FOOD AND DRUG ADMINISTRATION

P-R-O-C-E-E-D-I-N-G-S

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 10^th 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.

RECOGNITION OF COMMITTEE SERVICE

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?

(Applause.)

(Pause for picture.)

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

Dr. Tomford.

(Applause.)

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.

UPDATE - RESEARCH PROGRAM, OFFICE OF CELLULAR, TISSUE AND GENE THERAPIES

RESPONSE TO SEPTEMBER 2005 REVIEW OF OCTGT

RESEARCH PROGRAM

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 21^st 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.

(Applause.)

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. <