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3
Defining a Discipline of
Regulatory Science and Core
Competencies for Its Workforce
Key Messages
• egulatory science encompasses a wide range of subjects, including not
R
only disciplines traditionally associated with regulation, such as statistics and
clinical research, but also disciplines outside the biomedical sciences such
as conomics, risk communication, and sociology.
e
• egulatory science could be a methodological means of determining the im-
R
pact and value of the rules, principles, and laws governing FDA-regulated
research.
• strong relationship between regulatory science and translational science
A
could provide a path to creating a well-rounded discipline.
• efining a regulatory science workforce includes defining, and making promising
D
scientists aware of, regulatory science as an attractive, respected career option.
The discussions in the next session of the workshop recognized and
were built from the premise that developing a discipline of regulatory
science calls for defining what is meant by regulatory science and then
building a workforce equipped with a set of core competencies to fit that
definition.
In a dialogue, Barry Coller, The Rockefeller University, and Rob Califf,
Professor of Medicine, Vice Chancellor for Clinical and Translational
Research, Duke University Medical Center, described regulatory science
19
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20 STRENGTHENING A WORKFORCE FOR INNOVATIVE REGULATORY SCIENCE
as seen through the lens of translational science. In a panel discussion,
panelists provided observations about the core competencies needed for
an effective regulatory science workforce and offered perspectives on the
role of regulatory science in their respective sectors and agencies.
DEFINING REGULATORY SCIENCE THROUGH
THE LENS OF TRANSLATIONAL SCIENCE1
A Regulatory Science Taxonomy
In Coller’s view, regulatory science is a subset of translational science.
He provided the following definitions as a basis for the discussion:
• Translational science is the application of the scientific method to
address a health need.
• Regulatory science is the application of the scientific method to
improve the development, review, and oversight of new drugs,
biologics, and devices that require regulatory approval prior to
dissemination.
Translational science traditionally has been broken down into four
phases:
• T1: Discovery to candidate health application
• T2: Health application to evidencebased practice guidelines
• T3: Practice guidelines to health practice
• T4: Practice to population health impact
The taxonomy of regulatory science can be aligned with the transla -
tional science taxonomy through four analogous phases, as follows:
• RS1: Preclinical evaluation of safety and efficacy
• RS2: Clinical trial design and analysis
• RS3: Postmarketing review of safety and optimal utilization
• RS4: Health policies, including social aspects of regulatory science
From this taxonomy, it is possible to develop a list of the multi-
disciplinary research expertise needed in regulatory science. (See Box 3-3
1 This section is based on the presentations by Barry Coller, Vice President for Medical
Affairs, Physician-in-Chief, and David Rockefeller Professor, The Rockefeller University,
and Rob Califf, Professor of Medicine and Vice Chancellor for Clinical and Translational
Research, Duke University Medical Center.
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21
DEFINING A DISCIPLINE OF REGULATORY SCIENCE
for a list of regulatory science competencies identified during the course
of the workshop.)
Coller commented that the eight priority areas in FDA’s 2011 strategic
plan for regulatory science can be conceptualized within the regulatory
science nomenclature of phases RS1 through RS4. For example, the FDA
goals to modernize toxicology to enhance product safety, support new
approaches to improve product manufacturing and quality, and ensure
FDA readiness to evaluate innovative emerging technologies all fit within
“RS1,” the first phase of the regulatory science taxonomy. Others, such as
implementation of a new prevention-focused food safety system to pro-
tect public health and facilitate development of MCMs to protect against
threats to U.S. and global health and security, are crosscutting issues that
integrate several phases of regulatory science.
Califf articulated FDA’s definition of regulatory science (“regulatory
science is the science of developing new tools, standards and approaches
to assess the safety, efficacy, quality and performance of FDA-regulated
products” [FDA, 2010]), which in his view is complementary to the defi-
nition offered by Coller but contemplates the conduct of activities that
do not necessarily entail the application of the scientific method, such as
policy development, and disciplines such as decision science, sociology,
cognitive psychology, and behavioral economics. He also noted that regu-
latory science has multiple layers, and not every layer has the same goals.
Regulatory Science Training
It may be possible to create a training regimen for the regulatory sci-
ences that builds on the existing translational science training programs,
Coller said. Existing translational science meetings also may provide
opportunities for disseminating new knowledge in regulatory science.
Culturally, regulatory science could find an academic home within exist -
ing translational science centers and institutes. Similarly, existing journals
focused on translational science may provide opportunities for publish -
ing regulatory science scholarship. Building relationships between the
regulatory and translational sciences may provide a path to creating a
well-rounded discipline and earning the respect needed for any new field
to succeed.
Califf applauded FDA for increasing the size of its workforce but
added that the training systems for FDA scientists need to be improved.
More thorough training should occur before FDA scientists start their
duties at the agency so that they do not have to be trained so extensively
on the job. FDA regulators need lifelong education, he added.
Many clinical researchers are ill at ease with regulatory science, said
Califf. Much of this unease arises from the fact that regulations are not
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22 STRENGTHENING A WORKFORCE FOR INNOVATIVE REGULATORY SCIENCE
well integrated with an understanding of what is needed to conduct
first-rate clinical research. Researchers from the growing number of dis -
ciplines involved in clinical research, such as informatics specialists, data
managers, psychologists, sociologists, economists, and even Institutional
Review Board (IRB) members, must be given a better grounding in the
relationship between regulation and clinical research, he said.
Even within the medical products industry, regulatory science train-
ing often occurs on the job. Califf suggested that organizations such as
the Regulatory Affairs Professional Society (RAPS) become more involved
in establishing a more formal mechanism for regulatory science training.
DEFINING REGULATORY SCIENCE AS SCIENCE
OF EVALUATION OF REGULATIONS2
Several speakers called for a component of regulatory science to
include the evaluation of regulations. The concept was discussed in
depth by Clifford Lane, Deputy Director for Clinical Research and Special
Projects, National Institute of Allergy and Infectious Diseases (NIAID),
NIH. As defined by Lane, regulatory science is “the intellectual and prac-
tical activity encompassing the systematic study of the structure and
behavior of the regulatory world through observation and experiment to
determine the impact of the rules, principles, and laws governing FDA-
regulated research.” This definition gets to the notion that regulatory
science should address the value that regulations provide. Regulatory sci-
ence first would look at the purpose of the original regulation and then
generate a testable hypothesis about the impact of the regulation. Research
then would examine how successful the regulation has been at achieving
its original purpose, determine if the regulation produced any unintended
or unanticipated consequences, and quantify the broadly defined cost
of implementing the regulation. The analysis of the data would in turn
provoke a discussion on the overall value of the regulation and lead to a
conclusion about whether the regulation should be modified, eliminated,
or left unchanged.
Lane highlighted one law and one regulation that could be tested
using this research strategy:
• The FDA Amendments Act of 2007, Title VII, called for the expan-
sion of ClinicalTrials.gov with the aim of enhancing patient enroll -
ment and providing a mechanism to track subsequent progress of
clinical trials. A testable hypothesis could be that the expansion
2 This section is based on the presentation by Clifford Lane, Deputy Director for Clinical
Research and Special Projects, NIAID, NIH.
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DEFINING A DISCIPLINE OF REGULATORY SCIENCE
of ClinicalTrials.gov to include a results database has enhanced
patient enrollment and provided a way to track progress of clinical
trials without generating excessive costs. Studies could compare
the rates of enrollment by several metrics, such as the total num-
ber of patients in clinical studies, the percentage of studies filled
within a specified timeframe, the number of published papers
using data from ClinicalTrials.gov, and website utilization statis-
tics. The impact of additional regulation could be measured by
looking at new informed-consent language and additional staff
needed to comply with the regulation.
• Title 21, Chapter 2, Subchapter D, Part 314, Subpart I addresses the
approval of new drugs when human efficacy studies are not ethi-
cal or feasible, also known as the Animal Rule. The purpose of this
regulation was to enable the licensure of products that have been
studied for their safety and efficacy in ameliorating or preventing
serious or life-threatening conditions caused by exposure to lethal
or permanently disabling toxic biological, chemical, radiological, or
nuclear substances; for which definitive human efficacy studies
cannot be conducted because it would be unethical to deliberately
expose healthy human volunteers; and for which field trials have
not been feasible. A testable hypothesis could be that products in
this category that would not have been licensed have been licensed
since the regulation was developed. Research could identify poten-
tial products that fall into this category and assess the impact of the
regulation on the ability of those products to be licensed.
In the subsequent discussion session, Califf commented that regula-
tors need a well-developed understanding of why the regulations exist
and what they are supposed to accomplish, particularly emphasizing the
application of regulations to real clinical trials.
Coller noted that the regulatory process is part of the political process
and that regulatory science should include efforts to better understand
the relationship between the two. This has direct bearing on the research
scheme that Lane proposed because it has an impact on how the end
effect of regulation can differ from the intended effect. Mary Dwight, Vice
President for Government Affairs, Cystic Fibrosis Foundation, amplified
this comment by noting that political drivers are overwhelming regula-
tory concerns today. Patient education must be part of the solution to this
problem so that patients can speak out about their needs for more effec-
tive, efficient therapeutic development models based on good regulatory
science. Lane noted that policy makers are largely driven by data; provide
them with good data and they will make scientifically sound decisions,
but in the absence of data, they will make decisions driven by politics and
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24 STRENGTHENING A WORKFORCE FOR INNOVATIVE REGULATORY SCIENCE
opinion, he said. Regulatory science can tilt this process in favor of good
decision making by generating good data.
CASE STUDIES: REGULATORY SCIENCE IN PRACTICE
Two speakers presented case studies that could serve as examples
of the practice of regulatory science. Dwight presented a case study
involving the development of a therapeutic agent (see Box 3-1). Munir
Pirmohamed, Deputy Director, Medical Research Council Centre for Drug
Safety Science (CDSS), University of Liverpool, discussed a case study
involving an issue of drug safety (see Box 3-2).
CORE COMPETENCIES OF REGULATORY SCIENCE
As part of a panel discussion of the core competencies that a regula-
tory science workforce should have, Steven Galson, Vice President for
Global Regulatory Affairs, Amgen Inc., listed certain core competencies
that would be helpful in addressing the types of research questions rel-
evant to the impact of regulation on clinical research. (See Box 3-3 for a
list of regulatory science competencies identified during the course of
the workshop.) He added that FDA has long taken advantage of training
opportunities at NIH by sending staff to work in clinics and laboratories
there, but if FDA does expand its regulatory research, there may be a
need to create a specialized division at FDA that funds and conducts this
research.
Several panelists from federal agencies provided comments on regula-
tory science workforce capacity needs to carry out their agency missions.
FDA Center for Biologics Evaluation and Research (CBER). Carolyn Wilson,
Associate Director for Research, CBER, FDA, commented that CBER regu-
lates a broad spectrum of therapeutic biologics, including complex entities
such as gene therapies, cell therapies, and xenotransplants. Many of these
therapeutics cannot be terminally sterilized and may not even be subjected
to methods that might remove or inactivate infectious agents, raising issues
such as how to ensure the safety of these entities, determine appropriate
preclinical animal models, and ensure that there are not species-specific
toxicities or therapeutic responses. To deal with these issues, CBER needs
scientists who are trained in a variety of broad, scientific disciplines, includ-
ing immunology, biochemistry, cell biology, developmental biology, micro-
biology, genetics, and the new “omics” sciences. According to Wilson, this
workforce needs excellent analytical skills, the ability to adapt to new
technologies and research paradigms, and the expertise to apply findings
in a way that is not “checkbox regulation.” Solid training in the scientific
method is critical, along with experience doing team science.
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25
DEFINING A DISCIPLINE OF REGULATORY SCIENCE
BOX 3-1a
Collaboration in Cystic Fibrosis Research
Dwight described the Cystic Fibrosis Foundation’s role in a successful collab-
orative effort to develop new therapeutics to treat cystic fibrosis (CF). The key to
this effort was that the partners stayed focused on the desired goal but were flexible
enough to adapt to changing circumstances experienced during the drug develop-
ment process. She recounted how the mission of the foundation has changed since
its founding in 1955, from caring for patients to finding treatments for the disease.
This change reflects the tremendous advances in understanding the molecular
basis of disease that have occurred since the discovery of the CF gene in 1989.
Collaboration has always been a core tenet of the CF community of patients
and their parents; physicians, nurses, nutritionists, respiratory therapists, and
s
ocial workers; and researchers. The tremendous advances in life expectancy
that have occurred can be traced in part to a team approach to patient care.
Collaboration among three teams of researchers played a key role in the dis-
covery of the CF gene. More recently, the development of promising therapeutics
has been a result of collaboration among scientists in academia, industry, and FDA.
Each of these collaborations required a cultural change. In the case of drug devel-
opment, research teams needed to learn to share data among themselves and with
pharmaceutical companies. At FDA, regulators needed to adapt their concepts of
risk to recognize that risk has a different definition for patients suffering a certain
early death from their disease without new treatments. The Cystic Fibrosis Founda-
tion, Dwight explained, played the role of facilitator, coordinating and encourag ng i
communications among all of the groups participating in this endeavor.
Dwight noted that FDA was very responsive to the particular needs of this work.
In particular, large multicenter clinical trials would have been difficult to conduct
given the patient population. FDA also strengthened its staff expertise and facili-
tated communications with trial sponsors.
However, the process is still too slow for patients living with chronic, life-
threatening diseases, Dwight said. Direct communication between patient groups
and regulators needs to be enhanced to inform how FDA balances risk and
r
eward when it approves the design of even the earliest stages of the clinical
trials processes.
a Based on the presentation by Mary Dwight, Vice President for Government Affairs, Cystic
Fibrosis Foundation.
FDA Center for Tobacco Products (CTP). Regulatory science sits at the
core of what the CTP is now charged to do to protect the nation’s health,
but until now the country has never attempted to create science-based
regulations for tobacco products. Doing so requires a pool of professionals
in the biological and chemical sciences, toxicology, pharmacology, and
product engineering, said Laurence Deyton, Director of CTP, FDA. It also
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26 STRENGTHENING A WORKFORCE FOR INNOVATIVE REGULATORY SCIENCE
BOX 3-2a
Drug Safety
Adverse drug reactions impose a tremendous burden on human health. They
account for some 2.5 percent of emergency room visits and 6.5 percent of hospital
admissions in the United Kingdom and are a major problem for the pharma eutical c
industry. Between 1990 and 2005, FDA and the European Medicines Agency
(EMA) ordered 24 drugs to be withdrawn from the market because of adverse drug
reactions. Most of these withdrawals occurred not long after the drugs reached the
market, long before the costs of developing those drugs were recovered.
To better understand the fundamental biochemical mechanisms underlying
adverse drug reactions, the Medical Research Council established the Centre for
Drug Safety Science (CDSS). In addition to developing better methods for predict-
ing adverse drug responses, CDSS aims to train researchers in the science of
drug safety. Toward this end, the CDSS has established both research and clinical
pharmacology training fellowships that focus on drug safety and personalized
medicine. The center also offers master’s and Ph.D. degrees in drug safety science.
An important piece of the center’s training mission focuses on the collabora-
tive relationships that CDSS has formed with regulators, academia, industry, and
public advocacy groups. When CDSS identifies a research question, staff identify
the appropriate clinical networks in the United Kingdom and develop collaborative
hypothesis-testing research programs. The center then holds workshops involving
academics, regulators, industry scientists, and health care officials to disseminate
the results of those programs and develop recommendations to guide regulators.
As an illustration of CDSS’s approach, Pirmohamed discussed the development
of a new genetic biomarker for carbamazepine hypersensitivity in aucasians. He
C
described some of the research that identified this marker and then discussed the
implications of these findings. Regulators, for example, need to consider that this
biomarker was validated in at least three populations, but all from case-control
analyses, not prospective clinical trials. Regulators can consider changing the pre-
scribing label for this drug to require that all Caucasian patients be tested for the
biomarker before the drug is prescribed, or they might simply provide this informa-
tion to physicians. Only through the application of good science, said Pirmohamed,
can regulators make good decisions about such issues.
a Based on the presentation by Munir Pirmohammed, Deputy Director, Medical Research
Council CDSS, University of Liverpool.
requires public health experts, medical professionals, lawyers, educators,
communications specialists, and behavioral scientists, all of whom under-
stand and appreciate the role of regulatory science as it applies to tobacco
product regulation, said Deyton.
Centers for Disease Control and Prevention (CDC). Melinda Wharton,
Deputy Director, National Center for Immunization and Respiratory
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DEFINING A DISCIPLINE OF REGULATORY SCIENCE
BOX 3-3a
Disciplinary Components of Regulatory Science
• Basic investigation
• Bioengineering
• Bioethics
• Bioinformatics
• Biology
• Bionutrition
• Biostatistics
• Chemistry
• Clinical investigation and clinical trial design
• Clinical pharmacology
• Clinical research operations
• Communication
• Decision theory
• Drug/device discovery and development
• Drug disposition and metabolism
• Economics
• Epidemiology
• Genetics
• Government/policy
• Information technology
• IRB experience
• Law
• Medical informatics
• Medicine
• Metrics
• Microbiology
• Monitoring and quality assurance
• Nutrition
• Pharmacology (whole animal)
• Pharmacy
• Protection of human subjects
• Public health
• Regulatory knowledge
• Research pharmacy
• Risk assessment and communication
• Surveying/methods
• Systems analysis
• Systems biology
• Technology transfer
• Toxicology
• Veterinary
a This box provides an integrated list of disciplinary components of regulatory science
offered throughout the workshop by speakers and audience members.
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28 STRENGTHENING A WORKFORCE FOR INNOVATIVE REGULATORY SCIENCE
Diseases, CDC, discussed the type of workforce CDC needs to conduct
regulatory science, particularly in assessing risks and benefits. CDC’s
list of required disciplinary expertise encompasses epidemiologists, bio-
statisticians, and laboratory scientists such as microbiologists, chemists,
and toxicologists who focus on the identification and quantification of
disease burden. CDC also needs health economists who can study cost
effectiveness, she said, along with risk communications experts. She
emphasized the need for all staff to be comfortable working in a collab -
orative environment across disciplines and with external investigators.
Galson remarked that an understanding of how payers make reimburse-
ment decisions is also a critical competency, given that many decisions
about how new therapies will be used are being made not by regulators or
physicians but by those who pay for these therapies. Increasing the pool
of scientists trained in regulatory science who can conduct comparative
effectiveness studies would benefit the entire field. A participant com-
mented that FDA commissioned Duke University’s business school to teach
a course that included modules on funding drug development, pricing, and
reimbursement.
A member of the audience with prior experience at FDA noted that
a critical skill needed by FDA’s workforce is an understanding of the dif -
ference between predictability and probability, noting that FDA makes
probability-based decisions. He noted that ability to conduct quantitative
analyses is a core competency, emphasizing bioinformatics, statistics, and
other quantitative sciences.
DEFINING REGULATORY SCIENCE
A number of definitions of the term—and discipline—of regulatory
science were submitted by various speakers throughout the course of the
workshop. As described earlier, Coller conceptualized regulatory science
as falling along a set of phases analogous to those recognized in trans-
lational science. A participant observed that Lane’s definition to include
the evaluation of regulations could be seen to fall within the “RS4” stage
in Coller’s taxonomy. Other definitions offered related, complementary
perspectives on the definition and components of regulatory science.
Alastair Wood, Partner and Managing Director, Symphony Capital
LLC, remarked that, although science includes them both, innovation
and discovery are different things. Implementation, including adopting,
understanding, using, and modifying knowledge that already exists, is
also distinct from the process of discovery and from innovation. Wood
suggested that defining the science—and developing and training the
workforce to practice the science—should acknowledge and focus on
the difference in the domains involved, which demand different styles,
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DEFINING A DISCIPLINE OF REGULATORY SCIENCE
and these skills, in turn, could be acquired in different settings (e.g., a
focus on discovery in academics; a focus on innovation, implementation,
and adoption in industry).
Carl Peck, Professor of Pharmacology and Medicine, University of
California, San Francisco (UCSF), distinguished regulatory science from
regulatory research. Regulatory science, he said, is the entire body of
knowledge practiced by FDA and by those regulated by FDA, including
law, economics, and an overriding ethic of protecting the public health.
Regulatory research is the development of that body of knowledge as
well as new tools, standards, and approaches to assess the safety, efficacy,
quality, and performance of FDA-regulated products.
Several participants noted that it may not be necessary or desirable
to conceptualize regulatory science as a single, stand-alone discipline. It
was suggested by a participant that all facets of therapeutics development
are subject to science-based regulation. On this basis it was suggested that
regulatory science could be viewed not as a freestanding discipline but
rather as a subspecialty within every core discipline forming the basis of
drug development science. Others conceptualized regulatory science as a
multidisciplinary effort, and several workshop participants called for the
establishment of academic “homes” that would centralize and support
the workforce engaging in the practice of the regulatory sciences.
It was also noted that the fact that there is not a commonly agreed
definition of regulatory science should not necessarily be seen as a bar-
rier for advancing the field. Rather, it is an opportunity to create a multi-
component discipline that is adaptive and responsive to the needs of the
field.
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