Blood Products Advisory Committee
Meeting
August 16, 2007
OBRR Response to the Office Site
Visit Review Recommendations 2005
The OBRR research
program was reviewed by a group of Scientific Experts as a subcommittee of the
Advisory Committee (Appendix 1) on July 22, 2005, and the committee report was presented,
discussed and approved at a meeting of the Blood Products Advisory Committee (BPAC)
on March 10, 2006[1].
The Advisory Committee concluded that the OBRR research program has improved focus,
mission relevance, depth, diversity, quality, and productivity relative to the
previous CBER site visit in 1998. Additionally, the committee recognized OBRR’s progress
in establishing significant external collaborations and in leveraging external
research partners and support. The
committee expressed several other conclusions and offered a number of helpful suggestions.
This document contains
OBRR’s responses to the committee’s summary conclusions and recommendations,
which are cited as numbered in the Site Visit Report.
“1. The OBRR Intramural Research Site Review
Committee strongly supports the FDA’s continued emphasis on the importance of
having a strong intramural research program to support its Critical Pathway
program for effective and efficient regulatory activities. Having experienced and active research
scientists involved both in the regulatory process and in the development and
evaluation of scientific knowledge critical to the support of the regulatory
activities is both sound and an essential component of the regulatory process
that facilitates approval of biological products and protects the health and
safety of the American public.
2. The OBRR senior management and the
research scientists are highly commended for the depth and quality of the
research program that was presented at this review, especially considering that
each investigator is simultaneously responsible for a huge regulatory
workload. Both DETTD and DH have
developed productive and diversified research agendas that have increased in
value over the years despite both budget and personnel restrictions, and both
divisions have contributed to the Critical Pathway program.”
OBRR Response: OBRR senior leadership is thankful for the
comprehensive review that was conducted by the Advisory Committee. We appreciate the assessment of the committee
that our research adds value to the regulatory effort and that we have made
progress in development of our program under the Critical Path initiative.
“3. The issue of sufficient time and
qualified personnel to conduct the research remains important. The environment must be competitive to be
able to attract outstanding young scientists and to retain more senior
scientists as principal investigators and regulators. These issues are critical to the continuation
of an effective and productive research program that supports the regulatory
mission.
4. Among the most critical issues facing the
OBRR research program is funding to support the basic activities, including
reagents, supplies, and adequate equipment.
The meager budget available to OBRR through congressional appropriations
to support research directly is totally inadequate to conduct even a
significant part of the wide range of important program priorities for which
the Office is responsible.
5. Other options to increase the research
budget through sources outside the FDA, although difficult and time-consuming
for OBRR staff, are essential.
Opportunities for collaboration and to seek acceptable funding sources
must be pursued, although this must be done within the confines of the research
priorities established by OBRR.
6. Adequate laboratory space and equipment
are clearly essential components of a strong and productive research program,
and the inability to assure these in the future could have a definite impact on
future research activities. These issues
need to be addressed as funding is sought to support the research program.
7. As noted during the presentations and
discussions, it is imperative that OBRR have the flexibility, capacity and
resources to address new scientific and regulatory issues that become apparent
at any point in time, perhaps as a crisis.
Planning for these is difficult, especially when OBRR is also being
faced with decisions about trying to develop a more focused research
program. These issues must be factored
into the decisions, however.”
OBRR response: OBRR senior leadership makes every effort to
provide reasonable time for the PI’s to engage in mission related research and
ensures that such research fulfils the scientific needs of the regulatory challenges
that the Agency faces every day. A
comprehensive workload analysis has recently been undertaken to address and
resolve any potential workload inconsistency issues. In order for the scientific staff to be up to date
with current scientific and technological advances in the areas that OBRR
regulates, the Office recommends the participation of each PI to attend at
least one scientific conference in a year. On average, about half of the relevant
staff members attend scientific meetings in a given fiscal year, and the
proportion has been increasing in recent years. To sustain productive work of
the research-reviewers, OBRR is striving to provide seed monies to new
investigators and to those investigators who embark on new research projects to
meet new challenges relevant to the regulatory work in OBRR. When possible,
OBRR also supports PIs with non-FTE postdoctoral fellows to augment their
laboratory research. The Office, through
its newly appointed Associate Director for Research (ADR), has been evaluating
laboratory space needs, and, as an inter-office team effort, communicating
space needs with other Office ADRs and the Center ADR to secure additional
space if become available. We anticipate that FDA consolidation at the White
Oak campus would alleviate some of the current laboratory space issues. We are working
closely with the White Oak move-team to ensure a smooth transition from our current
facilities to the White Oak location.
To leverage
and make efficient use of finite internal resources, CBER has established core
facilities for oligo-nucleotide and peptide synthesis, flow-cytometry, confocal
microscopy, NMR, and proteomics technology.
Additionally, OBRR often contributes to major shared equipment purchases
and service contracts in CBER that would otherwise be cost prohibitive for a
single Office to bear.
To
leverage external resources, the Office ADR is engaged in identifying
appropriate external funding opportunities for the Office research staff as
well as finding ways to leverage scientific collaborations from neighboring
Academia, Governmental and other research institutions to strengthen the office
research programs. For example, in early 2007, the OBRR ADR worked closely with
Recently,
in 2006, the CBER Associate Director for Research established a Research
Leadership Council (RLC) to address CBER-wide research issues, with membership
composed of cross-Office Research and Regulatory Scientist leadership. The RLC
facilitates inter-office collaborations, helps the Center in prioritizing CBER
research and also identifies new external funding opportunities for CBER staff.
Several SOPPs and MOU templates have been developed within CBER recently to manage
the application process for requesting external funding from other government
institutes and offices (NIH institutes: NIAID, NHLBI and NCI, National Vaccine
Program Office, Office of Research Development and Coordination, DHHS, FDA’s
Critical Path Initiative and targeted national research foundations such as
National Hemophilia Foundation). The CBER ADR works closely with each Office ADR
in developing strategies to identify appropriate external collaborations by
meeting with senior management of domestic and foreign institutes and
universities (USAMRIID,
“8. Given the current realities of the
research funding limits, the committee recommends that OBRR must decide whether
it should try to maintain a broader array of research activities that attempt
to address the responsibilities within its mandate or whether it should focus
on a smaller number of research topics and priorities, allowing staff to develop
greater expertise and critical mass in fewer areas. If this model is adopted, OBRR could define a
research matrix based on the potential for collaborating effectively with
academia or industry through contracts and other mechanisms. The committee recognizes that this approach
also requires funds and other resources that may not be included in the budget.
9. A related issue is the need for OBRR to
define the best mechanism for identifying research priorities to be pursued,
either through intramural research or outsourcing. A good mechanism may already be in place, but
it was not discussed with the committee.”
OBRR Response: To
address research prioritization issues, the OBRR Director has established a
‘Senior Leadership Team’ (SLT) of managers that includes the Division
Directors, Deputies, and Associate Directors. The SLT identifies and monitors
progress in critical areas of regulation and Safety/Critical Path research
activities within the Office. Over the last few years, OBRR has increasingly worked to
focus research programs based on mission relevance. For example, programs on
SARS-CoV, HAV receptor, and HIV gene regulation, which were not directly
fulfilling the needs of OBRR’s regulatory mission, have not been supported. However,
at the same time we have expanded our programs on WNV, bioterrorism agents (e.g.
smallpox) and parasitic agents because of the emergence of threats to blood
safety by such agents. Further, based on input
from both research-reviewers and regulatory scientists in OBRR, the SLT has
recently developed a comprehensive prioritized research portfolio for the
Office in response to the ongoing CBER-wide managed research efforts to develop
a CBER list of priorities for mission-related research. The process has begun and the initial
steps have been completed. A fully
managed research process is to be completely phased in by 2008. As part of this
new process, each office, including OBRR, has been asked to develop
a managed research plan to address its priorities for beta testing this year.
Center and Office plans that are in development will be briefly presented to
the committee on August 16 to provide some insights on how this new managed
research process in CBER is evolving.
“10. OBRR needs to be attentive to the potential or perception of bias
introduced into the regulatory process by intramural research findings that are
portrayed as FDA policy positions.”
OBRR response: OBRR has rigorously
implemented the Agency’s SOPPs that are in place to ensure that any such
conflicts are prevented. In this direction, OBRR and CBER’s policy is to
require staff to publish scientific data in peer reviewed journals, thus
putting the information in the public domain for outside scientific
confirmation or refutation. Regulatory review activities are monitored by an
OBRR Managed Review Process in each division of the Office. Safeguards include the following: All research manuscripts and presentations by
the researcher/reviewer are reviewed for policy implications at the division,
Office, Center and the Agency level as appropriate. The FDA CRADA process includes internal CBER
and external FDA review and approval, and potential conflicts of interest are
identified and ameliorated.
Additionally, critical policy decisions are discussed at public meetings
of FDA Scientific Advisory Committees such as BPAC and TSEAC, where
non-conflicted external experts have the opportunity to weigh in on scientific
judgments of our staff.
“11. The visibility of the OBRR research program is an important aspect
of its broader acceptance and support.
Despite the meritorious work that is accomplished, there seems to be
little appreciation outside the FDA for the extent and quality and importance
of the work that is being accomplished.
It is important for OBRR to define and exploit opportunities to expand
their visibility. Certainly information
available through the new website may be one opportunity, as are workshops,
scientific presentations and publications, and other venues. Every opportunity should be taken to provide
strong links between the research program activities and the regulatory
capabilities that this research supports.”
OBRR response: as stated above, OBRR and CBER
require staff to publish in peer reviewed journals and to present ongoing
important research accomplishments at local, national and international
meetings. CBER scientists are encouraged to attend at least one scientific
conference of their choice per year to disseminate CBER research
accomplishments in a timely fashion. To
provide additional visibility to our research programs, OBRR and CBER have
increased the use of external web sites and ‘information booths’ at major national and
international scientific conferences and regulatory meetings. Also, OBRR periodically invites leading scientists
from recognized academia, industry and government representatives to make
presentations at the Center/Office/Division levels as appropriate and to
interact with our scientists. OBRR also
occasionally sends its invited staff to Academia, industry and other government
agencies to present and discuss their regulatory science and research results.
In addition to these activities, OBRR organizes timely scientific workshops of
public health relevance and publishes guidance documents to the industry, which
provides visibility to the FDA regulatory science activities. In order to
increase the visibility of CBER science within the organization, with the help
of each Office ADR, the Center ADR is developing a web-based database on CBER-wide
research expertise in order to establish “virtual Scientific Expertise teams”
and improvise science communication within the Agency that will link together
persons with complementary and collaborative research and regulatory knowledge
and experience. OBRR assures the committee that it utilizes every opportunity
to provide strong links between the research program activities and the
regulatory capabilities that this research supports.
“12. To directly enhance funding to support research activities, OBRR
should work with FDA and Department leaders to identify creative funding
mechanisms. Establishing a research
endowment fund, for example, that could be funded by major philanthropic
organizations, private donors, and regulated industry might be one example
(see, for example, the CDC Foundation).”
OBRR Response: The Center is actively looking
into ways to address this issue within the constraints imposed on FDA in this
regard, taking input from each Office. (See
discussion above re: leveraging activities.)
Further, there are several activities within the Agency and outside that
may lead to new research support opportunities in the near future.
Concluding Remarks
OBRR
managers take very seriously the overarching observation of the Site Visit
Committee that a structured and more transparent management system is needed to
ensure a proper focus for the research effort.
We believe that such a system has now been developed within OBRR and
CBER, with full implementation to be in place soon. We are confident that our newly established
infrastructure and tools will enable us to streamline, prioritize, and focus
our research programs so that we can best address the scientific needs of
regulation in our areas of responsibility.
Further, we look forward to frequent and continuing dialogue with the
Advisory Committee on OBRR’s research program successes and management
strategies.
Appendix 1
Blood Products Advisory Committee
Report
SITE VISIT REPORT
REVIEW OF INTRAMURAL RESEARCH
OFFICE OF BLOOD RESEARCH AND REVIEW
CENTER FOR BIOLOGICS EVALUATION AND
RESEARCH
FOOD AND DRUG ADMINISTRATION
1.
Date of Site Visit:
2.
Office: Office of Blood Research and Review
3.
On
4.
The members of the review
group were:
James
R. Allen, MD, MPH (Chairman)
President
and CEO
The
American Social Health Association
Harvey J. Alter, M.D.
Chief, Infectious Diseases Section
Department of Transfusion Medicine
Warren
G. Magnuson Clinical Center
National Institutes of Health
Michael P. Busch, M.D., Ph.D.
Director, Blood Systems Research Institute and
VP, Research and Scientific Affairs
Blood Systems Inc.
San Francisco, California
Donna M. DiMichele, M.D.
Associate Prof. of Pediatrics and Public Health
Marcos
Intaglietta, Ph.D.
Professor
of Applied Mechanics and Bioengineering
Department
of Applied Mechanics and Engineering Science
Harvey
G. Klein, M.D.
Chief,
Department of Transfusion Medicine
Warren
G. Magnuson Clinical Center
National
Institutes of Health
Suzette
A. Priola, Ph.D.
Senior
Investigator, Laboratory of Persistent Viral Diseases
Rocky
Mountain Laboratories
National
National
Institutes of Health
George B. Schreiber, Sc.D.
Vice
President, Health Studies
Westat
D.
Michael Strong, Ph.D.
Executive
Vice President and Chief Operating Officer
Peter
Tomasulo, M.D.
Executive
Vice President for Medical Affairs
Chief
Medical Officer
Blood
Systems, Inc.
Ching
C. Wang, Ph.D.
Professor
of Chemistry and Pharmaceutical Chemistry
5.
The FDA participants in
the review included:
Kathryn
M. Carbone, M.D.
Associate
Director for Research
Center
for Biologics Evaluation and Research
Jay S. Epstein, M.D.
Director,
Office of Blood Research and Review
Center
for Biologics Evaluation and Research
Jonathan
C. Goldsmith, M.D.
Deputy
Director, Office of Blood Research and Review
Center
for Biologics Evaluation and Research
Hira L. Nakhasi, Ph.D.
Acting
Associate Director for Science
Office
of Blood Research and Review
Center
for Biologics Evaluation and Research
Basil
Golding, M.D.
Director,
Division of Hematology
Office
of Blood Research and Review
Center
for Biologics Evaluation and Research
Alan
Williams, Ph.D.
Director,
Division of Blood Applications
Office
of Blood Research and Review
Center
for Biologics Evaluation and Research
6.
This site visit was a
periodic review of the progress and performance of the research program of the Office
of Blood Research and Review. The review
was intended to be an overarching summary of the research program’s goals and
support and not a focused review of individual investigators and their work.
7.
The review included
evaluation of background information about OBRR and its function within the
mission of CBER; written research program descriptions; the Review of Research
Programs at CBER report (dated
8.
Summary of the 1998
report recommendations: The 1998 review
committee strongly endorsed the fundamental need for basic science research at
OBRR to support the regulatory mission of the Office and for adequate funding of
that research program to assure its success and its ability to attract
first-rate scientists. “The Committee
recommends . . . that it is of greatest importance to provide the adequate
support and expanded funding so that cutting-edge research and cutting-edge
scientists continue to be attracted to work in an Agency that is so central to
both the health and welfare of our economy.”
And: “Independent of the money for the review process, this Committee
unanimously believes that it is critically important that the funding for basic
research within the Center be expanded to facilitate and allow CBER scientists
to carry out the evaluative part of their mission.”
9.
Summary of Review
Findings:
Background
As one of
three product offices within the FDA’s CBER, the OBRR seeks to fulfill the
Center's vision of “innovative technology advancing public health.” To achieve this and to participate fully in
the FDA’s Critical Path research initiative, the OBRR maintains an active
laboratory program with a focus on mission-related research to enhance the
scientific regulation of blood-derived and analogous products; medical devices
used to collect, process or store donated blood; and retroviral diagnostic
tests. The core programs are oriented
toward detection and control of infectious agents relevant to blood products
and the characterization and standardization of blood components, plasma
derivatives and related devices.
Additionally OBRR engages in epidemiological studies in methods and
development research to enhance product review and surveillance.
The OBRR research is primarily
targeted at current FDA regulatory issues, but it attempts to maintain
flexibility to respond to new regulatory concerns and safety issues. As is discussed below, these objectives
create their own set of issues. The FDA
concept of the researcher/regulatory scientist who both understands regulatory
issues and has scientific expertise and research experience is unique, but
absolutely essential for the continued successful implementation of the
Critical Pathway model. The
presentations and background material provided to the committee about the
research programs in OBRR clearly demonstrate that both the Division of
Emerging and Transfusion Transmitted Disease (DETTD) and the Division of
Hematology (DH) have successfully managed to develop research programs with
priorities that are directly relevant to the regulatory mission of the
FDA. These research programs have made
substantial and significant contributions supporting the Critical Pathway
program.
Principal
investigators and senior research staff at OBRR are expected to spend about
half their time on research activities and half on regulatory activities. In actual fact, however, this balance is
rarely achieved, and it does not account for other significant and
time-consuming activities such as program management and administration. Nor does it account for regulatory time
frames and priorities and similar issues that take precedence over
research. Despite the fact that the
senior scientists are clearly short staffed and under funded, their in total
programs have typically published more than 50 articles per year, many in
prestigious peer-reviewed scientific journals, and they have obtained favorable
assessments on their periodic external laboratory site visits.
In
addition to its regulatory and research responsibilities, OBRR has also
sponsored a number of workshops in recent years, which provide a forum for
broader discussion of new research and thought, contribute to the establishment
of standards, and allow comparison of progress being made in numerous fields
that relate to the OBRR mission.
General Findings
To
respond to the questions posed by the CBER staff, the committee identified and
discussed the challenges to further development of the OBRR research
program. These include:
1.
The breadth and focus of
the research agenda reflecting the wide range of identified needs.
2.
The need to remain in
complete control of the agency’s research agenda because of its unique mandate,
and the limits these places on the potential for extramural collaboration.
3.
The difficulty in
attracting new researchers given a relatively low pay scale, competition from
industry, the heavy workload and expected dual responsibilities in regulatory
affairs and research, and the limited opportunities and defined pathways for
advancement and academic promotion.
4.
The limited laboratory
resources, including fellows and technicians, space (an issue that may
intensify in the coming years), equipment, and other supplies.
5.
And a limited budget for
research, either appropriated by Congress or from other acceptable sources.
Overall,
the committee concurred that the OBRR research program merits high grades for
the depth and quality of the research, especially considering that each
investigator is simultaneously responsible for a huge regulatory workload as
well as working within the other limitations mentioned. The DETTD and DH have productive and
diversified research agendas. Both
divisions presented excellent examples of the current and future application of
their work to the Critical Pathway of biologics product development and
availability. They are to be commended
on their productivity in this regard in spite of the lack of resources both in
terms of staffing and money to conduct research.
Committee
members who have been familiar with the research programs at OBRR over a period
of years note that there has been a striking improvement over time in the
following areas:
1.Focus
and relevance. Previously, the program
was relatively unfocused and much of the research, though interesting, was not
relevant to the critical mission of CBER.
The research presented for this review had direct relevance to the
Critical Pathway of biologics product development and availability.
2.Quality. In addition to mission relevance, the quality
of the research has also improved; many of the ongoing studies are equal in
quality to those in the intramural program at the National Institutes of Health
(NIH) and of sufficient caliber to compete for RO1 and other NIH grants.
3.Diversity
of funding sources. In times of
appropriated budget restrictions at the FDA, the investigators have been
innovative in finding alternate funding sources and in establishing
collaborations that expand their capabilities without increasing costs.
OBRR
leadership is commended for their success at maintaining a stable, productive
research and regulatory organization, including key staff at multiple levels
that are bright, motivated, collegial and engaged. The challenge of maintaining a productive
program while balancing allocations of research principal investigators, other
fixed staff positions, and the very limited temporary fellowship slots and
dwindling equipment and reagent dollars is daunting. In general, OBRR appears to have successfully
maintained a strong interface between the research interests and activities and
the areas of regulatory oversight, resulting in capable investigators who both
contribute to the advancement of their fields of expertise and who are
knowledgeable and thoughtful regulators able to engage scientists in for-profit
and not-for-profit industry on an equal footing. This balance should be continued with the
goal being to enhance and assure this transparent but nurturing
research/regulatory interface.
One specific
point that bears mention is that many of the OBRR scientists have developed
ongoing collaborations with laboratories outside of the FDA that help support
the research program. They should be
commended for taking this initiative and the committee encourages them to
continue to initiate such collaborations whenever possible. The collaboration between FDA and NIH
laboratories provides an excellent example of how government agencies with
different missions can collaborate in ways that both support and enhance their
respective missions. Such collaborations
further the OBRR research program by providing access to equipment and
facilities that cannot be acquired at the current level of funding. The close proximity of the OBRR offices and
laboratories to the NIH on a single campus is extremely important for this
successful collaboration, and the committee strongly recommended that this be
maintained in order to encourage further research interactions between FDA and
NIH.
Research Program Concerns
Despite
the review committee’s affirmation of the quality and integrity of the OBRR
research program, a number of issues and concerns were raised during the
discussion.
The
committee discussed the challenges to the further development of the OBRR
research program. These include
1.
The breadth of OBRR’s
research agenda reflecting the wide range of identified needs.
2.
The need to remain in
complete control of the office’s research agenda because of its federal
mandate; this, in turn, limits the potential for extramural collaboration.
3.
The difficulty in
attracting highly qualified new research scientists given a low pay scale (and
competition from industry), the expected dual role of regulatory affairs and
research, and the poorly defined pathways for advancement and academic
promotion.
4.
The limited laboratory
personnel resources (fellows/technicians) and space (an issue that is likely to
intensify in the coming years).
5.
The extraordinarily
limited budget for research as appropriated by Congress (which is not likely to
increase in the near future).
BREADTH
OF OBRR RESPONSIBILITIES VERSUS NEED TO FOCUS RESEARCH EFFORTS
With
the limited financial and personnel resources available to it, a major
conundrum facing the OBRR research program is to define and adhere to the focus
and mission of the research program.
From a needs perspective, OBRR scientists should be engaging in all
types of research:
1.
Cutting-edge basic
science research that seeks answers to the theoretical questions and that
anticipates future developments and products and novel experimental therapies
but that may not have any practical application in the immediate future.
2.
Applied research to
assess the safety, potency, and efficacy of candidate products and therapies
that are currently under development or in clinical investigation or to address
questions and issues that arise during or after the licensure process of a
product.
3.
Directly applicable
research to develop methods and techniques to enhance regulatory oversight,
quality control and standard laboratory assessments to ensure the safety,
potency and efficacy of currently licensed products.
To do this effectively given the broad mandate of the OBRR’s areas of responsibility and the need to react immediately to new situations or crises (such as the discovery that the West Nile virus could be transmitted from asymptomatic donors through transfused blood components) would require far more staff, funding, and laboratory resources than are currently available. Another issue is the extent to which limited research resources should be directed to working with and understanding new technologies that are not being regulated directly (e.g., microarrays, nanotechnology), and how should priorities be established for these decisions and