Site Visit Date:  May 19, 2006


On May19, 2006, a team of independent reviewers conducted a review of the Office of Vaccines Research and Review (OVRR), Center for Biologics Evaluation and Research (CBER) research program.


The members of the team were:


Walter Royal, III, M.D. (Site Visit Chair)

Associate Professor of Neurology

University of Maryland School of Medicine


Ruth Karron, M.D.

Professor, Division of disease Control

Department of International Health

Johns Hopkins University


John Boslego, M.D.

Director of Vaccine Development

Program Appropriate Technology and Health


Pamela McInnes, D.D.S., MSc. (Dent)

Director, Center for Integrative Biology and Infectious Diseases

National Institute of Dental and Craniofacial Research

National Institutes of Health


Raphael Dolin, M.D.

Dean for Academic and Clinical Programs

Harvard Medical School


Alan Shaw, Ph.D.

President and C.E.O.

VaxInnate Corporation


Harry Greenberg, M.D.

Senior Associate Dean for Research & Training

Interim Co-Chair for the Department of Medicine

Stanford University School of Medicine


Carol Tacket, M.D.

Program Director

General Clinical Research Center

Center for Vaccine Development

University of Maryland School of Medicine


Erik Hewlett, M.D.

Senior Associate Dear for Research and

Professor of Internal Medicine and Pharmacology

Division of Infectious Diseases & International Health

School of Medicine, University of Virginia


Bonnie Word, M.D.

Assistant Professor of Pediatrics

Baylor College of Medicine




Purpose of the Site Visit

The principal charge to the committee was to provide a global review of the research program management and organization of the OVRR and to provide direction that will lead to strengthening of existing and development of future effective programs within the Office that will facilitate the development of safe and efficacious vaccines and biologics. 


Overview of Research Activities within CBER and OVRR

The committee heard a series of presentations by OVRR leadership which reviewed the status of administrative and research considerations and current plans for future programmatic development and directions.   The first was by Jesse Goodman, M.D., M.P.H, the Director of CBER, who gave an overview of the research and regulatory activities of CBER and OVRR.  He presented the vision for the Center, which is to facilitate the development of safe and effective products and new technologies for the improvement of the public health and, in the pursuit of this mission, to improve the status of CBER as the leading regulatory organization for biologics.  Four strategic priorities were articulated for the upcoming year:  1) to address the looming problem of pandemic influenza, emerging infectious diseases, and preparedness for counterterrorism; 2) to employ innovative approaches for assessing and monitoring product safety, such as implementing the use of safety teams and modern informatics; 3) to efficiently bring safe, effective, and innovative products to the public, and; 4) to use 21st century technologies to improve manufacturing and product safety.  Dr. Goodman also discussed the Center’s Critical Path Initiative, the purpose of which is to identify and pursue regulatory and scientific opportunities to improve product development and availability.  Reference was also made to a CBER Research Working Group and Leadership Retreat that was held in September 2005.  At the retreat it was decided to implement a set of guiding principles for Offices and the Centers, the creation of a CBER Research Leadership Council which will coordinate and develop the implementation of the principles, and the establishment of priorities for the following year (2006).  The guiding principles for the CBER research program are that it will be highly collaborative and will include basic science, laboratory, epidemiological, statistical, and clinical science areas.  The scope of the research will include the scientific basis of product innovation, preclinical and clinical studies, and the principles affirmed that the research will be of high quality, efficient, and will address the core scientific and regulatory missions of CBER.

The next presentation was delivered by Kathryn Carbone, M.D, the Associate Director for Research for CBER.  Dr. Carbone reiterated the points made by Dr. Goodman regarding the CBER’s vision and elaborated on the challenges that are faced by CBER scientists given the need for rapid development of more effective and safer products and the challenges of managing product development by CBER.  Such management involves resolving problems that are identified during the review of investigational and marketing applications, scrutiny of the recommendations that are developed by the public in the form of input from advisory committees, presentations at scientific workshops and meetings and through the peer review publication process.  Other foci for CBER research include increasing the visibility of the research that is performed, and increasing research funding and infrastructure though the establishment of core facilities.  Being able to meet research goals is increasingly difficult for CBER investigators due to the necessary and increasing regulatory responsibilities, an issue that could be addressed by the new FDA Critical Path Research Initiative.  In order to utilize Center resources more efficiently, the Research Leadership Council was formed.  The implementation of the functions of the Council would, by better coordinating the efforts of the various research programs, result in a more intradisciplinary approach to the scientific research within CBER.

Norman W. Baylor, PhD, the Director of OVRR was the next speaker and he described how priority was assigned to specific research areas.  First, programs that address the broad range of scientific disciplines, and the specific research in these areas are driven by the needs of the regulatory review process and are established by the OVRR leadership and the scientific staff.  Priorities are determined based on the relevance of a subject or research area, the degree to which it is appropriate for the research to be performed by an OVRR scientist because of the specific expertise, knowledge, or reagents that are required to conduct the research, and whether the research program can quickly respond to meet a need.  Current areas of high priority are vaccine and related products safety, product characterization, mechanisms of immune responses and microbial pathogenicity, and emerging issues.  Areas of current research focus are counterterrorism, pandemic influenza, analysis of cell substrates for the presence of adventitious agents and tumorigenicity, and the structure and function of specific allergens.

Michael J. Brennan, Ph.D., the Associate Director for Research for OVRR, then further described how research efforts are allocated within areas of the highest priority.  The highest preference will be given to issues that concern previously approved products.  For example, initial research efforts may be put towards the development and/or assessment of serological assays for detecting responses to bacterial multivalent vaccines, potency assays for flu vaccines, and assessment of the safety of cell substrates used for polio and flu vaccine development.  Next, efforts are allocated to research that anticipates regulatory issues that may arise with new products, examples of which include investigations to identify new and more effective vaccine targets and the development of new technologies for producing vaccines and new assays for evaluating new vaccine safety and efficacy.  In addition, the research program must be prepared to rapidly shift its priorities and respond to emergencies that threaten the health of the public, such as those related to counterterrorism and pandemic influenza. 

The final presentations were by Jerry Weir, Ph.D., Director, Division of Viral Products (DVP) and Richard Walker, Ph.D., Director, Division of Bacterial Parasitic and Allergenic Products (DPAP) who gave overviews of the research and regulatory activities taking place in the division laboratories and recent accomplishments by laboratory staff.  These discussions clearly demonstrated for the committee the exemplary mission-based research taking place within the OVRR Divisions, their high level of productivity, and the challenges that are faced related to the issues that the Committee was asked to address.  There are 7 laboratories within DVP and >134 people, which include 17 tenured principal investigators, 67 full-time equivalent staff, and >50 contract staff (post-doctoral fellows); no tenured track investigators were listed.  The DVP operating budget has been slightly greater than 1 million dollars, representing a significant decline over the past 2 years.  DVP researchers, however, have been able to obtain more than 3 million dollars in outside funding.  In DPAP, there are 6 labs and 76 persons, which include 13 principal investigators, 7 tenure track investigators, 43 full-time equivalent staff, and 13 contract staff.  Funds from intramural sources have similarly declined for DPAP within the CBER research allocation and funds for FTEs total at slightly greater than $750,000 with the balance of the approximately 2.5 million dollar budget coming from external funds.


Comments by the Site Visit Committee

In reviewing the research programs of OVRR, the Site Visit Committee was presented with a list of five specific areas to address.  The Committee’s comments are as follows:


1.      Comment on the contributions of OVRR research to the scientific mission of CBER and the FDA and to biological product regulation.

The committee members unanimously agreed that OVRR has done an outstanding job in meeting its mission by performing high quality research while at the same time generating an outstanding record of accomplishment with respect to the regulatory review of biologics.  This has been achieved despite severe budgetary constraints.  To make up for the limited support that is available for both staff salaries and research supplies and equipment, laboratories have, both individually and collaboratively, sought and successfully acquired funding from non-FDA sources, in some cases in the context of collaborations with outside labs. 

Despite this formidable record, OVRR could benefit from the development of a more comprehensive strategic plan to address its broad missions more effectively.  Such a plan would enumerate, prioritize, and coordinate common thematic areas such as immunogenicity, safety, and assay development across multiple offices/laboratories.  The strategic plan would also anticipate subject areas which would likely be of particular importance to OVRR (e.g., pandemic influenza).  Decisions regarding recruitment, resource allocation, and research expansion could then be based on the strategic plan.


2.      Comment on ways to improve visibility of the OVVR research programs and on its integration into the biologics regulation process.

Extra efforts that are being put forth to enhance the public image of the FDA address a worthy goal.  Of the regulatory and research missions of OVRR, it would be more reasonable to highlight the research successes, if for no other reason than because the intended outcome of scientific research is generally viewed by the public to be for the good of society.  In contrast, it is more difficult to package a regulatory “accomplishment” as a success.  In fact, regulatory achievements are more likely to carry a negative connotation, since it often involves enforcing limits, albeit that these are also implemented for the public good, that are determined as the result of continued oversight and periodic review.  Scientists who work in the same field as OVRR scientists are aware of the high quality science and scientists at the FDA.  However, such individuals or their activities are not known to the general public.  Therefore, a public relations campaign could inform the public about the high quality research that is carried on at the FDA. 

One approach for increasing the visibility of research efforts at OVRR would be to seek FDA representation on scientific advisory committees of major collaborative groups/centers for relevant research.  An example of such in the HIV vaccine field is the committee which advises the Vaccine Research Center at NIH, the NIAID-sponsored Center for HIV AIDS Vaccine Immunology (CHAVI), and the HIV Vaccine Trials Network (HVTN).  Such advisory representation should entail research interaction, rather than being restricted to regulatory issues.


3.      Recommend opportunities for research expansion, redirection and new collaboration/leveraging.

Encouraging the establishment of research collaborations may not be enough and it may be necessary to provide the staff scientists with more direct input with regard to working interactions. While this seems natural in the university setting, reaching out from FDA may be harder and consideration should be given to what the FDA scientist has to offer that is not available otherwise to the extramural potential collaborator.

There is clearly a "practical" side to the research in OVVR, with regard to assay development, problem solving and responsiveness to newly developing areas. The trend in academic institutions is to segregate such activity and to label it as "translational research". It appears there is a reasonable amount of collaborative and cooperative interaction between the FDA and industrial "clients" who need something specific, but it is unclear how much work is done with academic institutions, particularly clinical investigators. Making additional linkages with such potential collaborators is likely to be useful and productive.


4.      Identify research management strategies for anticipating future biological products and related research programs.

OVRR appears to lack a well developed strategic plan that overlays all the separate lab programs.  This plan needs to be cross cutting and integrative of expertise and resources in individual labs and use these components to address critical components of the FDA's vaccine mission such as a better understanding of vaccine immunity and safety.  Also, the career pathway in OVRR should be structured to make it more appealing to new members and what components of these very large issues need to be developed to help the individual programs move forward.

In order to have reviewers with relevant laboratory experience, one needs to have an active research program in-house that is at least in an area related to a new technology. Given the variety of new technologies coming over the horizon, this requires active programs in multiple areas.  Obviously, it is not practical to cover everything, but certain key areas should be treated in-house.  As an adjunct, an active seminar program would be useful to maintain awareness of activities not covered by internal programs and should seek out speakers from company labs as well as from academic/government labs.  There should also be a means for identifying and neutralizing potential conflicts of interest (an issue that is substantially overblown these days). 

Prior to filing an IND, it would be appropriate in some cases to present to CBER staff an overview of a technology and how it applies to an upcoming development program that will come under CBER scrutiny.  This would constitute an opportunity for an open, less-structured, two-way dialog about issues that may be anticipated as the program progresses.  None of the above can work without support in terms of personnel and funding.  If we are to maintain our lead in health care development in the USA, regulatory science needs to be given the priority it deserves, independent of the short-term political and economic flurries that can derail progress.


5.      Provide recommendations for attracting, developing and retaining high quality science and medical experts for OVRR.

Concern was expressed over the possibility that the leadership in OVRR is aging and not being replenished by younger people. If this is the case, it's a major problem that will take time to address and should be started immediately. An overall strategic plan needs to come from senior leadership but it needs input and buy-in from below and needs to be implemented with the understanding that the current structure seems fragile so that one must be careful not to destroy things in the process of improving them.

One way to attract new talent to OVRR is to implement a system of reward for successful research, either financially or in terms of providing more lab space or research funding, or promotion.  Certainly, there are also other types of rewards that can be considered, but these are not possible in the federal system.

Research conduct within CBER is similar to the operation of an academic institution; therefore, it is not unreasonable to look for additional ways to follow that model more closely.  Dr. Carbone mentioned creation of core facilities, which reduce the overhead and need for duplication of costly items of equipment.  It may therefore be useful to obtain more information from medical schools on the operation of a combination of research and service activities. For example, an academic institution may have an excellent faculty development program that provides assistance to junior faculty on a wide range of subjects from availability of childcare in the community to creation of a teaching and research portfolio to grant and manuscript writing.



The Committee believes research within OVRR to be of high quality and acknowledges the numerous scientific accomplishments of the research staff.  There is, however, clearly a pressing need for improved funding support and recruitment strategies to recruit talented young scientists in order to maintain the high quality of research, as well as to improve the public’s image of OVRR and the research that it performs. The committee wishes to convey its strong concern that without the addition of substantial and sustained new financial support for the OVRR research enterprise, OVRR runs a serious risk of not being able to accomplish its multiple missions.  In addition, CBER and OVRR, within the limits inherent in the fact that the FDA is a government institution, could consider following models that have been established by academic institutions.  All of these issues could be addressed by the development of a clear strategic plan that incorporates the preceding recommendations and aims at producing a program that is cross-disciplinary between the OVRR divisions and laboratories.