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APRIL 11, 2008


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This transcript has not been edited or corrected, but appears as received from the commercial transcribing service. Accordingly the Food and Drug Administration makes no representation to its accuracy



            The Committee convened at 8:00 a.m. in the Grand Ballroom of the Hilton Washington DC North/Gaithersburg, 620 Perry Parkway, Gaithersburg, Maryland, Walter J. Urba, M.D., Ph.D., Chair, presiding.





WALTER J. URBA, M.D., Ph.D., Chair





KURT C. GUNTER, M.D., Industry Representative



















SHARON TERRY, M.A., Consumer Representative
















         T-A-B-L-E O-F C-O-N-T-E-N-T-S


Welcome and Introduction of Members          4

      Walter Urba, M.D., Ph.D., Chair


Conflict of Interest Statement               4

      Gail Dapolito, Executive Secretary


Recognition of Committee Service             7

      Karen Midthun, M.D., Deputy Director

      CBER, FDA


Update-Research Program, Office of           9

  Cellular, Tissue and Gene Therapies

  (Response to September 2005 Review of

    OCTGT Research Program)

      Carolyn Wilson, Ph.D.

      Acting Associate Director of Research

      CBER, FDA


      Suzanne Epstein, Ph.D.

      Associate Director for Research



Q&A                                         51


Update-FDA Somatic Cell Therapy Letter      85

      Kimberly Benton, Ph.D.

      Deputy Director, Division of Cellular

        And Gene Therapies

        OCTGT, CBER


Q&A                                         98


Update-OCTGT Guidance Development Prog.    101

      Richard McFarland, Ph.D., M.D.

      Associate Director for Policy



Q&A                                        121




                                     8:02 a.m.

            CHAIR URBA:  My name is Walter Urba.  I'm the Chair, and Gail Dapolito will read a conflict of interest statement.

            MS. DAPOLITO:  Thank you, Dr. Urba.  Good morning.

            This brief announcement is in addition to the conflict of interest statement read at the beginning of the meeting on April 10th and will be part of the public record for the Cellular Tissue and Gene Therapies Advisory Committee on April 11, 2008.  This announcement addresses conflicts of interest for topic 2 related to the Committee updates of the September 2005 review of the research programs in the Office of Cellular Tissue and Gene Therapies, the FDA Somatic Cell Therapy letter, and recently released FDA guidance documents.

            Based on the agenda for this topic, it has been determined that the Committee updates present no actual or appearance of a conflict of interest for today's meeting.  Thank you.

            CHAIR URBA:  What I would like to do is have the Committee members introduce themselves.

            DR. CHAPPELL:  Rick Chappell, Department of Biostatistics at the University of Wisconsin Medical School.

            DR. ALLEN:  Matthew Allen, Associate Professor, Orthopedic Surgery, College of Veterinary Medicine, Ohio State University.

            DR. CHAMBERLAIN:  Jeff Chamberlain, Department of Neurology, University of Washington.

            DR. KWAK:  Larry Kwak, Chairman of Lymphoma and Myeloma Department at M.D. Anderson.

            DR. TOMFORD:  Bill Tomford, Professor of Orthopedic Surgery, Massachusetts General Hospital.

            DR. CALOS:  I'm Michele Calos, Professor of Genetics at Stanford University School of Medicine.

            MS. DAPOLITO:  Gail Dapolito, Center for Biologics Evaluation and Research.

            CHAIR URBA:  Walter Urba, Chiles Research Institute, Portland, Oregon.

            DR. GERSON:  Stan Gerson, Professor Case Western Reserve University and Director of the Case Comprehensive Cancer Center and The Center for Stem Cell and Regenerative Medicine.

            DR. TAYLOR:  Doris Taylor, Professor of Medicine and of Physiology, University of Minnesota and Director of the Center for Cardiovascular Repair.

            DR. GUNTER:  Kurt Gunter from Hospira, and I'm the Industry Representative.

            DR. WOO:  Savio Woo, Department of Gene and Cell Medicine, Mount Sinai School of Medicine in New York City.

            DR. WILSON:  I'm Carolyn Wilson, Acting Associate Director for Research, Center for Biologics.

            DR. EPSTEIN:  Suzanne Epstein, Associate Director for Research, OCTGT.

            DR BENTON:  Kimberly Benton, Deputy Director, Division of Cellular and Gene Therapy, CBER, FDA.

            DR. McFARLAND:  Richard McFarland, Associate Director for Policy in OCTGT.

            DR. WITTEN:  Celia Witten, Office Director of the Office of Cell Tissue and Gene Therapy at FDA.

            CHAIR URBA:  Thank you.

            I'd like to start by asking Dr. Karen Midthun to come up.


            DR. MIDTHUN:  Good morning.  I'd like to express my special thanks and appreciation on behalf of the Center for Biologics to three of our members who are rotating off their term and completing their term on the Committee today.  These individuals are Dr. Calos, Dr. Tomford and Ms. Terry.  Ms. Terry unfortunately can't be with us today, but nonetheless I just really want to express appreciation for the invaluable advice and countless hours that they have given to us in their efforts to advise us.

            And as you all know, this advisory committee deals with many complex issues, novel treatments that hold potential for great good but also present very complex issues, and we really appreciate your input as it really helps us advance and facilitate the development of these products, and as a small token of our gratitude I have some plaques.

            Let me read what it says.  It says that "This Advisory Committee Service Award is presented to Dr. Michelle Calos in recognition of distinguished service to the people of the United States of America."  Dr. Calos, do you want to come up please?


            (Pause for picture.)

            DR. MIDTHUN:  Thank you so much.  We appreciate what you've done for us.

            Dr. Tomford.


            DR. TOMFORD:  Thank you.

            (Pause for picture.)

            DR. MIDTHUN:  Thank you so much.

            DR. TOMFORD:  Thank you.

            DR. MIDTHUN:  Again, thank you so much.  We really do appreciate all you've done.  It really does help us do our work better and we're most grateful.  Thank you.

            CHAIR URBA:  Okay.  We'll move on to the next point on the agenda and Dr. Wilson.




            DR. WILSON:  Okay.  Good morning.  Now that I'm fully armed.  Good morning.  I'm going to try to review three major areas in terms of CBER's research programs.  First, give you just a brief introduction to CBER's mission, areas of products that we regulate, and how research fits into our regulatory mission and then give you an overview of how CBER manages its research programs and then finish with some themes that have come out from other reviews of Office research programs that occurred during the years 2005-2006.

            So to read the mission of CBER, it's to "Ensure the safety, purity, potency, and effectiveness of biological products including vaccines, blood, and blood products," and I've highlighted for the purpose of today's conversation, "cells, tissues, and gene therapies for the prevention, diagnosis, and treatment of human disease, condition or injury."

            Our vision is to protect and improve public and individual health in the U.S. and, where feasible, globally.  We facilitate development, approval, and access to safe and effective products and promising new technologies, trying to strengthen CBER as a preeminent regulatory organization for biologics.  Importantly, especially for today's discussion with this office in particular, I think, is the use of innovative technology to advance public health.

            As you can see, the products that we regulate cover a wide range, everything from blood, whole blood, and vaccines.  This range of products, of course, have huge impacts on public health and then the types of products that this office regulates somatic cell and gene therapy, devices that are involved in those products, xenotransplantation and tissues and also relevant devices to either tissues or these blood products.  So these together I think that this combination of product portfolio addresses key public health areas while also moving the field of medicine into the 21st century as we already are in terms of developing these very novel approaches to treatment of disease.

            Now CBER's approach to regulation is, of course -- our mission is to work within the legal framework provided by the Food, Drug and Cosmetic and Public Health Service Acts combined with regulations that we promulgate.  But under that umbrella, we use, as you heard, for example, yesterday, fora for external discussion.  Our own research programs at CBER review of data that are submitted within INDs or BLAs or other regulatory submissions and then obviously vigorous internal CBER discussion and from that develop rational policy and decision making.  So the point here also that I meant to highlight is that active research is an integral component to our regulatory process.

            And to make sure the researchers are relevant to the regulatory mission they are fully integrated in that they spend approximately 50 percent of their time doing regulatory work in addition to running their research labs, and the regulatory work covers the full spectrum of work that would be done by full-time regulator reviewers, reviews of INDs, BLAs, other regulatory submissions, actively engaging in policy and guidance documents, meeting with sponsors and advisory committees, working on inspection committees, looking at adverse drug reactions and risk assessment and then, again, performing this research is an integral component to the regulatory work.  And also our research regulators actively engage in outreach, going to scientific meetings of relevance to communicate with stakeholders.

            Our solutions, we use research to both look at long-term programmatic needs as well as providing an ability to respond to crises as they arise.  It's outcomes driven.  We try to identify and resolve specific high priority scientific challenges as we face them in the review of new products.  And we try to focus on critical gaps in the scientific tools and knowledge for product evaluation.  So, for example, if there is a vaccine that needed a better way to study the potency, that might be an area of focus or a safety assay as well as other developing new preclinical models to evaluate product safety or efficacy as well as a range of other activities.

            We try to support product development for critical unmet public health needs, and, where feasible, we use multi-disciplinary, coordinated team research to face these regulatory challenges.  Some of these teams are internal within CBER across various offices, and oftentimes we leverage extensively externally collaborating with other government agencies, academia, and so on.

            So the guiding principles for how CBER manages its research program are that it should encompass the scientific basis of manufacturing, preclinical, and clinical studies.  Outcomes should be taken into account in regulatory decisions, inspections, post marketing surveillance, and guidances.  So again, the point here is that the research is really a critical component to how we do our regulatory work.  We aim for high quality, efficient, and directed research, managed to provide outcomes addressing scientific and regulatory challenges in product development and safety, efficacy, and quality, and, where feasible, the research should be highly collaborative including not just the laboratory but also epidemiologic, statistical, and clinical sciences.

            So this cycle here gives you an overview of our approach to research, and, in fact, actually it's somewhat trivial that we've -- I've numbered this number one but you have to start somewhere.  But this truly is cyclical with each of these steps feeding into the other.

            The other component I wanted to emphasize is that external review and input is an integral component to each and every one of these steps.  I'm going to, in the next few slides, try to break down each of these four areas in more detail so that you can understand how we do each of these steps.

            So, first, to identify regulatory and public health needs, we look at what does our regulatory work load look like, what are the key areas where we have policy needs, and what are public health and emerging issues, often referred to as horizon scanning.  To identify these areas, we solicit the input of our own staff, research regulators, full-time review regulators, management and heavily rely on external input by participation in scientific meetings and workshops, input from advisory committees, and input from external site visit review committees.

            This information then, once this list is generated, feeds into the development of our research priorities.  These are first generated at the center level, and these are taking into account what are some areas that can impact facilitating product development in areas of product quality, safety, and efficacy, and we also take into account what are the ways we can leverage our unique CBER expertise, meaning our ability to look across broad product areas to identify the gaps in scientific knowledge that are needed to facilitate product development.

            To give you an idea of our research priorities for this fiscal year, and this is a list that was developed from CBER's Research Leadership Council.  This is a council of representatives from each of the four product offices that includes both full-time review staff as well as researcher reviewers and the associate directors for research from each office.  First, to improve or develop new methods to measure and augment biological product safety and efficacy; to evaluate, develop, integrate novel scientific technologies to improve biologics product regulatory pathways, availability, quality; facilitate the development of new biological products for high priority public health threats, including pandemic influenza, emerging infectious diseases and agents of bioterrorism; improve clinical trial design and evaluation, including adaptive design approaches; develop formal risk management and risk assessment approaches; and enhance safety surveillance by developing improved analytical tools and accessing large databases.

            Some examples of CBER research programs that were identified as high priority in the form of receiving Critical Path funding for fiscal year `08, I wanted to give you these, one example from each office just to give you a flavor of the types of research that would address these priorities

            In the Office of Biostatistics and Epidemiology, one of the areas is to analyze healthcare databases for biological safety and effectiveness evaluation.  The idea here is that by looking at a much larger database than just that which we have access to within FDA in the form of adverse event reporting, we can identify trends in terms of post marketing issues.

            Office of Blood is doing a program to use proteomics to identify biomarkers that may be predictive of efficacy for stored red blood cell and platelet products.

            Office of Cell, Tissues and Gene Therapies has a program to look at safety and efficacy of adenovirus vectors for gene therapy.

            And Office of Vaccines is developing an in vitro method to predict the in vivo toxicities of novel vaccine adjuvants, the idea being that this would be a faster and less expensive way to screen novel adjuvants.

            So then from our CBER research priorities, this feeds into development of CBER research plans and -- office research plans and priorities.  Again the same three major areas are examined except this time at the office level, and, in addition to those areas, there's also an annual as well as cyclical review of research programs.

            I wanted to just emphasize this for a moment to mention that this includes both an annual review by offices for scientific relevance, quality, and productivity as well as a four-year research program evaluation in the form of an external site visit review which many of you may have participated in at various times for some of the programs within OCTGT as well as an internal peer review through the Promotion, Conversion, Evaluation Committee which involves cyclical review.

            The annual review is a web-based research reporting where we collect scientific achievements in the form of publications, relevant guidance documents, presentations as well as an explanation of future plans, and then this is reviewed by office leadership.

            The programs are rated on the achievements based on the return of research resources expended, looking at the impact on regulatory challenges, what is the quality of the scientific publications and where are they presenting their scientific results, how does the work contribute to development of new policy, impact internationally, and they also are reviewed for their review workload and quality as well.  And then the future research plans are also evaluated, and these include both short and long term, and, again, they should be relevant to the regulatory challenges facing that office or division.

            The four-year cycle of the external site visits involves a site visit team comprised of -- usually chaired and co-chaired by two advisory committee members and then supplemented with appropriate expertise so that we can have relevant scientific input and their reviews -- based on the laboratory unit so that it's not just a research reviewer.  But it's in the context of their research program.  And this includes a very detailed submission by the PI as well as a day-long interaction through formal presentations as well as informal opportunities to interview each principal investigator.  They then draft a site visit report which is presented to the full advisory committee.

            The interval review through the Promotions and Conversion Evaluation Committee, all researcher regulatory staff are evaluated for conversion to permanent staff after an up-to-seven year period where they're in the conversion track, promotions, and every four years for progress.  And the Review Committee is comprised of senior research regulators as well as full-time review scientists, and the review includes not just the research but also a very detailed assessment of their regulatory work and the quality of that work.

            And the committee provides recommendations to the Center ADR and then also just to mention that there are formal SOP and procedures for this committee.

            So then to finish a review of the research management, as you can see, at that output of the research programs, this information then can drive and inform the development of the next cycle of regulatory and public health needs.  Again, as you can see, the external review is really a critical component.

            I wanted to just finish in the last few slides with some themes.  In 2005 and 2006, each of the offices were reviewed by their parent advisory committee supplemented with appropriate expertise to look programmatically at the office research programs which is the focus of today's discussion in terms of the OCTGT review.  But I thought it would be informative to share with you some of the themes that came out of the reports from the other office reviews.

            So, first, committee members who have been familiar with the research programs over a period of years note that there has been a striking improvement over time in terms of focus and relevance.  The research prevented had direct relevance to the critical pathway of biologics product development availability as well as the quality of research has improved.  Many of the ongoing studies are equal in quality to those of the NIH and of sufficient caliber to compete for R01 and other NIH grants.

            The advisory 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 and if we are to maintain our lead in health care development in the U.S. regulatory science needs to be given the priority it deserves, independent of the short-term political and economic flurries that can derail progress.

            Several strengths that were identified, the productivity, the scientific merit, and the mission relevance.  Scientists were well recognized for outreach efforts, complementary cross-office expertise, success at recruitment and retention, development of core facilities within CBER to provide some technology to support the science, and the leveraging and collaboration that goes on with a variety of different academic and government agencies.

            Concerns included the increased regulatory workload without decreasing support and the impact that may have on the research, how to best balance the mission of having research that's relevant without micromanaging the research programs, how to cover many research areas while still focusing on quality in a few areas, and how to develop an explicit strategic plan for the next two to five years getting -- how best to get regulatory and stakeholder input.

            Additional concerns involved needs for improved mentoring, recruitment, and retention, increased research program visibility -- I'm sure many of you before you were tasked with serving on the Advisory Committee didn't even realize FDA had research programs -- continuing education support for scientists, collaboration within and outside of FDA, increased FDA base funding support for research, how to identify new creative leveraging support, and actually on this last bullet, we now do have -- we're getting established a Reagan-Udall Foundation many of you may have heard of which may answer some of these concerns, and, then again, a public relations campaign and system of reward for successful research.

            I want to finish with a quote from the report in November of 2007 from the Subcommittee on Science Technology that was prepared for the FDA Science Board.  Commissioner von Eschenbach asked the Science Board Subcommittee to review the science at the agency level, and the outcome of that was a series of very detailed recommendations.

            But I wanted to note one quote from there that indicated that "CBER has a rigorous process for establishing priorities and the impact of Center research on regulation.  In addition, the leadership of CBER insists upon integration of laboratory science both in the review and manufacturing site inspection process."  And then again to emphasize, "External peer review of research program is the norm rather than the exception."

            So, finally, I wanted to thank you for your time, expertise, and input into our research programs, and, as you'll hear from Sue in the next talk, I think that the input that OCTGT received was very valuable, and they've considered it very carefully.  And I think we're going to take questions after Sue's talk.  But I thank you for your attention.


            CHAIR URBA:  Dr. Epstein.

            DR. EPSTEIN:  Okay.  Before I start the presentation, I want to first say a few words about Eda Bloom.  As many of you know, Dr. Bloom passed away unexpectedly in January, and we have lost a dear colleague and friend.  She contributed in many ways to CBER and to the public health community.

            Her research career of almost 40 years included work on topics including natural killer cells, regulation of immune responses to xenotransplants and, most recently, immune responses to allogeneic stem cell derived cell populations.  She was an insightful regulatory reviewer, an outstanding mentor of new reviewers as well as research fellows, and a leader in policy development in the area of xenotransplantation.

            She was my branch chief in the Gene Therapy and Immunogenicity branch of DCGT and a leader at CBER in many other capacities.  We greatly miss her presence and contributions.

            So I'll now be talking about the same topic Carolyn Wilson discussed but specific to OCTGT.

            The Office-wide site visit was held in 2005 as part of the CBER research management initiative, and the purpose of today's session is to respond to the recommendations, to indicate to those who review our programs that their input has an impact, and to provide information in an open public setting about our research programs and reviews of them.  This can provide transparency and accountability.

            I'll be discussing first an introduction to OCTGT and its products and programs, then the site visit process and report.  I'll then describe our research management and progress we feel we are making responsive to the recommendations in the report and then give a few examples of the research initiatives.

            The mission of OCTGT is to facilitate development of, approval of, and access to safe and effective medical products in the areas we review.

            The structure of the Office is shown here.  In addition to leadership and a regulatory management group, there is a Division of Cellular and Gene Therapies where the laboratory programs reside, a Division of Clinical and Pharmacology Toxicology Evaluation, and a Division of Human Tissues.  So all the research programs I will be describing are -- well, they're mainly within DCTG with interactions with the Clinical and Human Tissue groups.

            Here is the structure of the Division of Cellular and Gene Therapies.  There are review branches dealing with gene therapies and cell therapies and then the three branches that include laboratory research as well as regulation are Gene Transfer and Immunogenicity Branch, Tumor, Vaccines, and Biotechnology Branch, and then the Cellular and Tissue Therapy Branch.  There are currently ten principal investigators.

            This slide lists the products regulated in this office.  As Dr. Wilson mentioned, cellular therapies and gene therapies are included.  Tumor vaccines and immunotherapy can overlap both of those other areas.  Then tissue and tissue-based products, xenotransplantation products, a variety of combined products, and then devices that are related to the cellular and tissue products.

            The regulatory activities include a large number of INDs and amendments, one licensed product, and a growing number of products in Phase 3, a variety of devices.   Tissue regulations are established in this office.  We do a lot of pre-IND meetings and pre-pre-IND consults as you heard about yesterday as well as advisory committee meetings, inspections and then considerable effort has gone into enforcement actions on occasion.

            Our research strategies cannot include work on every type of product because the products are too diverse.  So we review new types of products.  To facilitate their progress towards delivering public health benefit, we have to work at the cutting edge.  In fact, we have to help define the cutting edge.  So our role is to stay ahead of the curve to prepare the way for anticipated products which can be complex, as you know, to perform studies relevant to entire product classes rather than one individual product.  A sponsor might study their product, but we try to look at the foundations for all the products.  And then to make the results public and thus accessible to all sponsors to advance the entire field.

            The main research areas are indicated here that support work on all these product categories.  We have virology research, immunology, cell biology and differentiation including stem cell biology, cancer biology, biotechnology approaches including microarray analysis, flow cytometry, and proteomics, and then in addition to the laboratory-based programs, we have some work in the area of clinical trial design.

            I'll now describe the office site visit process that led to the report we are responding to.  The office site visit was held to obtain suggestions concerning OCTGT research from experts in appropriate scientific and clinical fields.  The reviewers were 11 experts from academia, government, and industry who formed the CTGTAC Research Review Subcommittee.  We provided to them an extensive briefing package about our regulatory roles, our research programs and accomplishments, research management approaches, publications, and then on the Davis site visit there were extensive oral presentations.

            The benefits of this were we received their insights and suggestions.  The process provided transparency and accountability, and this is an opportunity to inform stakeholders about what we do.

            They drafted the report that went to this present advisory committee, and at a public meeting in 2006 the report was approved by the full advisory committee meeting.  Follow-up to the report has included our internal discussions leading to today's meeting.  We provided a briefing package for this meeting that contains more details than I will have time to present now about their comments, our responses, and our progress.

            There have been other CBER site visits as mentioned by Carolyn.  There have been office site visits to review the programs  in the Office of Blood and Vaccines, and the reports have been received.  The Office of Blood has already responded in this same way at a public advisory committee meeting, and the vaccine response is pending.

            In their report, the site visitors commented about our research management approaches.  They had comments in the areas of recommending explicit research priorities obtained by horizon scanning and they had recommendations about annual reporting and assessment, about internal resources and outside funding, recruitment and retention practices including mentoring and professional development, communication and collaboration, and they emphasized it was important that the research management process should stimulate innovation and creative problem solving, not  become micromanagement.

            They also divided their report into areas referring to the particular product areas on which they had expertise, gene therapy, cell therapy, combination products, xeno, counter-terrorism, tumor vaccines, and bioinformatics.

            I'm now going to summarize briefly a variety of our management initiatives that are responsive to the recommendations in the report and in which we feel we are making some progress.  I'll be discussing a little bit about the Research Leadership Council, communication, collaboration, some examples of activities, then how do we do our horizon scanning, what are the actual priorities of OCTGT, and a little about ongoing recruitments and funding.

            Carolyn described the Research Leadership Council which includes both researcher reviewers and regulatory scientists from each office, plus Center management.  The goal is to have transparent procedures that are shared across offices and explicit priorities so that we aren't just each doing things differently.

            So the CBER priorities have now been identified and announced, and she showed them to you.  We then identified office research priorities from workload analysis as well as horizon scanning, and our research programs are now expected to address these priorities.  Evaluation of the research programs is linked to their budgets.  So there are consequences.  And we have initial development of an automated regulatory workload system.  We're working on that.  It's not yet available.  We're also working towards a scientific expertise database.

            Some of the communication tools within the Office include work-in-progress talks.  The frequency was increased in response to the report.  The website includes annual reporting and brief summaries.  We get input from all the staff regarding priorities and recruitments.  And then an OCTGT leadership meeting or go-away within the building was held in November 2007 to discuss our research priorities.

            To communicate beyond our office, we used briefings of the Center and Agency leadership.  The FDA Science Board review was an opportunity to discuss research broadly with others.  There is a new FDA website that includes our programs.  For communication with stakeholders outside the Agency in fiscal `07, there were 32 research publications that came out of this office as well as contributing to regulatory publications and guidances.  And then we give talks at scientific conferences, workshops, and meetings as another way to communicate with stakeholders.

            The site visit report mentioned collaborations. So I have just listed here a brief summary of the collaborations.  I won't read them all, but the point is there are extensive collaborations of OCTGT investigators with other laboratories in the government.  These are many institutes of the NIH as well as The National Institute for Standards and Technology, CDC, and The National Toxicology Program, and then there are collaborations with a variety of academic centers throughout the country and in other countries.

            To give just a few examples of the other activities in the Office that provide the context for the research and that draw upon the research, in October of 2007, a Tissue Processing Workshop was held, also a Workshop on Clinical Use of Biomarkers.  In December, FDA collaborated with the National Institute for Standards and Technology on a Cell Scaffold Workshop.  We participate in the Interdisciplinary Pharmacogenomic Review Group, and here are some ongoing partnerships in which OCTGT participates: the NCI Interagency Oncology Task Force, the Multi-Agency Tissue Engineering Science or MATES working group and a Biomarker Consortium which involves a variety of Federal agencies plus other sectors including the private sector.

            This is a very brief listing of examples.  There could be a whole separate presentation on the activities and outreach activities of the Office.

            In terms of our horizon scanning, product trends are noted from submissions as well as pre-submission inquiries, scientific conferences, and the general literature.  We try to anticipate areas of major product activity that are related to Critical Path issues, and then we monitor for gaps and weaknesses or redundancies in our own staff expertise and address them.

            I'll now show you the priorities that were announced for this year.  These will be an evolving set.

            First, the development and evaluation of methods and standards for improved product characterization, including definition of product biomarkers predictive of safe, effective, and consistent product performance.

            Secondly, development and evaluation of non-clinical methods informative about the safety and efficacy of our products.  This includes both preclinical animal studies as well as in vitro studies, so thus, non-clinical.

            Thirdly, participation in CBER, FDA, and Department-wide initiatives including risk assessment, clinical trial design and monitoring, development of biomarkers, counter-terrorism, pandemic influenza preparedness, and HIV/AIDS programs as well as Office-specific initiatives in these areas.

            And fourth, improvement of the microbial safety of human tissue products by development and evaluation of methods for better processing conditions, pathogen inactivation and/or pathogen detection.

            This last one is a new area, and I'll return to this.  So these are very broad priorities.  We are not trying to micromanage the programs.

            I'll now discuss the recruitments of the recent past and then the ones that are currently ongoing.  Since the year 2000, we've had several recruitments.  In each case, a scientific gap was identified and the field of expertise endorsed by the Center.  Then an open public recruitment with a search committee was conducted.  The last five PIs recruited were all from outside the government.  They were in fields of development and cell fate, adeno and herpes viral vectors, organ development, and proteomics, and they came from these institutions.

            We have a recruitment ongoing now in the tissue area.  I referred to that new priority.  The history here is that in 2005 the tissue industry was required to begin submitting adverse events.  This is work of our Division of Human Tissues that's developing new regulatory paradigms.

            In 2006, 147 adverse reactions were reported, although not all of those are necessarily due to the tissue.  In 2006, the Human Tissue Task Force was also established and again planning additional regulatory activities.

            In 2007, the public health issues that had been highlighted by these events showed us that we had scientific gaps in our programs.  This led to planning a laboratory program in DCGT to work on human tissue safety.  This is in coordination with the Division of Human Tissues and the Office of Compliance and Biologics Quality, and our recruitment of a first principal investigator is now in progress.

            There are two other recruitments currently in progress.  Sorry, one has been completed.  In Virology, an investigator has just been recruited to start a new program in DCGT.  He has experience in lentiviral vector research and as the director of a core facility producing adenoviral, AAV and lentiviral vectors.

            In Immunology, immune regulation and tolerance has been identified as a gap in expertise that is needed for regulation of gene therapy, cell therapy, and xeno products, and a search is in progress.  So these are staff replacements.

            There were recommendations concerning funding sources and since CBER scientists are not eligible for many major grants, we seek other sources.  The mechanisms we use are interagency agreements and cooperative research and development agreements to avoid conflict of interest.  Several of the sources currently being used are the Interagency Oncology Task Force with NCI through a training program, the FDA Critical Path Initiative, Pandemic Influenza Initiatives, and, in the counter-terrorism area, various grant programs that address infectious agents and emerging threats and then chemical, biological, radiological, and nuclear emergencies.

            I'll now give you just a few examples of our current research initiatives.  There were more examples described and in greater detail in the materials on which these various reviews were based.  That is the briefing material for the office site visit and for the FDA Science Board.

            One project is addressing gene therapy risks and is in collaboration with the National Toxicology Program through NIEHS and some academic partners.  We recognize the need for new pharm-tox models for the unique risks in gene therapy, and Dr. Wilson has coordinated this program establishing a preclinical model for assessing the risk of retroviral vector-mediated insertional tumorigenesis.  This will permit comparing modified vectors and new types of vectors to see if they provide reduced risk.

            The animal studies involved use large sample sizes and are very long-term studies.  So it would not be possible to carry them out at CBER alone, and it would not be possible for single sponsors to carry them out.  So this consortium approach is leveraging the answer to an important public health question.

            Another project is addressing adenoviral vector issues.  Why are adenoviral vectors cleared so quickly?  Intravenous use of gene therapy vectors to target disseminated cancer cells might be a valuable approach.  But with adeno, the pharmacokinetics are very unfavorable.  They disappear quickly.

            The CBER research finding is that adenoviral vectors are rapidly recognized by scavenger receptors and are cleared by Kupffer cells in the liver, thus removing them from the system and preventing them from reaching their targets.

            This has implications that might be useful.  If you could block the scavenger receptors, you might have an ability to reach the targets more efficiently.  This problem is a hurdle in the path to effective therapy which then could use lower doses and thus would be safer.

            Another example is a collaboration with NIST looking at improved characterization of human mesenchymal stem cell based products.  The goal is a simple and robust measure that can predict the differentiation capacity of these cells.  NIST provides computerized, high throughput cell measurements of size, morphology, proliferation rate, and biomarker detection.  DCGT provides quantitative bioassays for the frequency of progenitors.

            These mesenchymal stem cells differentiate into three lineages.  They have  progenitors for fat, cartilage, and bone, but those assays take a very long time.  Those would not be good product testing assays.  So the approach is to find out whether NIST measurements that can be made rapidly and quantitatively correlate with progenitor frequencies in the mesenchymal stem cell population.

            We also have research programs related to CBER, FDA, and Department initiatives as I mentioned in one of the priorities.  These are related to emergency responses, counter-terrorism, and pandemic flu.  So we have projects on blocking of Ebola virus infection, on new approaches to control of pandemic influenza, and to cell therapy for radiation exposure.

            There are also laboratories that have established cutting edge technology which will be valuable in product characterization.  We're using gene expression microarray and proteomics to provide high throughput screening and detailed information.  These can be used to characterize cellular products or cell substrates for manufacturing other biological products.  These could be gene therapy vectors or vaccines and they can also be used for characterization of patient samples.

            OCTGT has also contributed to development of reference materials that are important in moving our product areas forward.  A retrovirus reference material was developed.  Carolyn Wilson led that effort.  It was developed by CBER and is now available from ATCC to investigators throughout the world.

            An adenovirus reference material was developed by a consortium which included multiple members of OCTGT staff as well as other partners.  That reference for adenovirus standardization is now available also from ATCC.

            External RNA spike-in controls are being prepared and will be valuable for standardizing PCR and microarray analyses.

            In the area of quantitative flow, CBER has collaborated with NIST to develop standards.  These are now available for distribution from NIST.  They include a fluorescent standard solution and fluorescent microbead standard.  The value here is if flow cytometry is standardized from one site to another and one day to another, different clinical sites and different patient evaluations can be directly compared quantitatively.

            So to summarize, our research deals with new products that present novel scientific and regulatory challenges and opportunities.  We identify questions of regulatory importance and address them.  The solutions to key problems can contribute to patient safety and product development and can inform our regulatory decisions and policy.

            To quote just one bit from the office site visit report, they felt that "new treatment modalities like cell and gene therapy will never move from effective laboratory reagents to products for patients with disease unless the FDA maintains a strong cadre of researcher-reviewers," and "an active research component within the FDA is essential."

            So I want to join Carolyn in thanking you for your attention to CBER research programs, and I want to thank many OCTGT colleagues for contributing to this presentation and to Gail Dapolito and the Advisory Committee staff for organizing the meeting.  Thank you.



            CHAIR URBA:  Thank you, Dr. Epstein.

            Questions from the Committee?  Dr. Taylor.

            DR. TAYLOR:  You showed us an organizational development chart in one of your slides, and I guess my question is who within that organizational structure sets these research priorities?

            DR. EPSTEIN:  The office leadership does it in consultation.  I'm the Associate Director for Research and working with Celia Witten, our Office Director.

            (Off the record comment.)

            DR. EPSTEIN:  So Celia Witten and all the office leadership.  Stephanie Simek is the Deputy Director.  I'm the Associate Director for Research.  Richard McFarland.  Then the division directors, Raj Putri, Ashok Batra, and Ruth Solomon, form a management group and as in my role, it's my responsibility to seek them out, communicate with them, bring issues to their attention.  They bring issues to my attention as well.

            For example, the area of Human Tissues was a collaborative development between the public health team working on tissues and making us aware of those issues and then with Dr. Puri and Dr. Witten, the idea was developed that there should be a laboratory program.  They took that to CBER leadership.

            So the list of priorities I showed you was drafted by myself and with input from a lot of people and then went through many iterations with first the management team and then the entire office for input.

            DR. TAYLOR:  So you said there is some sort of leadership council or research leadership group or some -- I didn't fully understand that.  What is that and how does that --

            DR. EPSTEIN:  I'm sorry about one semantic thing I may have made confusing.  The Research Leadership Council is CBER-wide.  I should use a different term here.  But within OCTGT the leaders listed on this slide.  It's basically the Office director, deputy director and the division directors and the associate directors form a group that discusses priorities.  They don't discuss each research project or the budgets and the evaluations and all that.  But they discuss the priorities and they attended this Go-Away that was a half day meeting last November to examine the priorities proposed by myself and the research staff and the other people who had contributed and see if it addressed the proper public health priorities.  They had contributed some of those themselves in earlier rounds.

            There are meetings held periodically both at NIH and at Woodmont which is the site of our full-time review offices to accept input from horizon scanning.  So it's a two-way interactive process.  This is the leadership.

            DR. TAYLOR:  And one final kind of follow-up to that to try to put it all together for me.  You've talked about the research priorities.  You all were -- it was suggested that you create a two-year and five-year plan and who -- is this the group that does that?  Are you the person who does that and who then, if that's true, who then checks to see if scientists within your program are fitting within that two- to five-year plan?

            DR. EPSTEIN:  Okay.  Very good.  The two- to five-year plan is reflected in the priorities which will be evaluated every year.  But similar to the research programs, there will be an even more intensive four-year cycle approximately of going more deeply into whether changes are needed.

            The evaluation of whether the principal investigations are addressing the priorities appropriately is conducted once a year and then more intensively every four years.  The annual evaluation is by the division director, associate director for research and then with input from the office director.  The in-depth, every four years evaluation includes external peer review.

            And in the future -- this is the first time we've had such explicit priorities.  A laboratory-based site visit in the future will have a copy of the current version of the "priorities" and in the past what we did was to say what products were regulated in that area and how this person's work was relevant.  But it will now be all explicit and so we will have both internal and external review.

            Carolyn, did you want to comment?

            DR. WILSON:  I wanted to just add one additional point to what Sue said which is this year we're actually doing a new process within the Center which is each of the product offices are developing research program plans which do provide a broad framework programmatically for the direction of their research programs incorporating into that what is their regulatory portfolio.  From that, are there critical gaps in scientific knowledge, areas of future direction that they would want to pursue if resources were available, and then also a section that will sort of link the research priorities to the previous year's scientific accomplishments and how those are linked.  And this is sort of a pilot this year, but we hope that every year after that.  And that's reviewed at the Center level.

            DR. GERSON:  I wonder if I could comment after having observed and watched and reviewed for a short period of time about to me the remarkable accomplishments of this effort and of the strategic response, if you will.  It is not easy to move an organization and to move a scientific group.

            I think I see an incredibly reaction to the rapidly moving field and your desire and capabilities sort of keep up both at the cutting edge in terms of the research efforts and the issues that the field is raising.

            And, if you will, it's astonishing to me that you have on your shoulders the need to engage with every type of this broad base of product development and have expertise in it both of the research and of the review process.  So I really am humbled by the accomplishments that I see and the rapidity of the response and the creativeness that you've taken in organizing the office around the issues that came up during the review.

            DR. WOO:  I would add my support to that comment just made by Dr. Gerson.  I think it's very important for the FDA to continue with this research program so that you can talk the same common language with the stakeholders when they come to you and you understand what the issues are and what are the problems they face and so this interaction is critically important and many of us on the outside appreciate this very much.

            My question to you is that you have mentioned that you have a priority setting mechanism in-house, whatever the name of that is, to identify new areas that are important for public health and so on and so forth, and that's wonderful.  My question to you is that with the limited budget it's one thing to identify new areas to focus your research efforts on.  What that means is also that you have to discontinue some of those other less important areas.  So I was wondering.  Do you have a mechanism of doing that as well so that it would facilitate your ability to continue with this wonderful process?

            DR. EPSTEIN:  You're aware of something that's certainly a reality.  We do seek new sources of funds and have had some success.  So not everything is a replacement.  But I mentioned some of our recruitments happen to be replacements for departures.  Then Tissues is a new initiative that is additional that if there's a new public health problem of magnitude that gets the attention of the Center and agency level it can be possible to launch a new initiative.

            But then a lot of it otherwise is the gradual shifting of investigators if they've finished answering a question and they  themselves perceive a new area rising in importance, our staff are fairly nimble, and we have had staff members not change their whole field, it would be within virology or within immunology, but they move on to tackle that issue that they see.  There have been some very productive shifts.

            DR. KWAK:  I have two comments.  Actually, the first is a comment and the second is a question.  First is to simply congratulate you on the recruitments, and second is a question just of clarification.  How does this site visit that you've described differ from the every four year laboratory site visits that we participate in?

            DR. EPSTEIN:  Okay.  Good question.  The every four year laboratory site visits are at the individual investigator level.  They involve very detailed presentation of data both in the briefing package and in the presentations on the day of the site visit, and those are for evaluation of individuals for productivity and relevance, and that feeds into their conversion which is the equivalent of tenure or promotion.

            The office site visit was much broader because it covered all the laboratories.  So it could not drill down to the level and was not intended to drill down to the individual performance issues and the individual projects.  It was intended to look very broadly at the portfolio, the research priorities, the procedures and management practices of the office and make recommendations very broadly about how we conduct the research programs.

            So the every four year laboratory site visits will continue.  That's simply how we have outside peer review of our staff.  The office site visit was a unique event which may be performed again at some future time, but it's more like a blue ribbon panel evaluation of the whole FDA but at the office level.

            CHAIR URBA:  Dr. Chappell.

            DR. CHAPPELL:  I echo others' congratulations of your programs and also ask that you mentioned the existence of a biostatistics office which does important analyses of data sets and also yesterday the issue of design arose, and so I was wondering if -- and I think this is a relatively new area in which new designs may be needed or at least considered for Phase 1 and higher level trials.  So is that a priority?  I mean I would hate to add anything to your list and tell you what to delete.

            DR. WILSON:  Those may or may not overlap with the office priorities, but at the Center level, I probably went through it pretty fast, but we actually had three Center level priorities that were related to biostatistics related to clinical trial design as well as surveillance issues for post marketing.  But there is a very active effort right now to improve clinical trial design methodologies, incorporate Bayesian statistics and that kind of thing.  So our Office of Biostatistics and Epidemiology is actively engaged in thinking about those new paradigms for clinical trial design.

            Does that answer your question?

            DR. CHAPPELL:  Sure.  Who is the head of that now?  I think it changed recently.

            DR. WILSON:  Right.  The new Office director is Robert Ball, and Steve Anderson is remaining as the deputy Office director.

            DR. CHAPPELL:  Thank you.

            DR. TOMFORD:  Thank you.  That was a good presentation.

            I'm intrigued by the idea of horizon scanning so that hopefully you pick up problems or potential problems.  How do you interact with the private sector?  You know, there are about 1.5 million tissues transplanted annually now.  Let's say you see a potential area of problems or a few problems that have occurred.  What is the -- do you have interaction with this non-governmental sector?  How does that occur, or do you do basic research yourself?

            DR. EPSTEIN:  There could be several parts to the answer, but I want to mention how it works for other products as well as tissues.  We have pre-IND contacts and pre-pre-IND contacts.  In the tissue area it would be other communications.  But the fact that people talk with us at meetings and on the phone and to ask us questions gives us some sense of what's going on.

            Then in terms of if a problem develops, our response can be multiple.  There will be people in the Human Tissues Division who are engaged in regulating that industry who may be talking with those centers and working out the response to the problems.  The research program will support that by addressing underlying scientific questions.  For example, is there a way of processing that could get rid of new organisms?  Say there is some cutting edge technology that people aren't even aware of yet or can be developed that could either get rid of organisms, could detect more sensitively than just taking a swab from the outside, could be more representative than a snip.

            So the research program will be interactive with the Division of Human Tissues and the Office of Product Compliance.  I never get the name of that office right.  It was on the slide.  Those groups are involved in the tissue inspections and so on.

            The new Tissue Research Program will interact with them and talk with them.  Information will flow in both directions, and then we would hope the research will lead to some solutions to some of these problems or at least ideas about how to better define and measure the problem.  That's often a step forward in itself.

            DR. WITTEN:  I'll just add.  We do have also the regulatory component that has regular discussions with AATB, EBAA and other organizations that are involved on the outside with tissues across the board, cord blood programs, and, as Dr. Epstein just said, when we have the research program up and going then I think it will be sort of a three-way dialogue, the research and regulators together, and there will be some discussion with the outside groups like AATB.

            DR. TOMFORD:  I think that's good because a lot of these groups don't do a lot of research as you probably know.  So I think the office can function at least in promulgation of research efforts or ideas in that area.

            DR. WITTEN:  Yes, I think that's exactly part of the goal of that program is to do research but also stimulate some work on the outside in some of these challenging problems.

            DR. GUNTER:  I guess my question is for Dr. Wilson, and it has to do with the promotion and conversion activities, and I think you said that the scientists in the office are looked at both on their research and regulatory activities.  But how is that weighted?  Are they 50/50?  Is research more important?

            And then I have a second part.  Can you give me a sense or give us a sense as to how the regulatory burden is trending over the last few years for the individual reviewers in the office?  Are they having to do more regulatory work at the expense of research, for example?

            DR. WILSON:  Okay.  I will answer the first part which is that when the committee reviews each individual investigator it really is a 50/50 balance in that the review process involves an assignment of four individuals to each package that comes before the PCE, and those four individuals are two research review scientists as well as two full-time review scientists.  So each is tasked with -- obviously, the research reviewers are looking very carefully at their research outcomes and productivity and quality taking into account the site visits, external recommendation letters that are required in addition to a recommending memo from the division director that gives a narrative of their research accomplishments and the relevance to the regulatory program.

            And then the full-time reviewers are looking -- they are given specific examples of review memos, a portfolio of their review workload.  They do detailed interviews with their branch chiefs and division directors to assess the quality of their review work.

            So really it's very important that both of these are weighted carefully because you may have the most stellar scientist in the world, but if they're a complete disaster or ignoring their review work, then obviously that's not the type of individual we would want to retain.  So it's very important and very different for CBER in that respect that our research scientists are competent and dedicated to both aspects of the their work.

            In terms of the regulatory workload, that's a more difficult question to answer partly because as Sue can attest to because she's tried really hard to do these analyses, it is sometimes very challenging to get an accurate picture of what the regulatory workload looks like, and this is confounded because, for example, one IND may have 200 amendments in a given year.  But those amendments may be very trivial and take five minutes of a reviewer's time.  So counting 200 amendments versus maybe one amendment that took two weeks to review, it's just really apples and oranges.

            So these are really challenging issues.  It's something that both the Offices and the Center are trying to address to get a better metric on how do we measure the regulatory workload.  So I can't really address that as well as I can.

            I can say that the Center this year has been fortunate, and we've received an additional 84 FTEs.  Many of those are, I think almost all of them are, going into review positions and so this should help alleviate the review workload in coming years.  Obviously, right now, we're in the process of recruiting and filling those positions.

            DR. EPSTEIN:  We have tried a system of putting INDs into three tiers, very active and original submissions and controversial ones, ones getting a few amendments and ones where it's just the annual report.  So it is possible to try this form of analysis and, Stephanie, you may want to comment.  I think there's no question the workload has gone up.

            DR. WOO:  Having participated in one of these reviews recently and appreciating the importance of these researchers and reviewers, the dual function, I would urge the Agency to protect these researcher reviewers in terms of their research time.

            I understand the importance of review.  Obviously, this is the FDA, and I understand that.  But if you are going to do research with less than 50 percent time or when you're in the middle of your very exciting research program and you get pulled away to do an IND for months, this is not conducive to productivity in research, and if we are demanding that your researcher-reviewers to be competitive with the outside review groups and to publish in quality scientific journals, then I think you are really asking too much of your researcher-reviewers.

            So it's critically important in my mind for the Agency to protect these folks, to have at least 50 percent review time and -- otherwise, you're putting these people's careers at risk.

            CHAIR URBA:  Dr. Puri had a comment and then Dr. Taylor.

            DR. PURI:  I also wanted to comment on the question from Dr. Gunter that we do have 50/50 workload for 50 percent research, 50 percent review.  But most of how our staff does actually not do only 40 hours a week.  They work a lot more than they are required to, and actually it's a balancing act, and as you heard from Dr. Wilson that you can't actually tell when you're going to get too many, you know, one particular amendment have a lot more work than the others.  But I must say that most of our staff spends more time in doing regulatory work than the research.  But they balance it by adding on additional hours like you folks in the academic institutions and others as well.

            And I appreciate Dr. Woo's comment about protecting our research which is a -- provides underpinning to regulatory research as well as regulations.

            DR. TAYLOR:  I actually want to follow up on that if I could and then also ask the original question I wanted to ask.  In terms of having participated in two of these site reviews now, the issue that seems to emerge over and over and over is that there are some incredibly productive, great scientists doing fabulous work at the FDA, and they seem to have increasing regulatory workloads that limit their ability to do their work.  So I echo Dr. Woo's concern in that regard and that's come up at every site visit in which I participated.

            But the other thing that's come up is there are unfortunately some scientists who aren't as productive as they could be in terms of peer reviewed publications and top tier publications, and when we've tried to dig deeper into that, one of the issues that seems to come up is they don't feel they get the guidance they need or the mentoring they need.       And so I know that's been an issue of conversation, and I'd like to know what you have put in place to help these scientists who aren't perhaps right on track going forward.

            DR. WILSON:  CBER-wide in the past year, we've instituted a formal mentoring program which involves actual deliberate pairing of individuals with a mentor and then the individuals who elect to participate in this program receive specific training about mentoring.  What are the expectations of a mentor?  What are the expectations of a mentee?  What are the responsibilities of both and so on?

            But in terms of research scientists, they can choose to participate in this formal mentoring program, but it's certainly not required, and so I think your point is well taken that the way process works now is that the mentoring is really the responsibility of the individual scientist branch chief to make sure that that individual investigator is on track and is maintaining product of quality research.  But I certainly take your point that that type of mentoring may be uneven across the Center, but it is something that we are trying to address, and Sue may have some additional points to add.

            DR. EPSTEIN:  I was going to mention both of those and then just the fact that if there isn't progress, the individual scientist is brought to discussions with the leaders.  That would be noticed before, say, a four year laboratory site visit.  It's not a perfect world, and there's a spectrum of the outcomes, but the effort to advise people about how they can become more on track, say, where on track includes both relevance and productivity, those efforts like the other efforts to announce priorities are becoming more explicit.

            They used to be implicit.  In response to the recent office site visit report, all of these activities are more forefront and more explicit.  The outcomes will still be a spectrum, and that is part of -- the consequences  include budget and tenure decisions, for example, and not everyone achieves tenure at CBER.

            DR. TAYLOR:  I had my original question, but if you have a follow-up.

            DR. SIMEK:  I just want to make a point that as Carolyn mentioned we do understand the issue of our researchers.  It's a very difficult position to be in, and they really need to be credited with what they do.  They spend a tremendous amount of time doing both regulatory and research.  What we have been lucky this year as Carolyn has mentioned is we have received a number of positions that are for full-time reviewers.  Now this in no way -- our review load increases every year and so we are hoping that with this increase in full-time reviewers this will be able to help our researchers.  I mean, they still do their considerable load of regulatory work, but it will allow them to do the research that's extremely essential to be able to help with the mission of the FDA.

            So this in answer to, Dr. Woo, one of your questions is this is one way that we have been fortunate to be able to handle this situation.

            DR. TAYLOR:  Can I ask my original question?  When you were discussing research, you used mesenchymal stem cells as an example of an interaction with the FDA and NIST, a collaborative effort to look at -- to try to develop some high throughput assays for predicting differentiation.  So mesenchymal stem cells are one kind of cell and the differentiation markers you're looking at are very specific for even subpopulations.

            And I guess in terms of relevance, my question is how do you generalize these kinds of findings and obviously you're asking one very specific research question which we all have to ask to move science forward.  But it seems to me that the goal of the Agency is to develop broader, more generally applicable assays.  And so are these kinds of questions viewed as frameworks and models and proofs of concept so that you can go forward and develop more broadly applicable programs?  Help me here.

            DR. EPSTEIN:  I'll give you an analogy.  If we want to study viral vectors we have to study a particular viral vector, and suppose we solve the problem of standardization of retroviral vector assays with reference material and RCR testing, but then the whole field moves on and those vectors are no good anyway and gene therapy starts to use AAV, by horizon scanning we would realize that and move on.

            We always have to pick a particular example, and it may not always even be the example of the broadest product use at that moment.  But it's partly what you said about proof of concept.  It's partly that stimulating interest in the whole field in this case in a more quantitative approach and in assays that can be carried out more quickly, for cell therapy in general we want to stimulate use of biomarkers or other parameters that can be measured before the cells all die and that won't consume all the cells in the process of measuring it.

            So, yes, we do like everyone have to pick out examples to work on, and we may not always be able to move on to a particular example that solves the whole field, but we will be much better informed in viewing other assays for having this experience.

            CHAIR URBA:  Dr. Witten, it looked like you were going to make a comment.

            DR. WITTEN:  I think Suzanne made it which is primarily one of the goals is to  stimulate interest in the field in this type of method.  If it proves to be useful, I don't think the goal would necessarily be that FDA develops or FDA and NIST develop this method for every type of cell marker but that we would show that this method was possible, could be useful, and hopefully if it was something useful to the field would get developed further in the specific cases where it's needed.

            DR. GERSON:  Implicit in our discussion about how you've redirected the research orientation of the Agency and some of the priorities of interest and investment, is a dissemination of this effort through all of the resources you directly control and perhaps even more through the collaborations that you've very effectively showed us?  But you didn't describe terribly well for us actually how it gets to the troops, if you would pardon the expression, folks who are in the laboratories whether they be principal investigators or the associates or technicians who would be involved in some of the shifting of research efforts or the encouragement of these collaborations that you want to be strategically prioritized.

            DR. EPSTEIN:  So you're saying how do we communicate with our own staff the need for the shifts.  You don't mean how do we communicate our research results to the outside world.

            Okay.  Within the division or the office, the principal investigator is the nidus of this kind of decision making.  I work a lot with the PIs to advise them about being more clear and explicit in explaining their research.  They have to be able to explicitly connect what they're doing to the priorities or to the products we regulate.

            In terms of the post doctoral fellows or technicians, it's less important that they be fluent in this kind of dialogue, but their research will be directed into a reasonable area by the PI and as they mature and may become part of the CBER staff, they also will attend meetings where they hear all of this.

            But the most important level to communicate it to is the PIs because they have to both make good decision about what to do, and they have to become communicative about why that work addresses that priority.  That latter part is something where I feel many of our past problems lay.  People might be doing projects that were of reasonable public health value, but they were not explaining it explicitly enough, and someone not in the field might not realize the value of why are you doing that.  So we are working hard.

            This is true of science in general.  If scientists won't speak in a manner that others can understand, we won't be funded.  It's critically important, and Dr. Gooden has now hired a communications expert who is a very good writer who used to be at St. Jude's, and we're working with him.  He may be able to assist us in getting the word out about some of these projects.

            CHAIR URBA:  Other comments?  Questions?

            DR. GUNTER:  Well, this is just a very specific question, I guess, for Dr. Epstein and has to do with the discussion yesterday on embryonic stem cells.  In part of your horizon scanning process, where do you see that, and do you have the expertise in-house now to review those kind of products and, if not, what are the plans to obtain the expertise?

            DR. EPSTEIN:  Okay.  We have expertise in-house based on reviewing other kinds of cellular products, work on other kinds of stem cells.  I do -- as I mentioned very briefly, Dr. Bloom was actually working on embryonic stem cell lines and looking at immune responses to them.  So this is a bit early for me to try and -- it's a sad loss for us that we did have that very specific expertise.

            But we still have in-house expertise on laboratory use of other types of stem cells and from yesterday's discussion it's not clear the problems will be always different.  There will be perhaps different awareness of certain risks.  Whether it calls for a new laboratory program, I think that's a matter for future discussion.  It's not clear. 

            If anyone else wants to comment, but we do have a very active program in cell biology and work on cell-based therapies.

            CHAIR URBA:  Thank you.  We set aside a few minutes for open public hearing.  It's scheduled for 9:45 a.m. after the break.  But I thought we might open the floor at this time for any comments from the public.

            If not, I guess it's probably good to take a break now then.  Is that okay?  Yes, we'll take the break now, 15 minutes.  We'll meet back here at 9:40 a.m. and hear from Dr. Benton.

            (Whereupon, at 9:23 a.m., the above-entitled matter recessed and reconvened at 9:42 a.m. the same day.)

            CHAIR URBA:  Okay.  It looks like we're about ready.  Before I introduce Dr. Benton, Dr. Taylor had one additional comment she wanted to make about this morning.

            DR. TAYLOR:  I appreciate it.  I just wanted to make one more comment about mentoring that I would like to strongly urge for the record that scientists who are viewed, either by their peers or by their supervisors as to not be on track that maybe the mentoring program should not be an optional event, but that it might be something that should be at least required for a year.

            CHAIR URBA:  Thank you.

            Okay.  Dr. Benton?


            DR BENTON:  Good morning.  This presentation will provide to the Committee and the stakeholders an update on the somatic cell therapy letter.  Although we don't have a question to pose to the Committee on this topic, we appreciate the opportunity to use this public forum to respond to the question that they raised at our 2005 office-wide site visit regarding our progress and the outcome of our review of the somatic cell therapy letter responses.  So I'm going to summarize our experience and discuss our plan to discontinue both issuing the somatic cell therapy letter to new INDs and requesting submission of yearly updates from sponsors in this particular format.

            The somatic cell therapy letter was a request for information issued by our office to all sponsors of somatic cell therapy INDs.  The letter was issued since June of 2002.  So throughout my slides, you'll see I've abbreviated somatic cell therapy letters as SCTL, but for ease of pronunciation, I'm going to refer to it in my talk today as the letter.

            So the letter requested the submission of information by IND sponsors on topics of product manufacturing, quality control procedures, product testing and clinical trial oversight and monitoring.

            We issued the letter to address the recurring deficiencies that we had noticed in our review of INDs and master files and also through inspections of cell manufacturing facilities and clinical sites.  We determined that the letter would be a beneficial activity, based on our experience with a similar letter that was issued to the gene therapy field.

            As many of you know, in March 2000, we issued a Dear Gene Therapy Sponsor letter, following the death of a subject in an adenoviral vector clinical trial.  Although there was not a specific safety concern in the cell therapy field that prompted us to issue the letter to cell therapy sponsors, we felt there was a need to request updated information because the field was very diverse and constantly evolving and also for some IND sponsors, we have very frequent communications in the initial period of IND review and then significantly less communications.  Sometimes just brief annual reports are submitted.

            So our goals in issuing the letter were to ensure that all cell therapy products in ongoing clinical trials met our current expectations for safe conduct of the trial, to identify lapses in product testing with potential safety implications, to obtain information on the status of product characterization and manufacturing practices, and to encourage the development of clinical trial monitoring programs that would adhere to good clinical practice and to encourage the submission of final study reports.  Additional goals were to gather information on the need for additional guidance or other regulatory documents and other forms of outreach that we could provide to the somatic cell therapy field.  All of these fed into our larger overall goal of enhancing the safety of somatic cell therapy products and facilitating product development.

            The letter consisted of eight multi-part Chemistry, Manufacturing and Controls -- which is commonly referred to CMC  questions -- and three multi-part Clinical questions.  The requested date for response or to submit their response was 60 days from the anniversary date of their IND file.  Lack of response was not considered a cause for placing the file on clinical hold.

            I've simplified the content of the CMC questions to the topics that are listed on this slide and the following slide: quality control and quality assurance program; providing an overall description of the procedures; the personnel that are involved in the program and their responsibilities; and the conduct of audits; qualification of the starting cells, reagents used in manufacturing and equipment; product tracking and segregation and container labeling; cleaning and sanitization of the manufacturing facility and equipment; and control of contamination; additionally, the timeline of product manufacturing process and when tests were conducted; a description of the test methods, both those used in-process to test intermediates in the manufacturing process and testing of the final product for lot release; sterility validation and aseptic processing; product characterization activities; stability program; and cross-referenced files.

            The clinical questions requested an update of the following information: a complete description of the clinical trial monitoring program, including a description of the personnel responsible for the monitoring activities and a summary of the procedures for clinical study conduct and monitoring; and, additionally, provided a request that final study reports be submitted for all studies.

            Responses that we received to the letter were reviewed by the specific IND review team that was assigned to that IND.  The focus of the review was to ensure ongoing clinical trials met our current expectations and to identify any lapses in product safety testing.  We identified safety issues in a small number of INDs, but these were not generalizable across the field and these issues that we identified for a specific file were addressed between the IND review team and the sponsor and the issues were resolved by communication through a teleconference and submission of additional information.

            One generalization we could make is that we observed very broad differences in the status of product characterization.  And the major outcome of our review activity was identification of the need for additional CMC guidances and other forms of outreach to the somatic cell therapy field.

            In response, since the time that we began to issue the letter in 2002, our office has developed multiple CMC guidances, and I'm going to give a very brief description of those most relevant to the somatic cell therapy letter activity today, and I'd also note that in the talk following mine, Dr. McFarland will give a more thorough overview of guidance development in our office.

            So a few years ago, we published the draft guidance which is blacked out, faded out, on the left and this was a draft guidance for FDA reviewers for instructions on a template for completing their CMC review of INDs.  Just this week, I think it was Wednesday, we have published the finalized guidance of this document, which is Guidance for FDA Reviewers and Sponsors; Content and Review of Chemistry,  Manufacturing and Controls Information for Somatic Cell Therapy INDs.

            So this finalized guidance provides information on the data and information that sponsors should provide in their IND submissions and that CMC reviewers should document in their review of IND.  There is a template that is appended to this guidance and our CMC reviewers use this template to ensure consistency in the documentation in their CMC review activity and we also note that sponsors may use this template as a format for formatting their CMC section for their IND submissions.

            Additionally, our office was the lead in developing guidance shown here, Validation for Growth-Based Methods for Sterility Testing of Cell and Gene Therapy Products and this was in response to the broad interest in alternatives to traditional sterility test methods.

            Our office also contributed to agency wide or multi-center guidances that have sections on special considerations for somatic cell therapy products.  Most notably of these are INDs: Approaches to Complying with Current Good Manufacturing Practice During Phase 1, and Sterile Drug Products Produced by Aseptic Processing: Current Good Manufacturing Practice.  So these four CMC guidances which I've shown on the past few slides contain information and guidance to sponsors on the topics that were the subject of our CMC questions in the Somatic Cell Therapy Letter.

            In the clinical area, guidance relevant to the topic of the clinical questions is provided in good clinical practice guidances, provided in the International Conference with Harmonization, document E6, Good Clinical Practice: Consolidated Guidance.

            In addition, our office has a number of guidance documents in development.  An example that I'm showing you today from the CMC area is a guidance that's under development for potency measurements, which was the topic of the February 2006 meeting of this advisory committee.

            In addition to guidance documents, we have increased and improved our outreach activities to the cell therapy field.  We regularly give presentations at numerous conferences each year which reach broad audiences in the field, and we regularly hold liaison meetings with several groups in the field and the focus of our CMC talks commonly includes a discussion of product characterization and potency measurements.  And again, I'll remind you that these were areas that we found were ongoing challenges to cell therapy sponsors.  And CMC talks also commonly address the regulations in 21 CFR Part 1271 which are commonly referred to as the tissue rules.

            Just to give a brief expansion on this point, when we released the somatic cell therapy letter in 2002, the tissue rules were still proposed rules and in subsequent years these have been finalized and went into effect in May 2005.  The tissue rules focus on the prevention of the transmission of infectious disease and donor testing and screening and design of manufacturing practices to control contamination and cross-contamination are critical safety issues in the production of cell therapy products.  The sponsors may refer to the Guidance for Industry Eligibility Determination for Donors of Human Cells, Tissues and Cellular-and Tissue-Based Products for more information on donor testing and screening.

            In addition to eight sponsors in locating resources such as our guidance in other documents, our office has consolidated relevant information on our website.  Specifically the link is References for the Regulatory Process for the Office of Cellular, Tissue and Gene Therapies and the link is shown here.  And we intend to update this site periodically as new information is available.

            So in summary, our experience in reviewing the data that was submitted to the somatic cell therapy letter responses contributed to multiple guidance documents, some have already been issued and others are in preparation, and also to numerous ongoing outreach activities that are broadly applicable to the field of cell therapies.

            And so we've concluded that there are now guidances available which address our expectations for IND submissions and clinical trial conduct and, therefore, it is not necessary to convey these expectations and request responses from sponsors in the separate format of the somatic cell therapy letter.  Our office will therefore discontinue issuing the somatic cell therapy letter to new INDs and no longer request that sponsors provide updates in the format of the somatic cell therapy letter questions.  So IND sponsors may submit updates and information to their INDs in amendments and in their annual reports, as appropriate.

            We would like to thank the sponsors of somatic cell therapy INDs who provided the responses and the data that led to our experience and also to thank the Committee members for their interest in this topic, both at the 2005 site visit and for your attention today.  Thank you.


            CHAIR URBA:  Thank you, Dr. Benton. 


            CHAIR URBA:  Any questions or comments from Committee members.  Dr. Chamberlain.

            DR. CHAMBERLAIN:  I was struck by your comment that individuals that didn't respond to the letter were not placed on clinical hold, and are there still any groups that have not responded or how did you deal with that situation?

            DR BENTON:  Well, this letter, unlike the gene therapy letter, there wasn't a specific safety issue that prompted us to issue the letter.  Our goal was to bring existing INDs up to the current expectations and consider it as a tool to the way we could communicate to all the IND sponsors.

            But since there wasn't a specific safety issue that we were seeking information on, we determined it wouldn't be appropriate to place someone on hold for lack of response.  We do have other mechanisms people are required to submit yearly, annual reports, and if that isn't done we send reminder letters and that sort of thing.

            So we probably received about a 50 percent response rate and some of the responses -- factoring into that, let me also say -- some of the responses are trials inactive.  You've reminded me to reactivate my file and therefore, if I decide to initiate a new clinical study and reactivate, I'll respond to the letter then.

            CHAIR URBA:  Any other comments from the Committee?  Questions?

            DR. TAYLOR:  Is there any -- you may have given us this and I don't recall it.  Is there a time line for the guidance document that's in preparation on --

            DR BENTON:  I mentioned that a guidance document for potency measurements is in preparation.

            DR. TAYLOR:  Yes.  The potency measurements.

            DR BENTON:  We definitely have an early draft prepared.  We considered the comments that we received at the advisory committee and also, as with any other CBER guidance it's very difficult for us to give an exact issue date.  But we've already put some time into it and we certainly hope it will be published soon.

            DR. TAYLOR:  And are any of these  -- these are all documents for somatic cell therapy.  Given our conversation yesterday, are there guidance documents being generated for non-somatic cell therapy?

            DR BENTON:  Our cell therapy guidances are really broadly applicable to all the cell products that we regulate as biologics.  The distinction would be, these don't apply to cell-based products that are regulated as tissues in general.