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By J. Michael French, MS, Seth Michelson, PhD, and Lisl K. M. Shoda, PhD
Biodefense:
A Systems Biology Approach to
Drug Discovery and Development
Figure 1. Anhrax-Laced Envelope Addressed to Senator Patrick Leahy (D-VT).
The United States’ biodefense program has been active for biodefense effort is focused on both bioterrorist attacks and
decades. The majority of the past effort has been dedicated to naturally occurring infectious outbreaks, this article will
the protection of troops on foreign soil. However, after the address challenges presented by weaponized infectious
events of 11 September 2001, the subsequent dissemination of agents (e.g., Anthrax) versus naturally occurring diseases
anthrax spores through the US postal system (see Figure 1) (e.g., Ebola) or purified toxins such at botulinum toxin.
and identification of numerous references to biowarfare (BW) Weaponized infectious agents in many ways present the
in Al Qaeda training manuals captured during Operation greatest threat to a biodefense program in that they can be
Enduring Freedom, the government’s biodefense efforts have engineered to increase their communicability, morbidity/
shifted substantially to protecting its citizens on US soil.1,2 mortality and resistance to therapy.
This reassessment and, in some cases, expansion of the
biodefense effort emphasizes and exacerbates differences and Drug Development for Biodefense
challenges between protecting soldiers on the battlefield and There are many elements of an integrated biodefense pro-
protecting people in their homes and offices. Although the US gram. Generally, they can be defined in three broad areas:
36 Regulatory Affairs Focus November 2003
detection, protection and treatment. otics. In such an instance, significant the evaluation of safety to the drug
Detection is focused on identifying time and money could be invested in without exposure to the noxious agent.
the potential threat. In the broadest developing a therapy only to find that On 30 May 2002, FDA amended its
sense, it is an effort across both intelli- the specific pathogen is resistant to that new drug and biological product regu-
gence and scientific communities to therapy or to some aspect of the pro- lations so that certain human drugs and
predetermine who has the capability to posed therapeutic regimen. biologics that are intended to reduce or
manufacture agents, what agents are Additionally, companies are reluctant prevent serious or life-threatening con-
being manufactured and how these to pursue many chronic diseases for ditions may be approved for marketing
agents will be deployed against soldiers fear they will not meet FDA’s stringent based on evidence of effectiveness
and civilians. In the narrowest sense, drug approval standards. The agency from appropriate animal studies when
detection refers to the equipment and often requires them to show that a new human efficacy studies are not ethical
assays used to identify specific agents drug will prevent or significantly delay or feasible.19 Industry executives say
that have been deployed against friend- worst-case scenarios such as organ fail- this change will help those pursuing
ly forces. ure and death. That can require years of countermeasures to toxins to plan the
Protection is related not only to the studies with thousands of patients. This further development of agents.
protective nature of equipment and leads to another key challenge to devel- What would be equally helpful is a
clothing, but also to those prophylactic oping therapies against BW pathogens: flexible technology that will predict
drugs and vaccines provided pre- and human clinical testing. In conventional human immune response to a variety of
post-exposure in the hopes of prevent- pharmaceutical drug development, a pathogens. This technology should be a
ing disease. significant portion of the $800 million single, cohesive framework; a “whole-
Finally, treatment refers to the is expended in clinical development system” of human immunology capable
numerous therapies and therapeutic because of high failure rates (e.g., of dynamically representing the relevant
regimens provided to those exposed to ~53% of compounds fail during Phase regulatory mechanisms governing
a BW agent in the hopes of reducing II). These failures are often attributed to immune response. Additionally, the
person-to-person infection as well as unanticipated system-wide effects due researcher must be able to pose multiple
reducing morbidity or mortality in the to the complexities that underlie human hypotheses of pathogen effect, potential
exposed individual. physiology. For example, redundancies, therapeutic interventions and the subse-
compensation mechanisms and multi- quent immune response to those
The Regulatory Challenges of ple timescales can all contribute to pathogens and therapies.
Developing Drugs to Deal with unanticipated clinical effects. Another challenge is that the market
Bioterrorism Not only is the development of thera- for therapies to combat bioterrorism is
There are multiple aspects of detec- pies to BW pathogen faced with the tentative because there is no guarantee
tion, protection and treatment that pres- same challenges as traditional drug that vaccines or therapies will ever be
ent scientific and technical obstacles to development, but also there is no ready required. Because of this, many within
the development of an integrated pool of patients upon whom the therapy the pharmaceutical industry have called
biodefense program, none more so than can be tested for efficacy. The tradition- on the government to provide immedi-
the challenge of rapidly developing al drug development model assumes the ate and aggressive support to hasten the
vaccines and therapies for the prophy- existence of an adequate patient popula- development time, as well as long-term
laxis and treatment of exposure to BW tion. Healthy individuals cannot be contracts to help maintain product
pathogens. exposed to lethal pathogens for the sole development.
To successfully deliver a drug to purpose of observing how they will Executives from biotech compa-
market, the pharmaceutical industry respond to experimental drugs. nies—which are developing vaccines,
requires an average of 14 years and In 1999, the Food and Drug antidotes and other therapeutics against
$802 million, and these figures contin- Administration issued proposed regula- anthrax, smallpox and other biowarfare
ue to rise.3,4 In developing drugs for tions on efficacy data for products to agents—have called for federal protec-
biodefense, this effort is further compli- prevent toxicity that would allow the tions from liability, particularly when it
cated by the fact that the pathogen may data showing that the agent is effective comes to vaccines that are likely to
be an elusive target. The BW agent against a certain biological, chemical, have side effects.20
might be known, as was the case with radiological or nuclear substance to be As part of the Homeland Security
anthrax; but the pathogen may have demonstrated through animal data only. Act of 2002, Public Law 107-296,
been altered to be resistant to antibi- The only human testing would involve Congress enacted several liability pro-
November 2003 Regulatory Affairs Focus 37
Biodefense: A Systems Biology Approach to Drug Discovery and Development
tections for the providers of anti-terror- clinical outcome. Although many defi- to take 14 years to develop a vaccine or
ism technologies. Bioterrorism legisla- nitions and thoughts have been associat- get a drug to patients. The need for an
tion working its way through Congress ed with systems biology, the following, innovative, flexible and rapid means of
would give the Department of Health by Leroy Hood, founder of the Institute answering the question “Will this work?”
and Human Services the authority to for Systems Biology, captures the key is paramount for a successful biodefense
guarantee vaccine purchases from points: hypothesis-driven; uses global research and development effort.
biotech and pharmaceutical manufac- analysis; is quantitative; is integrative; is There are several companies develop-
turers through long-term contracts, iterative; and examines the dynamics of ing technologies and platforms to sup-
regardless of whether the products are life rather than looking at an organism port a “systems biology” approach to
used or not. The legislation also pro- in a static state (i.e., at one time point).5 drug discovery and development.
vides limited antitrust exemptions to Hood’s points, however, are but one Among them, Entelos, Inc., Foster City,
allow potential sponsors to agree on the part of an equation for success. They CA, has taken a purely in silico
development, manufacture and produc- are one side of the “equal” sign: approach and has developed large-scale,
tion of vaccines and drugs. hypothesis-driven + global analysis + mathematical models of human patho-
Nevertheless, it does not expand on the quantitative + integrative + etc. They physiology which predict human clini-
liability protection. describe an approach, a summation of cal outcome. Entelos scientists currently
In the last two years, FDA has issued factors that lead to a correct answer. use these technologies to support several
proposals to streamline drug testing What is critical to a researcher is pharmaceutical companies’ research and
and approval, provide greater federal what is on the other side of the equa- development programs.6
support for pharmaceutical and biotech tion; what is the answer? What does
research, lift antitrust restrictions and this approach lead? From a pharmaceu- Predictive Biosimulation
extend liability protection for vaccines tical-centric point of view, the other In silico modeling is an approach that
and therapeutics. These initiatives can side of the equation is a very specific integrates relevant and sometimes
be found online at the agency’s Drug deliverable related to drug discovery disparate biological data—genomic,
Preparedness and Response to and development: a validated target, an proteomic and physiological—into a
Bioterrorism Web site, www.fda.gov assay, a screen, an optimized lead or a computer-based platform to reproduce a
/cder/drugprepare/default.htm. biomarker. system’s control principles.7 Given a set
But from a broader perspective, per- of initial physiological conditions repre-
Systems Biology and Biodefense haps in the context of the practice of senting a normal or defined disease
Many fields of science are emerging medicine, the other side of the equation state, mathematical models can predict
within the pharmaceutical industry to is simply “Does whatever I’m going to through simulation a system’s biological
decipher the tremendous amount of prescribe to the individual (vaccine or behavior, a process termed biosimula-
data being generated from the human therapy) prevent that person from get- tion.8 Predictive biosimulation provides
genome. The industry is trying to ting sick, or will it make a person who a human in vivo context, which allows
understand human pathophysiology is already sick better?” And this, given pharmaceutical re-searchers to conduct
and the onset and progression of dis- the challenges facing the development effective research in a data-rich environ-
ease by investigating the building of vaccines and therapeutics against ment by helping them predict clinical
blocks upon which humans are built. weaponized infectious agents, is the responses to novel therapeutics.
These fields predominately include crux of biodefense research. One strategy for building such models
the “omics:” functional genomics, Although there are many efforts is “top-down,” behavior-driven model-
functional proteomics, metabolomics underway to increase pharmaceutical ing. This approach begins by defining a
and pharmacogenomics. One of these productivity, the industry is constant in general set of behaviors (human in vivo
fields, however, is not based on a spe- their process: identify novel targets; responses) indicative of the normal or
cific “omics” (or a related data-driven validate target against known biology; diseased state, normal physiology, or
method), but rather a broad approach to develop high-throughput screen for disease pathophysiology.9 Then, while
integrating and understanding these lead identification; optimize leads; per- ensuring that the model is constrained
data in the context of a whole-system form preclinical tests in animals; test by these behaviors, a set of integrated
human. That field is systems biology. for toxicity; first into man; and finally, physiological subsystems is developed
Systems biology provides the broad human clinical trials.6 whose relationships and interconnectivi-
“systems” approach to understanding The efforts to develop vaccines and ty are defined by the behaviors initially
the entire human system from gene to treatments for biodefense cannot afford identified.
38 Regulatory Affairs Focus November 2003
Each physiological subsystem is then tem’s complexity and identify causal aerosolized form. When a person
modeled using an iterative process of factors that will lead to efficacious thera- inhales B anthracis spores, the spores
biological mapping, calibration and val- pies and vaccines. are thought to be deposited in the alve-
idation. Many disparate pieces of data By providing this rational human in oli of the lung.12 Macrophages and pos-
are used to “map” the biology of a vivo context to the pharmaceutical sibly dendritic cells ingest the 1 µm
given subsystem. These data may be in researcher, biosimulation is improving diameter spores and either lyse them or
vivo, in vitro or ex vivo human and ani- R&D decision-making throughout the transport them to the draining lymph
mal data. These data are presented in discovery and development pipe- nodes. Germination is thought to occur
the model as discrete biological entities lines.10,11 For example, optimal binding, in the lymph nodes, resulting in repli-
and are connected in a mechanistic (i.e., pharmacokinetic, and mechanism- of- cating bacilli. Because macrophages
knee bone connected to the shinbone) action profiles can be derived for devel- and dendritic cells have been shown to
manner to represent human biology. oping and optimizing compounds and be impaired by anthrax toxins, a con-
Calibration within these subsystems biologics against BW pathogens. siderable amount of attention has been
is done by creating mathematical equa- Simultaneously, biomarkers can be iden- placed on these cells as critical to the
tions that characterize the relationship tified that would characterize patient pathophysiology.14 However, recent
between two or more biological enti- exposure to those pathogens. Further, work has suggested that mortality
ties. These equations are developed certain biomarkers might be used to pre- might be due to hypoxiainduced injury
upon data derived from human in vivo, dict responders and non-responders to that is macrophageindependent.15
in vitro and ex vivo experiments proposed therapies. Finally, by using Currently, antibiotics are the primary
designed to isolate the specific biologi- predictive biosimulation to simulate a treatment for anthrax exposure. Due to
cal processes of interest. These calibrat- clinical trial, researchers will be able to concerns over antibiotic resistance in
ed subsystems are integrated into a investigate the optimal therapeutic regi- weaponized strains, the Centers for
whole system representation of human men for humans including dosing and Disease Control and Prevention (CDC)
physiology and then validated against a dose regimen, leading to the more rapid has offered guidelines recommending
broad set human in vivo clinical data development of efficacious therapeutics the use of two or three antibiotics in
(i.e., the behavior of the system). than could be achieved with the current combination when treating patients.16
An iterative process occurs between technologies and animal models In the prevention arena, there is one
calibration and validation, but at no approved vaccine and there are three
point is validation data used for calibra- Biosimulation of the Human vaccines under development. The
tion or vice versa. This eliminates the Immune System Against BW approved vaccine, an Anthrax absorbed
possibility of creating a circular Pathogens vaccine (AVA), is produced by Bioport
model—one built to match the data that Anthrax is a disease caused by Corporation in Lansing, MI. Of the
it used to build the model. The value of Bacillus anthracis and may occur as an three under development, one is rPA102,
this modeling technology is that it per- inhalation, cutaneous or gastrointestinal originally developed at the US Army
mits researchers to pose and rapidly disease, corresponding with the route of Medical Research Institute of Infectious
develop hypothesis-driven, “what if” exposure. Inhalation anthrax is thought Diseases and licensed to VaxGen, Inc. in
scenarios. These scenarios identify to pose the most significant threat as a Brisbane, CA. The second is a recombi-
inconsistencies and knowledge gaps biological weapon, for reasons of dis- nant vaccine being developed by
within commonly accepted, but yet semination, infection rate and mortality Panacea Biotech in New Delhi, India.
unproven, hypotheses. Once these gaps rate.12 Inhalation anthrax results from the The third was recently announced by
and inconsistencies are identified, in inhalation of B anthracis spores, and Wang, Harvard Medical School in
vivo and in vitro experiments can be infection might result from inhalation of Cambridge, MA.17
more appropriately focused such that as few as one to three spores.13 B Safety of the AVA vaccine has been
their design yields the appropriate data anthracis spores may be disseminated extensively studied in man, but effica-
to fill the knowledge gap. by several methods. In 2001, B cy has been addressed predominately
By focusing model development and anthracis sporecontaining powder was in animal studies; one placebo-con-
data collection efforts on those subsys- mailed to several locations, resulting in trolled human trial has been conduct-
tems with the greatest impact on the key the infection of 22 people (11 inhalation; ed, where incidence of natural anthrax
aspects of a disease’s pathophysiology 11 cutaneous). infection was monitored in goat hair
and pathogenesis, predictive biosimula- B anthracis poses a potentially mill workers immunized with an AVA
tion can more clearly represent the sys- greater threat if released in an precursor.18
November 2003 Regulatory Affairs Focus 39
Biodefense: A Systems Biology Approach to Drug Discovery and Development
Figure 2. Specific Modeling Considerations* for an Figure 3. Specific Modeling Considerations* for a
Immune-Centric Model Pathogen Representation
• Pulmonary microenvironment, including cellular • Recognition and phagocytosis of spores by pulmonary
composition at sites of spore deposition macrophages/dendritic cells
• Mechanisms of uptake or infection • Intracellular spore localization
• Local inflammatory reaction, including local spore lysis • Trafficking to or escape from lysosomes
• Transport of spores to the draining lymph nodes • Normal cellular metabolism
• Spore germination and replication of bacilli • Bacterial requirements for germination
• Antigen presentation and T lymphocyte • Bacterial requirements for replication
expansion/retraction
*Not inclusive
• B cell response, including requirements for T cell help
• Dissemination of bacilli locally and/or systemically
*Not inclusive
So, the high-level summary of the developing a model of the human ment of systemically targeted
state of research surrounding the pre- immune system to support biodefense therapeutics versus development
vention and treatment of an anthrax research. First—and most important— of locally administered
BW agent is that: the model must be useful to scientists adjuvants);
• There is one vaccine approved for conducting biodefense research there- • Biological focus (i.e., human
use in man but whose efficacy has fore it must make measurable predic- immune representation (see
only been primarily demonstrated tions of human in vivo immune Figure 2) and pathogen represen-
in animals; response. Secondly, the technology tation (see Figure 3); and
• There are three vaccines under must be rigorously validated in that its • Validation strategy (i.e., what
development whose efficacy is physiological predictions must be rea- experiments/clinical trials should
likely to be shown only in sonable and consistent with known the model reproduce).
animals; data. Thirdly, the assumptions in the Once a model is created, its useful-
• CDC has recommended a model must be clearly articulated and ness is measured by the breadth of its
combination of multiple antibi- understood and the technology must applicability to the research problem or
otics be used in the treatment of permit the exploration of alternative issue. In the case of biodefense
anthrax exposure; and hypotheses to understand the conse- research against anthrax pathogens, we
• There are multiple hypotheses of quences of competing hypotheses. would look to the model to aid in the
the biological processes that give Finally, customization and expansion of development of vaccines (see Figure
rise to mortality (i.e., toxic- the model are needed so that 4) and therapeutics (see Figure 5).
induced macrophage impairment researchers can incorporate new biolo- Modeling in this area has already
versus macrophage independent, gy, new data, and new hypotheses relat- begun, and the ability to build a com-
hypoxia-induced injury). ed to the pathogen, therapies, or under- prehensive predictive biosimulation
This is a complex, multi-faceted standing of human immune response. capability to support biodefense
research problem that requires a sys- Additional considerations in the research is nearby. For example,
tems biology approach. A more thor- development of a model of anthrax Entelos has already modeled HIV
ough and better understanding of B. challenge to the human immune sys- infection, population dynamics and
anthracis biology and host response tem might include: host T cell response; dynamics of an
(human immune response) is likely to • The intended uses of the model acute inflammatory response to an
be extremely helpful, if not essential, (i.e., therapeutics to treat primary immunological stimulus; macrophage
for the development of vaccines and anthrax exposure versus prophy- activation and contribution to an
therapeutics. lactic vaccine development); inflammatory state; dendritic cell
There are several requirements for • The site of activity (i.e., develop- dynamics and trafficking to draining
40 Regulatory Affairs Focus November 2003
Figure 4. Applications of Predictive Biosimulation in Figure 5. Applications of Predictive Biosimulation in
Biodefense Vaccine Development Biodefense Therapy Development
• Optimization of CD4+ T cell response • Identification of antimicrobial targets (e.g., inhibition of
germination/replication)
• Optimization of antibody production
• Prioritization/validation of antimicrobial targets
• Comparison of adjuvant efficacy
• Identification of immunomodulatory therapies
• Identification of new adjuvant target effects
• Exploration of patterns of bacterial dissemination, with
• Comparison of vaccination efficacy via two different implications for the clinical response
routes of administration
• Exploration of pathogenesis associated with genetically
• Identification of surrogates for the immune response and modified bacteria
vaccine efficacy
• Identification of antimicrobial targets
• Prioritization/validation of antimicrobial targets
• Identification of immunomodulatory targets
• Identification of rate-limiting steps or bottlenecks to
bacterial activity
lymph nodes; lymph node T cell into the whole system model. 5. M. Moser Jones, “GSAC Sashays into
dynamics and endothelial cell life cycle. Finally, the platform provides a Savannah, Starts with Systems Biology,”
dynamic representation of human GenomeWeb, 22 September 2003.
Conclusions response portraying, through mathe- 6. A. Barrett, “Feeding the Pipeline: How
To address the significant challenges the Drug Giants Are Reinventing Their
matical relationships, the physiology in
Labs to Boost Productivity,” Business
facing the biodefense research commu- a time appropriate manner.
Week, 12 May 2003.
nity, a systems biology approach is By providing a human in vivo con- 7. R. Somogyi and L. D. Greller, “The
warranted. An in silico-based, predic- text of human immune response, in a Dynamics of Molecular Networks:
tive biosimulation technology creates predictive biosimulation platform, to Applications to Therapeutic Discovery,”
the necessary research environment to the biodefense community, researchers Drug Discovery Today 6 (2001):
capture the key tenets of a systems can significantly affect the efficiency of 1267–1277.
biology approach. The predictive their research efforts and expedite the 8. K. Hall, R. Baillie and S. Michelson,
biosimulation platform itself is hypoth- development of novel therapies and “Biosimulation: Dynamic Modeling of
esis driven through its top-down, vaccines against BW pathogens. Biological Systems,” Annual Reports in
behavior driven approach to capturing Medicinal Chemistry 37 (2002): 279–288.
and modeling human physiology. The 9. T. Paterson, “Applying Simulation
NOTES:
technology allows multi-disciplinary Technology to the Life Sciences,” Seventh
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1. D. B., Jernigan, P L. Raghunathan, B.P .
Annual Symposium on Frontiers of
teams to input their data, hypotheses Bell R. Brechner, E.A. Bresnitz, J.C.
Engineering (2002): 85–90.
and ideas, thus permitting that same Butler, et al., “Investigation of
10. C. J. Musante, A. Lewis and K. Hall,
team to analyze simulated data and Bioterrorism-related Anthrax, United
“Small- and Large-Scale Biosimulation
results and draw global conclusions as States, 2001: Epidemiologic Findings,”
Applied to Drug Discovery and
to what is occurring in the physiology. Emerging Infectious Diseases 8(10)
Development,” Drug Discovery Today
Predictive biosimulation is quantita- (October 2002): 1019–1028.
7(20) (2002): S192–S196.
2. Dominic Evans, “US Troops Found
tive; the relationships between biological 11. Thomas S. Paterson and Alex L.
Afghan Biological Lab,” Reuters, 22
entities are described mathematically Bangs, “Finding Value in In Silico Biology,”
March 2002.
and, therefore, generate measurable 3. J. A. Dimasi, “New Drug Development
March 2003, <www.entelos.com/news
results. Additionally, the process of cali- in the United States From 1963 to 1999,”
/pubArchive/BioSilico_Bangs_Published
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Clinical Pharmacology and Therapeutics
and iterative. Through each stage of 12. T. V. Inglesby, et al., “Anthrax as a
69 (2001): 286–296.
Biological Weapon, 2002: Updated
development, both biology and clinical 4. J. A. Dimasi, Tufts Center for the Study
Recommendations for Management,”
outcome must be reconciled as more of Drug Development Annual Forum,
Journal of the American Medical
and more system detail is integrated 2001, Philadelphia, PA.
November 2003 Regulatory Affairs Focus 41
Association 282 (2002): 2236–2252. 17. G. E. Rhie, et al., “A Dually Active Subcommittee on National Security,
13. C. J. Peters and D. M., “Anthrax Anthrax Vaccine That Confers Protection Veterans Affairs and International
Inhalation and Lethal Human Infection,” Against Both Bacilli and Toxins,” Relations, 23 October 2001.
Lancet 359 (2002): 710-711. Proceedings of the National Academy of
14. A. Agrawal, et al., “Impairment of the Sciences 100 (2003): 10925–10930. IIIIII
Dendritic Cells and Adaptive Immunity by .
18. P Brachman, “Field Evaluation of J. Michael French, MS, is senior vice presi-
Anthrax Lethal Toxin,” Nature 424 (2003): Human Anthrax Vaccine,” American dent for business development & alliances
329–334. Journal of Public Health 52 (1962): for Entelos, Inc. in Foster City, CA, which
15. M. Moayeri, et al., “Bacillus Anthracis 632–645. provides predictive biosimulation technolo-
Lethal Toxin Induces TNF-{alpha}- 19. FDA, “New Drug and Biological Drug gy and research to the pharmaceutical
Independent Hypoxia-mediated Toxicity in Products; Evidence Needed to and biotech industries. Seth Michelson,
Mice,” Journal of Clinical Investigations Demonstrate Effectiveness of New Drugs PhD, and Lisl K. M. Shoda, PhD, are also
112 (2003): 670–682. When Human Efficacy Studies Are Not with Entelos and serve respectively as
16. Centers for Disease Control and Ethical or Feasible,” Federal Register 31 vice president for In Silico research and
Prevention, “Investigation of Bioterrorism- May 2002). development and scientist, immunologic
related Anthrax and Interim Guidelines for 20. From the Testimony of Stephen G. diseases.
Exposure Management and Antimicrobial Sudovar, president and CEO of EluSys
Therapy, Morbidity and Mortality Weekly Therapeutics, Inc., to the House Commit-
Report (October 2001). tee on Government Reform
Copyright by the Regulatory Affairs Professionals Society (RAPS). Posted with permission on www.entelos.com. Reprinted from the November 2003 issue of
Regulatory Affairs Focus. This article may not be published, reposted or redistributed without express permission from RAPS and payment of appropriate fees
when applicable. To obtain such permission, send a message to reprints@raps.org.
42 Regulatory Affairs Focus November 2003
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