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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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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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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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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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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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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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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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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.
Representative terms from entire chapter:
nih guidelines
