" over the re- sults of these "dual use" research activities may be implemented at the point of information dissemination in the peer-reviewed literature.73 A critical question is whether the various regulations and laws can be adapted, enhanced, supplemented, and linked to provide a system of oversight that will give confidence that the potential risks of misuse of dual use research are being adequately addressed. The Committee's an- swer to that question is contained in the following chapters. ANNEX

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70 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM

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THE EVOLVING REGULATORY ENVIRONMENT FOR LIFE SCIENCES 71

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72 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM

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THE EVOLVING REGULATORY ENVIRONMENT FOR LIFE SCIENCES 73 NOTES iThe P1-4 terminology, used to represent the four ascending levels of physical containment, was subsequently changed to correspond with the Biosafety Level 1-4 terminology later adopted by CDC and NIH. 2 BMBL. 1984. HHS Publication No. (CDC) 86-8395; March. Also available from National Center for Injury Prevention and Control, Office of Health & Safety, Rich- mond, l.Y., et al. eds. 1999, "Biosafety in Microbiological and Biomedical Labora- tories," 4th ed. HHS Publication No. (CDC) 93-8395, May. 3 Richmond, l.Y. et al., eds. 1999. "Biosafety in Microbiological and Biomedical Laboratories," 4th edition, op. cit. p.5. 4 The Biological Weapons Anti-Terrorism Act of 1989; 18 USC sec. 175. 5 "The Antiterrorism and Effective Death Penalty Act of 1996," April 24, 42 U.S.C. 262 et seq. For a discussion of the events and considerations leading to this enact- ment, see Kellman, B. 2001. Biological Terrorism: Legal Measures for Preventing Catastrophe, Harvard Journal of Law and Public Policy 24:417. 6 U.S. Congress. "Uniting and Strengthening America by Providing Appropriate Tools Required to Intercept and Obstruct Terrorism (USA Patriot Act) Act of 2001," Public Law 107-56, October 26. Available at http://news.findlaw.com/hdocs/ does / doj / oig71 703patactrpt.pdf. 7 U.S. Congress. "Public Health Security and Bioterrorism Preparedness and Re- sponse Act of 2002." P.L. 107-188. 42 U.S.C. 243, June 12. Available at http:// tis.eh.doe.gov/biosafety/library/PL107-188.pdf.

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74 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM Sec. 817 of the Act concerns Expansion of the Biological Weapons Statute. A "restricted person" is defined as "anyone who: is under indictment for or has been convicted in any court of a crime punishable by imprisonment for a term exceed- ing one year; is a fugitive from justice; is an unlawful user of any controlled sub- stance; is an alien illegally or unlawfully in the United States; has been adjudi- cated as a mental defective or has been committed to any mental institution; is an alien who is a national of a country which is currently designated by the Secretary of State as a supporter of terrorism; or has been dishonorably discharged from U.S. armed forces." Currently there are seven countries on the State Department's List of State Sponsors of Terrorism: Cuba; Libya; Iran; Iraq; North Korea; Sudan; and Syria. 9Ibid. in In the loins Explanatory Statement of the Committee of Conference, the Manag- ers stated that the primary goals of the new provisions in the Law are to "ensure the prompt reporting to the Federal government of possession of select agents (including by those who were in possession prior to April 15, 1997, the effective date for reporting transfers of select agents), to increase the security over such agents (including access controls and screening of personnel), and to establish a comprehensive and detailed national database of the location and characteriza- tion of such agents and the identities of those in possession of them." ii See FBI Bioterrorism Preparedness Act: Entity/Individual Information Form at http: / /www.fbi.gov. /terrorinfo/fd-961.pdf. i2 For a discussion of the judiciary's role in overseeing protection of the public in this context, see Mack v. Califano, 447 F. Supp. 668 (D.D.C. 1978~. i3 More about IBCs and the registration process can be learned at the following website: http: / /www4.od.nih.gov/oba/IBC/IBCindexpg.htm. i4 The RAC was first established in 1974, two years before the NIH Guidelines. i5 Section III: Experiments Covered by the NIH Guidelines. i6 Section IV-C-2. i7 See Rosenblatt, D.P. 1982. "The Regulation of Recombinant DNA Research: The Alternative of Local Control." 10 British Columbia Environmental Affairs Law Review 37. i~ Section IV-B-2-b: Functions of IBCs. i9 The BMBL has issued instructions for laboratory directors to develop better methods of handling, storing, containing, and sterilizing infectious agents. 20 Section II-A-3: Comprehensive Risk Assessment. 2i See 42 U.S.C. s262 (a) 2000. 22 Section V-L. 23 Section IV-D-5-b: Pre-submission Review. 24 U.S. Congress. Antiterrorism and Effective Death Penalty Act of 1996, P.L. 104- 132, April 24, sec. 511. 25 42 CFR 73 for HHS; 7 CFR 331 and 9 CFR 121 for USDA. 26 In determining whether to list a biological agent, the Secretary of HHS, in con- sultation with scientific experts representing appropriate professional groups, was required to consider the agent's effect on human health, its degree of contagious- ness and methods by which the agent is transferred to humans, and the availabil- ity of immunizations and treatments for illnesses that may result from infection

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THE EVOLVING REGULATORY ENVIRONMENT FOR LIFE SCIENCES 75 by the agent. These regulations should include measures to ensure proper train- ing and appropriate skills to handle such agents; and proper laboratory facilities to contain and dispose of such agents and provide: safeguards to prevent access to listed biological agents for use in domestic or international terrorism or for any other criminal purpose; procedures to protect public safety if there is a transfer or potential transfer of a listed biological agent violation of the established safety procedures and safeguards; and for the appropriate availability of biological agents for research, education, and other legitimate purposes. 27 Neither the term "bona fide" nor "legitimate" is defined in the Act, however. 28 See fn.8. 29 Regulatory Control of Certain Biological Agents and Toxins, available at http: / /www.asmusa.org/pasrc/pllO7188.pdf. 30 The statute prohibits the knowing possession of any biological agent, toxin, or delivery system that is not reasonably justified for prophylactic, protective, bona fide research, or other peaceful purposes. In addition, the law makes it a criminal offense to allow restricted persons to possess, transport or receive select agents. U.S. Congress. Uniting and Strengthening America by Providing Appropriate Tools Required to Intercept and Obstruct Terrorism (USA Patriot Act) Act of 2001. P.L. 107-56, October 26, sec. 817. 3i The Uniting and Strengthening America by Providing Appropriate Tools Re- quired to Intercept and Obstruct Terrorism (USA PATRIOT Act) Act of 2001. P.L. 107-56. 32 Section III-D-l-d. 33 Section V-M. 34 42 biological agents and toxins are listed in Appendix A of 42 CFR Part 72. 35 The purpose of registration was to control domestic transfers based upon a permitting system. A registered laboratory could legally transfer select agents only to another registered laboratory; some transfers were denied because of concerns about the adequacy of the facility proposed to receive the agent. Transfers to non- registered laboratories were prohibited. Registration, however, was principally a matter of notification: a laboratory was obligated to notify relevant authorities of a transfer to another registered facility and that the transfer itself complied with applicable safety standards. Specific information about particular pathogens that the facility possessed did not have to be reported, not even if they were the sub- jects of extensive research, so long as they were not transferred. This was not intended to be a strict licensing system but merely a way of overseeing transfers and shipments of lethal pathogens. 36 42 U.S.C. 243 et seq. New considerations for listing agents include the availabil- ity and effectiveness of pharmacotherapies as well as immunizations to treat and prevent any illness resulting from infection by the agent or toxin, the needs of children and other vulnerable populations, and consultations with groups with pediatric expertise. The secretary must establish and enforce safeguard and secu- rity measures to prevent access to listed biological agents and toxins for use in domestic or international terrorism or any other criminal purpose. 37 The law further provides comparable regulatory authorities to the Secretary of the Department of Agriculture regarding the possession, use, or transfer of listed biologi- cal agents and toxins that present a severe threat to plant or animal health or animal or

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76 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM plant products and includes provisions to facilitate coordination and cooperation be- tween the Department of Agriculture and the Department of Health and Human Ser- vices with respect to agents or toxins that are regulated by both agencies. 38 The Bioterrorism Response Act also establishes a national database to collect registration information including the names and locations of registered facilities; the listed biological agents and toxins they possess, use or transfer; and character- ization and source data for listed agents they possess. The purpose of this data- base is to assist public health and law enforcement officials to identify the origin or source of a listed agent used to cause harm to the public. 39 Persons (facilities) and individuals who possess, use, or transfer listed biologi- cal and toxins agents must register with the Secretary, Department of Health and Human Services. Registered facilities that transfer a select agent to any person one knows or has reasonable cause to believe has not registered could be fined or imprisoned up to five years or both. Also, whoever knowingly possesses a select agent for which the person has not obtained a registration shall be fined or impris- oned for up to five years. 40 The Public Health, Security and Bioterrorism Preparedness Act, H.R.3448, 107th Cong 351A (e)~2~(A). Facilities should promptly submit the names of such indi- viduals to the Secretary of Health and Human Services and the Attorney General who shall promptly use criminal, immigration, national security, and other elec- tronic databases available to the federal government to check if the individual is a "restricted person." 4i In the loins Explanatory Statement of the Conference Committee's report, the Managers stated that the primary goals of the new provisions in the law are to "ensure the prompt reporting to the Federal government of possession of select agents (including by those who were in possession prior to April 15, 1997, the effective date for reporting transfers of select agents), to increase the security over such agents (including access controls and screening of personnel), and to estab- lish a comprehensive and detailed national database of the location and character- ization of such agents and the identities of those in possession of them." 42 The Public Health Service Act was first passed in 1944, with numerous subse- quent amendments to its provisions, including those governing the foreign quar- antine regulations. 43 A detailed account of the system in place as of early 2003, on which this section is based, may be found in White, W.D. and L. Peterson. 2003. "Visas for Visiting Stu- dents and Scientists: Current Situation January)," The Physiologist, April. Available at http: / /www.the-aps.org/publications/tphys/2003html/aprilO3/visas.htm. 44 In response to continuing concerns about the impact of the visa system on inter- national scientific collaboration and to the need to keep the scientific community informed about its responsibilities under the evolving system, The National Acad- emies created an International Visitors Office in the spring of 2003. Its website may be found at www.nationalacademies.org/visas. 45 Cited in White and Peterson, op. cit. 46 Further information on the Technology Alert List and the screening system may be found on the State Department website, available at http:// travel.state.gov/statel47566.html.

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THE EVOLVING REGULATORY ENVIRONMENT FOR LIFE SCIENCES 77 47 White and Peterson, op. cit. Available at http://www.the-aps.org/publications/ tphys /2003html / aprilO3 /visas.htm. 48 Unclassified State Department Cable 136100, May 21, 2003. 49 October 26, 2004 is the deadline for biometrics on visas and passports. 50 The State Department has designated seven countries as sponsors of terrorism: Iran, Iraq, Syria, Libya, Sudan, North Korea, and Cuba. An analysis of NSF data by Paula E. Stephan and her colleagues found that between 1990 and 1999 1,215 citizens from five of the seven countries received Ph.D.s from U.S. institutions (students from Cuba and North Korea were awarded fewer than five doctorates and were not included in the analysis). Of these, 147 were in fields that the authors considered "sensitive," including bacteriology, biochemistry, biotechnology re- search, microbiology, molecular biology, and neurosciences. Stephan, P.E., et al., "Survey of Foreign Recipients of U.S. Ph.D.s" Letter in Science 295 (5563~:2211- 2212. 51 Parsons, P.J.2001. "Ethics Codes: The Good, The Bad, and the Almost Ugly," PR Canada. Available at http://www.fastmpr.com/CODEST.HTM. 52 Online Ethics Center: Codes of Ethics and Conduct, Online Ethics Center for Engineering and Science at Case Western Reserve University. Available at www.onlineethics.org; wysiwyg: / /17/http: / /onlineethics.org/codes/. 53 Rotblat, 1.1999. "A Hippocratic Oath for Scientists," Editorial, Science 286 (5444~: 1475. See also commentary by Kent, S. 1999. "Misuse of Science is Simply Wrong and the Scientists Involved are Responsible," Science 286 (5447) and Buckmaster, H. 2000. "Hippocratic Oath for Scientists," Science, February 8, 2000; and Gozum, M. 2000. "Societal Responsibilities," Science February 11, 2000. 54 See S. Kent, op.cit. 55 Ibid. 56 U.S. Department of State. 2001. "New Ways to Strengthen the International Regime Against Biological Weapons," Fact Sheet, Bureau of Arms Control, Wash- ington, D.C., October 19, p. 5. 57 International Committee of the Red Cross. 2002. "Biotechnology, Weapons & Humanity: An Informal Meeting of Government and Independent Experts," Montreux, Switzerland, September 23-24. 58 Foreign and Commonwealth Office. 2002. "Strengthening the Biological and Toxin Weapons Convention Countering the Threat from Biological Weapons," April 29. Presented to Parliament by the Secretary of State for Foreign and Com- monwealth Affairs by Command of Her Majesty, April. Available at http:// www.bradford.ac.uk/acad/sbtwc/other/fcobw.pdf. 59 loins statement by the Presidents of the National Academy of Sciences and The Royal Society. "Scientist Support for Biological Weapons Controls," Science 298 (5596~:1135. 60 For a detailed discussion of this issue see Tucker, 1.2001. Scourge: The Once and Future Threat of Smallpox (New York: Atlantic Monthly Press). 6i Source: http://www.australiagroup.net/agbwc.htm. It should be noted, how- ever, that some developing countries view the Australia Group as discriminatory and claim that it unfairly impedes the economic development of those states tar- geted by harmonized export controls.

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78 BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM 62 E.U. Council Regulation, 3381/94/EED. On the Control of Export of Dual Use Goods (Official l.L. 367), p. 1. 63 IATA Dangerous Goods Regulation. 2004, 45th edition. IATA Packing Instruc- tion 602 (Class 6.2) (IATA). For guidelines for shipping of microorganisms, see www.gbf.de/dsmz/shipping/shipping/htm. 64 Smith, D., C. Rhode, and B. Holmes. The Safe Handling and Distribution of Micro- organisms under the Law, at http://www.ukncc.co.uk/html/Information/docs/ Postal.doc. 65 September 1957. European Agreement concerning the International Carriage of Dangerous Goods by Road (ADR). 66 The text of the Act is available at http://www.hmso.gov.uk/acts/acts2001/ 20010024.htm. 67 Health & Safety Executive In Action. Available at http://www.hse.gov.uk. 68 HSC Advisory Committee on Genetic Modification. Available at http:// www.hse.gov.uk/foi/openacgm.htm. 69 Human Genetics Advisory Commission Second Annual Report. 1999. Avail- able at http: / /www.doh.gov.uk/hgac/papers/papers_f/f_09.htm. 70 The CWC does include toxins, which provides a modest degree of international oversight for one portion of biology. 7i Under Article IV of the BWC "teJach State party to this convention shall...take any necessary measures to prohibit and prevent the development, production, stockpiling, acquisition or retention of the agents, toxins, weapons, equipment and means of delivery specified in Article I of the Convention, within the territory of such State, under its jurisdiction or under its control anywhere." 72"Decision of the Fifth Review Conference of the Parties to the Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriological (Biological) Weapons and on Their Destruction," BWC/CONF.V/17, Geneva, November 2002, pares. 18-20. The first intercessional experts group meeting held in Geneva, Switzerland (August 2003) addressed regulation of pathogens by states parties to the BWC. Enhanced disease surveillance systems will be discussed in 2004 and "codes of conduct" in 2005. 73 Journal Editors and Authors Group. 2003. "Statement on Scientific Publication and Security," Science 299 (5610~:1149.