Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 15
2
MCM Enterprise and
Stakeholder Perspectives
FDA REGULATORY SCIENCE RESEARCH NEEDS
To provide a framework for subsequent discussions, representatives
from FDA’s Center for Drug Evaluation and Research (CDER), Center
for Biologics Evaluation and Research (CBER), and Center for Devices
and Radiological Health (CDRH) provided a broad overview of current
efforts underway at the agency to support research, development, and
evaluation of MCMs, and discussed current challenges and how regula -
tory science can assist in advancing MCM development and evaluation.
Center for Drug Evaluation and Research (CDER)
The regulatory review process is an ongoing, iterative process,
explained Susan McCune, deputy director of the Office of Translational
Science at CDER. It is hoped that gaps and questions identified during
a regulatory review can be addressed through application of regulatory
science and that regulatory science in turn informs the broader regulatory
review process.
Within CDER, the Science Prioritization and Review Committee has
identified science and research needs across seven key areas. McCune
pointed out that although these identified needs are centerwide and not
limited to MCMs, all are relevant to the MCM initiative:
• mprove access to postmarket data sources and explore feasibility
I
of their use in different types of analyses.
15
OCR for page 16
16 ADVANCING REGULATORY SCIENCE FOR MCM DEVELOPMENT
• mprove risk assessment and management strategies to reinforce
I
the safe use of drugs.
• valuate the effectiveness and impact of different types of regula-
E
tory communications to the public and other stakeholders.
• valuate the links among product quality attributes, manufactur-
E
ing processes, and product performance.
• evelop and improve predictive models of safety and efficacy in
D
humans.
• mprove clinical trial design, analysis, and conduct.
I
• nhance individualization of patient treatment.
E
McCune briefly reviewed the drug regulatory review life cycle (Fig-
ure 2-1) and offered a number of examples of potential areas for Pillar 2
research across the drug life cycle (Table 2-1). CDER scientists are already
working in many of these areas. For each of these areas, she said, there
are numerous potential scientific studies that could be done. One of the
primary challenges is prioritization of studies as they relate to the MCM
initiative.
In closing, McCune said, CDER has a robust regulatory science pro -
gram with significant expertise to support the research agenda of the
MCM initiative, and CDER researchers and reviewers are eager to collabo-
rate on efforts to advance the regulatory science needs of the initiative.
NDA/BLA Postmarketing
Review Surveillance
Pre-IND IND
• Adverse
• Identification • Phase I studies
event
of potential • Phase II studies
reporting
compounds • Phase III studies
• Data mining
• Animal • Manufacturing
toxicology
studies
FIGURE 2-1 FDA regulatory review cycle.
NOTE: BLA, biologics license application; IND, investigational new drug applica-
tion; NDA, new drug application.
SOURCE: Susan McCune. 2011. Presentation at IOM workshop; Advancing Regu-
Figure 2-1
latory Science for Medical Countermeasure Development.
OCR for page 17
17
MCM ENTERPRISE AND STAKEHOLDER PERSPECTIVES
Center for Biologics Evaluation and Research (CBER)
Products regulated by CBER include blood, blood components and
derivatives, vaccines, allergenic products, cell and gene therapies, xeno -
transplantation products, human tissues, and various related devices,
explained Carolyn Wilson, associate director for research at CBER. MCMs
fall into several of these categories. For example, in the area of cell and
gene therapies, mesenchymal stem cells are being evaluated for treat -
ment of acute radiation syndrome; pathogen-specific immunoglobulins
come under the area of blood components and derivatives; and there are
a variety of MCM-related vaccines (e.g., anthrax, botulinum, smallpox,
influenza).
Wilson highlighted five areas under Pillar 2 of the MCM initiative in
which CBER is conducting research (Table 2-2).1 The anticipated public
health outcomes of such research include the development of new scien-
tific tools and biomarkers to facilitate development of safe and effective
MCM biologics and improved guidance to sponsors on how to develop
and evaluate MCM biologics, including guidance on how to implement
the Animal Rule. Research could result in, for example, earlier identifica -
tion of toxicity, improved means to assess potential for efficacy, and more
rapid detection of safety signals, potentially leading to improved decision
making regarding benefits and risk.
One example of current CBER research on animal model biomarkers
involves luciferase-expressing Bacillus anthracis, which allows for more
precise staging of the bacterial infection in mice, and improved design
for studies of such things as postexposure prophylaxis and combina-
tion therapies. This approach is generalizable, Wilson said, and could be
applied to other pathogens and to the development of improved animal
models. Other examples of ongoing CBER research mentioned by Wilson
include using phage display libraries to evaluate the human immune
response, developing faster methods to generate reference reagents for
influenza vaccines, and improving detection of adventitious infectious
agents in complex samples.
Center for Devices and Radiological Health (CDRH)
The devices regulated by CDRH include diagnostic and detection
devices, personal protective equipment (e.g., N95 respirators), emergency
devices (e.g., ventilators, intravenous administration sets, resuscitation
equipment, drug or vaccine delivery systems, needles), and combination
1 Further information on CBER biologics research projects can be found at http://www.
fda.gov/BiologicsBloodVaccines/ScienceResearch/default.htm (accessed June 9, 2011).
OCR for page 18
18 ADVANCING REGULATORY SCIENCE FOR MCM DEVELOPMENT
TABLE 2-1 Examples of Potential Areas for Pillar 2 Research in
CDER
Phase of Development Potential CDER Research Areas
Identification of Repurposing drugs
Potential Molecules for Molecular modeling
Study Screen approved drugs for other pathogens
Effects of combinations of antimicrobials
Animal Toxicology Animal models:
Studies and For pregnancy
Animal Models for Modeling of disease states in general
MCM To study toxin effects on organ systems
Qualified through the drug development tools
qualification process
For combination added benefit studies
For placebo studies
For postexposure prophylaxis
To evaluate potential safety signals
For studies of natural history and pathophysiology
of disease
Conversion of data from animal model studies to
standard format
Animal model database
Human Safety Studies Evaluation of the effects of genetic variations
for MCMs or Studies of dosage forms for special populations
Clinical Safety and Extrapolation models from animal to human,
Efficacy Studies for including dose scaling for special populations
Influenza Pediatric safety studies, including ethical issues
Understanding human disease through the world
literature
Development of clinical endpoints for seriously ill
influenza patients
Development of threat-based data standards
Development of standardized case report forms for
data collection
Modeling drug interaction studies
Modeling of PK/PD to labeled drugs for special
populations
Manufacturing and Therapeutic protein PK/PD comparability studies
Product Quality Shelf-life extension studies
Develop stable product formulations
Rapid detection of problems with marketed products
OCR for page 19
19
MCM ENTERPRISE AND STAKEHOLDER PERSPECTIVES
TABLE 2-1 Continued
Phase of Development Potential CDER Research Areas
Incident-Related Studies Develop hospital networks for rapid information
transfer
Communication studies on emergency notification
Data mining for adverse events associated with
therapy
Develop protocols for use during events
Real-world use studies on home preparation
instructions
Real-time epidemiology cluster monitoring
NOTE: PK/PD, pharmacokinetic/pharmacodynamic.
TABLE 2-2 Examples of Potential Areas for Pillar 2 Research in
CBER
Pillar 2 Program Research Needs
Animal Model Biomarker Identify in vitro or in vivo correlates of bioactivity,
Program safety, toxicity
Methods development
Develop and evaluate animal models
Clinical Biomarker and How to bridge from animal studies to the human
Immunology Program immune response to vaccines
Insufficient knowledge of human disease
Clinical trial design
Ensuring MCM Product Measurable product characteristics that correlate with
Quality safety and efficacy
Improved methods to assess new cell substrates
New methods that incorporate new technology and
are faster, use fewer animals, and have improved
sensitivity/specificity
Radiation Injury Protection Improved tools to assess critical product attributes of
and Response Program cell therapy-based products used to treat radiation
injury
Animal models to evaluate product safety and
potential for efficacy
Health Informatics/ Improved means to detect rare adverse events
Scientific Computing Improved methods and access to health care data
sources to monitor safety of marketed MCM
biologics
Improved use of high-performance computing
Tools/models for risk assessment
OCR for page 20
20 ADVANCING REGULATORY SCIENCE FOR MCM DEVELOPMENT
products (a combination of drug or biological and a device), explained
Murray Malin, acting director of the Medical Countermeasure Initia-
tive at CDRH. There are MCM devices in each of these categories. The
CDRH Office of In Vitro Diagnostics has developed multiple guidance
documents that affect MCMs and has improved transparency by posting
device clearance reviews on their website.
Malin highlighted the regulatory science priorities in CDRH, noting
that they are similar to those of the other centers:
• evelop infrastructure to support development of diagnostics and
d
other MCMs;
• haracterize the medical device supply chain;
c
• nable real-time or near-real-time surveillance of supply, utiliza-
e
tion, and availability of medical devices to avoid shortages;
• ddress special needs populations, point of care, and personalized
a
use of MCMs;
• nhance ability to capture, monitor, and analyze large datasets;
e
• reate statistical tools to develop innovative clinical trials, perform
c
comparative effectiveness research, and perform active surveil-
lance of adverse event reports;
• enomic sequencing devices and assays for the detection of patho-
g
gens and antimicrobial drug resistance;
• ultiplex/microarray diagnostic devices capable of simultaneous
m
detection/identification of multiple organisms;
• evelop new tools to evaluate nanotechnology-based devices,
d
including use as diagnostic markers;
• ncrease scientific capacity and expertise to prepare for and facili-
i
tate new technologies;
• evelop guidance for development of multiuse products and plat-
d
forms to expand MCM product pipelines during emergencies;
• nfrastructure, comparator sequencing database, data processing,
i
and resources to enhance reviews of MCMs, facilitate innovative
statistical techniques and clinical trials, and develop regulatory
pathways for MCMs;
• greement with Centers for Medicare and Medicaid Services (CMS)
a
on data necessary for Clinical Laboratory Improvement Amend-
ments (CLIA) waiver of authorized products during an emergency;
and
• evelop high-performance/scientific computing to facilitate the
d
following:
answering questions related to comparative effectiveness associ-
■
ated with patient subsets;
support for genomic sequencing, multiplex devices;
■
OCR for page 21
21
MCM ENTERPRISE AND STAKEHOLDER PERSPECTIVES
identification of improved methods for characterizing failure
■
analysis, validation of factors affecting manufacture of MCMs,
and development of forensic evaluation techniques necessary to
support multiplatform/product development; and
development of innovative statistical methods and clinical trial
■
design.
Discussion
Much of the discussion with the FDA panelists focused on commu-
nication and collaboration as key components of advancing regulatory
science. Wilson pointed out that CBER has “research reviewers” who are
actively engaged in both the regulatory science agenda and review activi -
ties. Research reviewers can help identify gaps in the science, as well as
methods, tools, and reference materials that could help move a technol-
ogy or a whole product area forward. McCune added that many CDER
review team members are actively engaged in research at the agency
and bring a significant amount of clinical and scientific expertise to the
review process. From the CDRH perspective, Malin noted that formal and
informal collaboration is key to understanding needs and opportunities
for products. Solving the needs for a certain product may be translated to
other types of products as well. The speakers highlighted the numerous
interactions among their centers, from sharing supercomputing capabili -
ties to collaborating on the development of modeling approaches, soft -
ware, and analytic tools.
With regard to dissemination of information, panelists noted that
information about a product or process that is generalizable knowledge
is released by FDA in the form of guidance documents. The panelists
noted that FDA scientists are encouraged to publish their research in the
peer-reviewed literature. There is also a wealth of information on the FDA
website; for example, the CDER Office of In Vitro Diagnostics has several
databases on its website with information about approved and cleared
devices.
Professional development for FDA scientists and reviewers is also
important to keep agency science on the cutting edge. For example, CDER
has weekly “scientific rounds” where novel scientific and regulatory
issues are discussed. There are online programs as well as classroom-
based programs. Reviewers also need to be able to attend scientific meet -
ings and have access to the latest information.
With regard to potential indicators or metrics of success of the regu-
latory science initiatives underway, it was noted that it is difficult to
measure precisely the public health impact of any particular initiative.
While the long-term, big-picture goal is an increased number of approved
OCR for page 22
22 ADVANCING REGULATORY SCIENCE FOR MCM DEVELOPMENT
MCMs, the metric cannot simply be approvals, because not all products
will (or should be) approved. The FDA panelists suggested that metrics
should be associated with smaller, incremental steps, such as solving a
problem that allows for a potency assay in vitro instead of in hundreds of
animals, thereby increasing speed and decreasing the cost of that potency
assay.
ENTERPRISE PARTNER AND STAKEHOLDER PERSPECTIVES
Immediately following the panel presentations from FDA representa-
tives, stakeholders representing the other key components of the MCM
enterprise provided remarks in which they identified key issues in MCM
development and utilization that can be addressed through regulatory
science and offered suggestions of regulatory science needs or priorities
to advance MCM development.
Department of Defense (DoD)
Gerald Parker of DoD said there is a need for affordable, easy-to-use,
rapid, point-of-need diagnostics that can be made available on a global
basis and that can be connected to an information backbone so the result-
ing data can be rapidly shared (within minutes or hours, rather than
weeks). This includes diagnostics not only for pathogen identification but
also for antibiotic/antiviral resistance patterns, presymptomatic biomark-
ers, and host response markers.
Biodefense research at the DoD is focused on both traditional threats
and endemic diseases that the nation’s adversaries could choose to use
against U.S. forces around the world. The DoD is working in a collabora-
tive manner, seeking to use platform technologies that incorporate rapid
pathogen characterization and the ability rapidly to turn that information
into a discoverable product. While the DoD program has a sound science
and technology base, Parker noted that the department lacks the ability
to rapidly develop discoveries and manufacture new candidates against
unknown threats.
The DoD MCM Initiative strategy consists of two major elements,
each with multiple initiatives: (1) science and technology (novel plat -
form/expression systems for MCMs, regulatory science technologies,
manufacturing technologies for biologics that support good laboratory
practices [GLP]/good manufacturing practices [GMP]) and (2) advanced
development (further maturation of novel platform/expression systems
and integration into a production process; innovative, flexible, and agile
manufacturing capabilities).
In closing, Parker said that MCM development needs a clearly
OCR for page 23
23
MCM ENTERPRISE AND STAKEHOLDER PERSPECTIVES
defined regulatory pathway for products approved under the Animal
Rule, including early and ongoing real-time engagement of all partners.
He also noted that a DoD diagnostics leadership meeting held in October
2010 called for more inclusion in discussions and greater collaboration
to develop diagnostics and to inform the regulatory roadmap for next-
generation diagnostics.
National Institute of Allergy and Infectious Diseases (NIAID)
Michael Kurilla, of NIAID, explained that NIAID is taking a compre -
hensive approach to MCM development, with certain general criteria for
vaccines, therapeutics, and diagnostics. By way of example, he noted that
in the case of vaccines, it is important to consider alternatives for immu -
nocompromised persons and special populations such as the elderly and
children.
There are several unique aspects of bioterrorism agents that add to
the challenge of developing MCMs:
• here are limited facilities to conduct studies under appropriate
t
biological safety containment;
• here is limited prior art on fundamental aspects of specific patho-
t
gens (e.g., tularemia);
• here is limited human pathogenesis data available (necessary to
t
inform animal model development); and
• here is increased regulation and oversight of bioterrorism agents
t
(e.g., rules addressing the possession, use, and transfer of select
agents).
Kurilla defined MCMs as falling into four broad classes: (1) previ-
ously licensed MCMs for which the mechanism of action would support
efficacy (e.g., a licensed antibiotic); (2) previously licensed MCMs that
are being repurposed for a nonintuitive application (e.g., the oncologic
drug, Gleevec, which demonstrates activity against smallpox in vitro);
(3) MCMs that are currently in development for other clinical indications
(e.g., novel anti-infective agents); and (4) MCMs developed solely for a
CBRN application (e.g., an anthrax or Ebola vaccine).
Kurilla posed several questions for consideration regarding the evalu-
ation of new science and technologies:
• hat should be done in cases of limited or nonexisting human
W
clinical data with which to define an appropriate animal model?
• ow can we study species-specific biological agents, those for
H
which there may be no appropriate animal model?
OCR for page 24
24 ADVANCING REGULATORY SCIENCE FOR MCM DEVELOPMENT
• hat criteria define an animal model correlate?
W
• an mechanistic efficacy substitute for disease efficacy? (If the
C
mechanism of an intervention is understood, can that be applied
across a wide array of different disease spectrums where that
mechanism is identified as crucial for a resolution of that disease?)
In discussion, Kurilla pointed out that much of what was discussed
by the panels, and many of the major elements needed, are product-
independent regulatory science and product-independent tools. How-
ever, the traditional regulatory paradigm is regulation in the context of a
product, and there is little interaction with the agency in the absence of a
specific product. Product developers approach FDA when they are ready
to take a product into pivotal efficacy and safety studies, and it is at that
late point that some of the development tools, such as the animal models
used thus far, begin to be critically reviewed and questioned (e.g., is the
species relevant, is the challenge strain appropriate). Development of
acceptable tools has always occurred concomitant with product develop -
ment, and consequently, Kurilla said, developing these components in a
product-independent manner, and in the most expeditious and rational
manner, is quite challenging.
Biomedical Advanced Research and Development Authority
(BARDA)
The 2009 H1N1 influenza pandemic brought to light some of the
challenges of responding to a major public health emergency. Richard
Hatchett, chief medical officer and deputy director of BARDA, cited the
August 2010 report of the President’s Council of Advisors on Science and
Technology (PCAST) on influenza vaccine technology, which identified
two response issues directly involving regulatory science: the need to
improve sterility testing of influenza vaccine, and the need for new tech-
niques to test potency of vaccine preparations (PCAST, 2010). BARDA is
investing in research in these areas, he noted.
With regard to regulatory science more broadly, Hatchett said that
BARDA is looking to FDA for the following:
• nternal competency—FDA needs to have the expertise to keep up
I
with advances in science, to be able to engage creatively with MCM
product developers, and to adapt to new technologies (e.g., nano -
technology, bioinformatics, regenerative medicine, in vivo imag-
ing, new approaches to clinical trial design).
• apability—FDA needs to have the capability to help BARDA
C
understand the requirements for proving safety, efficacy, sterility,
OCR for page 25
25
MCM ENTERPRISE AND STAKEHOLDER PERSPECTIVES
and potency of vaccines or other products. This requires FDA to
interact with BARDA partners in a collaborative fashion (which the
agency is already doing, Hatchett noted).
• larity—FDA needs to be confident and assertive in defining the
C
requirements for licensure and approval of new products. BARDA
is looking for clear pathways, where those pathways can be defined
in advance.
Hatchett also emphasized the need to better understand animal mod-
els and apply them in a variety of settings.
Hatchett concluded by drawing attention to a forthcoming BARDA
request for proposals (RFP’s) on multiproduct facilities and rapid response
manufacturing capabilities. This will require new approaches from FDA,
he said, to be able to license products manufactured in facilities where
there may be rapid changeover in response to emerging novel threats
(e.g., pandemic influenza, sudden acute respiratory syndrome [SARS]).
Centers for Disease Control and Prevention (CDC)
The Laboratory Response Network (LRN) at the Centers for Disease
Control and Prevention (CDC), a key national stakeholder in the MCM
enterprise, is currently facing a variety of challenges in the area of diag -
nostics development, said May Chu, director of the Laboratory Science
Policy and Practice Program at CDC. Chu described CDC’s most sig-
nificant current challenge as obtaining FDA clearance of LRN-developed
assays (including 11 polymerase chain reaction [PCR]-based assays and
seven other assays). Chu noted that an LRN technical review committee
oversees assay design, development, validation, and quality assurance
prior to deployment, and she anticipated that transformational changes
in regulatory science could provide relief while preserving quality and
resilience.
Chu also noted that changes to a diagnostic platform require renewed
validation. Chu suggested that collaborative discussions are needed to
determine what validation is needed when changes occur. A software
change, for example, should not necessarily lead to a full reevaluation.
Chu listed the top regulatory science priorities in the diagnostics field
as follows:
• llow for quick and nimble preparedness and response to public
A
health emergencies.
Prevalidate and preposition diagnostic tests in the field.
■
Rapid, real-time, step-in-step MCM development with regula-
■
tory oversight. This, Chu explained, would allow data collected
during an emergency to be used later to validate test platforms.
OCR for page 26
26 ADVANCING REGULATORY SCIENCE FOR MCM DEVELOPMENT
Validation methodology for assessing lot-to-lot differences of
■
commercial products.
• llow for recognition of the diversity of diagnostic test producers.
A
• aintain evidence-based quality and postmarket monitoring with
M
stipulated controls and restricted use.
Academia
A perspective from academia was provided by Rick Lyons, director
of the Infectious Disease Research Center at Colorado State University.
Academicians are now accepting that for maximal benefit, an innovation
must be translated to an application, Lyons noted. Regulatory science tar-
gets the pathways that are required for this translation (e.g., biomarkers,
animal models, correlates of protection).
The most significant challenge, Lyons said, is the extrapolation of
animal immunological and pathophysiological data to the human setting.
What makes a good animal model is highly dependent on the research
question, he said. One must consider, for example, whether there is similar
pathophysiology as the human disease or similar mediators of immune
protection. For product development, are there well-defined generic ani-
mal models or platforms that could be used? Most of the time, Lyons said,
researchers are working with a nonvalidated surrogate that is “reasonably
likely” to predict clinical efficacy.
Lyons opined that it is unlikely one species model will reflect human
disease adequately and suggested a compartmentalization strategy,
pooling data from several species models. This systems and pathways
approach would require strong comparative immunology and physiol-
ogy, he noted.
It will be important to educate the public regarding advances in regu-
latory science, Lyons pointed out, particularly the use of animal models
for approval of products. It has been difficult, for example, to convince
people to be vaccinated, or to have their children vaccinated, with prod -
ucts that have been FDA approved based on clinical trials in humans.
How much more difficult will it be, Lyons asked, to get them to take a
vaccine that has not been tested in humans?
Industry
A biotechnology industry perspective on regulatory science was pro-
vided by Eric Rose of SIGA, Inc. The biotechnology industry has devel-
oped and manufactures essentially all of the new CBRN countermeasures
that have been procured into the SNS, Rose said. Companies are BARDA
partners for most of the advanced development contracts. Most compa-
OCR for page 27
27
MCM ENTERPRISE AND STAKEHOLDER PERSPECTIVES
nies, however, are small and not profitable, sustained by private capital
and government grants and contracts. Biotechnology companies are, Rose
stated, “an essential effector limb of the PHEMCE implementation plan.”
The goals of regulatory science, Rose said, should be development
of a broad array of safe and effective MCMs; alignment of stakehold-
ers, products, and product uses; appropriate transparency throughout
the process; and speed (i.e., there should be a sense of urgency as these
agents are not just causes of illness, they are potential weapons of mass
destruction).
In industry, there is a science to process improvement that Rose sug-
gested can be applied to the process of MCM development. The first step
is to design a process (hypothesize). That process is tested by use (experi -
ment), assessed (analyzing performance metrics), redesigned (refine
hypothesis), and the cycle continues. The ultimate validation of animal
efficacy models requires clinical trials during an outbreak situation. This
is something that should be planned for, he said. Rose also noted that,
with regard to development of animal models, criteria for euthanizing
animals when they have reached a certain degree of illness needs to be
transparent and prespecified.
Rose concluded by noting that while robust evidence of meaningful
outcomes from controlled clinical trials remains the scientific gold stan-
dard for efficacy, the challenges facing MCM development are not neces -
sarily new, and FDA has helped foster other industry segments in the
absence of feasible trials, including, for example, orphan drugs, complex
medical devices (e.g., artificial hearts), and diagnostics.
Discussion
There was some discussion around reverse engineering to evaluate
what processes might work best. One suggestion was to select several
products that are currently in the SNS and retrospectively simulate the
process as if they had been new molecular entities. It was also noted that
there is a lot of animal data available that is associated with approved
products. Although these products are not MCMs, it might be helpful to
look back at the animal data submitted for product approval and evaluate
which models were predictive and which were less so.
Participants also discussed benefit-risk assessments for MCMs and
whether the criteria should be the same or different from that for routine
products. George Korch of HHS noted that a challenge is conducting
a benefit-risk calculus that captures rare and yet highly consequential
events. Hatchett added that it is very hard to define, in advance of a real
event, criteria for a benefit-risk analysis that are able to take into account
the operating environment that exists once the event has occurred. Cal -
OCR for page 28
28 ADVANCING REGULATORY SCIENCE FOR MCM DEVELOPMENT
culating the risk and benefit of an anthrax antitoxin today, for example, is
very different from calculating the risk and benefit of the anthrax antitoxin
once there has been a widespread anthrax release. Jesse Goodman of FDA
said that the language around FDA’s EUA authority regarding the known
and potential benefits outweighing the known and potential risks leaves
a lot of room for different interpretations. Goodman, Parker, and others
all noted that defining the emergency scenario up front would allow for
different benefit-risk decisions than those that would be reached for use
of common products by generally healthy people. Hatchett cautioned
that the calculus done in anticipation of an emergency tends to be much
more stringent than that which would actually be made during a real
event. To aid benefit-risk decisions, Rose suggested, reviewers of MCMs
ought to have the requisite security clearances to be allowed to read the
associated confidential population threat assessments. In later discussion
about safety assessment, Richard Forshee of the Office of Biostatistics and
Epidemiology at CBER, mentioned current agency efforts to develop risk
assessment models to support regulatory decision making. These proba-
bilistic quantitative computer simulation models can help explore how
different regulatory science options could ultimately have an impact on
public health, and thereby improve decision making. FDA is also engaged
in a number of computational toxicology computer simulations to help
assess, for example, potential risk from vaccine adjuvants.
Key Messages: Enterprise Stakeholder Perspectives
• The regulatory paradigm for MCM development needs to be supported by new
regulatory science and evaluative tools that are product-independent. There is
a need for a format to permit engagement between product developers and
FDA outside the context of a specific product approval.
• MCM development needs more clearly defined regulatory pathways. Priorities
include:
Products approved under the Animal Rule, and
■
Diagnostics—prevalidated and pre-positioned in the field
■
• The benefit-risk calculus may be different for MCMs to be used in low-probability/
high-consequence events than for traditional products.
• Repurposing of previously licensed products needs to be studied in a system-
atic and comprehensive manner.
