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December 14, 2010: Cellular, Tissue and Gene Therapies Advisory Committee Meeting Amended Transcript

Open Session

Date:December 14, 2010
Time:3:00 p.m. - 4:00 p.m.
Location:

National Institutes of Health
Building 29B, Conference Room C
Bethesda, Maryland



MS. DAPOLITO: We're waiting for Dr. Gerson to join us, and then we'll get started, I think, with who we have.

DR. GERSON: Gail, could you take us through the roll call?

MS. DAPOLITO: Yes, I will. I'll do the roll call, and then I'll do the conflict of interest statement for the meeting.
So, Dr. Gerson, present?
DR. GERSON: Yes.
MS. DAPOLITO: Dr. Ahsan?
DR. AHSAN: Yes.
MS. DAPOLITO: Dr. Couture?
DR. COUTURE: Yes.
MS. DAPOLITO: Dr. Dahlgren?
DR. DAHLGREN: Yes.
MS. DAPOLITO: Dr. Galanis?
DR. GALANIS: Yes.
MS. DAPOLITO: Dr. Goldman?
DR. GOLDMAN: Yes.
MS. DAPOLITO: Dr. Horowitz?
[No response.]
DR. DAPOLITO: Dr. Horowitz?
DR. HOROWITZ: Am I being summoned?
MS. DAPOLITO: Okay. Dr. Hornicek?
[No response.]
DR. DAPOLITO: All right. Dr. Rao, are you on a line?
[No response.]
DR. DAPOLITO: Dr. Snyder?
DR. SNYDER: Yes.
MS. DAPOLITO: Dr. Lee?
[No response.]
DR. DAPOLITO: Okay. And Dr. Kwak?
DR. KWAK: Yes.
MS. DAPOLITO: Okay. We do have a quorum.

I'm going to read the FDA conflict of interest statement, and then I'll also -- then we'll go around the room and perhaps identify the FDA individuals at the table and in the room. There's also a transcriber. The proceedings are being transcribed and will be posted on the web, and there is a member of the public also here in the room with us today.

So this is the FDA conflict of interest disclosure statement for the Cellular, Tissue and Gene Therapies Advisory Committee, December 14, 2010 via teleconference. The Food and Drug Administration is convening today's meeting of the Cellular, Tissue and Gene Therapies Advisory Committee under the authority of the Federal Advisory Committee Act of 1972. With the exception of the industry representative, all participants of the committee are special government employees or regular federal employees from other agencies and are subject to the federal conflict of interest laws and regulations.

The following information on the status of this advisory committee's compliance with federal conflict of interest laws, including but not limited to 18 U.S.C. 208 and 1712 of the Federal Food, Drug and Cosmetic Act, are being provided to participants at this meeting and to the public. FDA has determined that members of this advisory committee are in compliance with federal ethics and conflict of interest laws.

Today's agenda includes an overview of the research programs in the Tumor Vaccines and Biotechnology Branch, Office of Cellular Tissue and Gene Therapies, Center for Biologics, Evaluation and Research in FDA. These overviews are non-particular matters. Based on the agenda, it has been determined that these overviews present no actual or appearance of a conflict of interest.

Dr. Mahendra Rao is serving as the industry representative, acting on behalf of all related industry and is employed by Invitrogen. Industry representatives are not special government employees and do not vote.

We would like to remind members, consultants and participants that if discussions involve any products or firms not on the agenda for which an FDA participant has a personal or imputed financial interest, the participants need to exclude themselves from such involvement and their exclusion will be noted for the record. FDA encourages all other participants to advise the committee of any financial relationships that you may have with firms that could be affected by the committee discussions.

Okay. I think I'll go around -- we're having a bit of microphone issue here right now. There might be only one microphone where the FDA speakers can speak. So what I'll do is I will introduce the FDA individuals today, and I'll start with Dr. Carolyn Wilson who is the associate director for research at CBER.

Dr. Suzanne Epstein is the associate director for research in the Office of Cellular, Tissue and Gene Therapies; Dr. Raj Puri is the director of the Division of Cell and Gene Therapies; Dr. Shyh-Ching Lo is principal investigator in the Tumor Vaccines and Biotechnology Branch; Dr. Michail Alterman, also principal investigator in the Tumor Vaccines and Biotechnology Branch; and the director of the Office of Cellular, Tissue and Gene Therapies; Dr. Celia Witten is with us today; and researchers in the Tumor Vaccines and Biotechnology Branch are also here today, Dr. Rafat Husain and Dr. Bharat Joshi.

So I think with that, we shall -- Dr. Gerson, if that's okay with you, we'll start with the presentations?

DR. GERSON: That would be terrific, unless you've got any other people joining us on the phone since --
MS. DAPOLITO: All right. I can --
DR. GERSON: -- the interruption. So just confirm that we have or have not.
MS. DAPOLITO: Okay. We can do that.
Is there anyone who's joined us who was not here for the roll call?
Dr. Rao?
[No response.]
MS. DAPOLITO: Dr. Lee?
[No response.]
MS. DAPOLITO: Dr. Hornicek?
[No response.]
DR. DAPOLITO: Okay. I'll keep listening, Dr. Gerson, if people have joined us.

DR. GERSON: If we could maybe in the background just check their availability to participate, otherwise, why don't we go straight ahead to -- I presume from the agenda that Dr. Wilson will present first?

MS. DAPOLITO: That's correct, and we will do that. We'll follow up with the others.

DR. WILSON: This is Carolyn Wilson. While we get everything up and going, I just want to add my welcome to the committee members who called in today and thank you for your input in to the site visit review.

So I assume you have everything in front of you, so if you go to the second slide, I wanted to just start with a brief review about the Center for Biologics, and that would start with the mission to ensure the safety, purity, potency and effectiveness of biological products, including vaccines, blood and blood products. And what you'll be hearing about today are cells, tissues and gene therapies for prevention, diagnosis and treatment of human disease, condition or injury.

Our vision is to really apply innovative technology to advance the public health and to do this in a manner where we can protect and improve public and individual health in the U.S. and, where feasible, globally, and to facilitate development, approval and access to safe and effective products, and, in particular, promising new technologies, which is a lot of what the Office of Cell, Tissue and Gene Therapies sees.

Our next slide shows an overview of the types of products that we regulate. And, of course, your particular advisory committee is probably most familiar with these cutting-edge medicines. Cell and gene therapies are innovative therapies that are coming into the center. These include things like xenotransplantation products. And then the Office of Cell, Tissues and Gene Therapies, of course, also regulates tissues.

In addition, the center regulates all blood, blood components and derivatives and all the vaccines that are used both for preventing infectious disease as well as therapeutic vaccines, as well as all the allergenic products, and then various related devices associated with some of these products. So it's a very diverse array.

On the next slide, it shows how the role of research provides a critical part of serving the regulatory mission in order to address the numerous and complex issues that arise from the review of this diverse set of products. And shown here, really at the center of this cycle, is the public health. There's a public health issue driving either development of a new product or it may be development of a new methodology to assess an existing product.

These things then may pose regulatory challenges, and there may be scientific gaps in meeting these regulatory challenges. And that's where CBER's research can provide a critical role, both in terms of discovery, developing new tools, new standards and new methods that may help to inform and improve regulatory policy and decision-making.

This improved regulatory policy and decision-making, which may request additional information from sponsors -- for example, change guidance and policies can lead to improved data, which will allow us to make a better and more informed decision as far as benefit-risk ratios. And then, hopefully, the end product of all of that would be a licensed product that's both safe and effective and having a positive impact on the public health.

This provides just an overview of our organizational structure. Because I'm the director of research, I do a little different org chart than the typical one. I've used laboratory plasticware. And so at the top in the tissue culture flask is the office of the center director where deputy and associates reside, and then there are seven offices surrounding that. The three petri dishes are management; communication, outreach and development; compliance and biologics; quality.

These really help serve these four product areas that are down below; or these Eppendorf tubes that are below are the four offices where we have some component of research. Biostatistics and epidemiology is not lab-based, but they do a lot of research in the areas of biostatistics and epidemiology. And then there are three lab-based offices, cellular, tissues and gene therapies, which you'll be hearing a lot more about later; vaccines research and review and blood research and review.

Our research facilities provide a certain amount of core support. We have a biotechnology core facility that provides an array of services. This is a fee-for-service facility. I won't read through the list, but it gives you a sense of the type of support we provide to our scientific program. We have some limited core support for some of the other types of methodology like flow cytometry and confocal microscopy.

We have a vivarium with procedure rooms that supports use of both rodents and non-human primates with BSL-2 capacity for working with infectious agents. And we also have BSL-3 laboratories on site with also the capability of using animals in those BSL-3 laboratories.

We have an array of scientific expertise within the center, including a variety of novel technologies, some of which were the subject of this site visit: things like NMR, mass spectrometry, flow cytometry, high throughput sequencing; an array of microbiology expertise, parasitology, bacteriology and virology; a lot of immunology expertise; biochemistry and molecular biology; and cell and developmental biology.

One of the things that CBER does that's a little bit different is our research scientists are what are called researcher regulators. And what these individuals do is they not only have their own research program, but they also take on and have active assignments for regulatory work. They do, in fact, all of the same types of assignments that a full-time reviewer would do in the center so that includes review of submissions to the FDA to the center, going on inspections, participating in advisory committee and writing policy documents, organizing workshops and so on. And the fact that our research scientists are so tightly integrated into the review process means that we can hopefully apply our research in a relevant way and use our expertise in a timely manner.

So to ensure that our research resources are being applied to those highest priority areas that impact our regulatory mission, we have a program of sort of integrated research management where we do a variety of things, identifying regulatory and public health needs based on the portfolio that we currently have in-house and also the anticipated portfolio. From that, we derive priorities, both at the center level and at the office level. We involve strategic planning also at the office and the center level; and then we also -- of course, individual research programs are aligning themselves with these stated priorities, but it's a PI-driven model. And a critical part of this whole process is this opportunity for external review and input, which we do periodically.

This just shows our most current list of CBER research priorities. For time purposes, I won't go through and read all of this. It's two slides. You can read them. It's just to show you that we do have stated research priorities. But what we do is every four years, we do cyclic review of each PI, and it's done within a laboratory unit when we do an external review by the site visit, which is the subject of today's meeting. And then, in addition, we have an internal committee called the Promotion, Conversion, Evaluation Committee that reviews individual PIs, accomplishments every four years, to make sure that they're still on track.

In addition to the four-year cyclic review process, we also have an internal annual review of all of our research programs. We have a database that collects on an annual basis the research accomplishments and future plans and publications, relevant presentations, guidance documents and so on that an individual PI might have done in that particular year. And that is then reviewed by the division, the office, and the center level, and it's looked at for relevance, productivity and quality. And the funding is then allocated based on the relevance to stated priorities, scientific and regulatory output, and the feasibility of the proposed plans.

So the subject of today is to look at this draft report that has been distributed to the full advisory committee. The task before you is to decide whether or not you accept it in its current form or whether or not it needs to be changed. But at the end, at some point, we need to have an approval by the full advisory committee.

Once that committee [sic] is approved, we use it in a variety of ways. It becomes a part of the package for the internal peer review I mentioned by the promotion, conversion, evaluation committee for personnel actions and cyclic reviews. The PIs take the recommendations and the site visit seriously for improving their own research program, and management also views these recommendations seriously as it may impact decisions about future resource allocations.

Then, finally, I just want to finish with a hearty thank you, first to the site visit review team who came and evaluated the programs that we'll be talking about today, and then to all of you as well for your time today to consider the site visit report and make your final decision as to accepting it. And, again, I just want to reiterate how important this part of the process of external review is to making sure our research programs are relevant and fulfill our regulatory mission.

Any questions? Thank you.

DR. GERSON: So are there questions either from the site visit team or from the other members of the committee?

DR. WILSON: Okay. I'll turn it over to the next speaker who is --

DR. GERSON: Carolyn, could I just ask, you indicated that 20 percent of the staff are research evaluators. What portion of the evaluators have a research program?

DR. WILSON: Oh, I couldn't answer that off the top of my head. I don't know if you know, at least within the CTCGT -- if any of you know what the -- or within maybe DCGT what the proportion is.

DR. EPSTEIN: Of the other 80 percent, a few are administrative and secretarial –
DR. WILSON: Right.
DR. EPSTEIN: -- but most of them would be regulatory.
DR. WILSON: Well, but you have people like OCAD (ph) and OM that aren't involved in review at all, so I think we want to --
DR. WITTEN: Just in DCTG, it's about half. For the program reviewers, it's --
DR. GERSON: Just a ballpark, that helps us --
DR. WITTEN: It's about half.
DR. WILSON: Thank you.
Okay. Any other questions?
[No response.]
DR. WILSON: Okay. Thank you for your attention.

DR. GERSON: We are going to move on now. I believe Dr. Epstein will talk to us about the –- I guess the committee –

DR. EPSTEIN: I'll be giving an overview of the approach to research in this particular office, the Office of Cellular, Tissue and Gene Therapies.

DR. GERSON: Go ahead.

DR. EPSTEIN: The mission of OCTGT is to facilitate the development of, approval of, and access to safe and effective cellular, tissue and gene therapy products.

Dr. Wilson described the big range of products regulated by CBER. In this office, cellular therapies are regulated, tumor vaccines and immunotherapies, gene therapies, tissue and tissue-based products, xenotransplantation products, combinations, devices used in association with cells and tissues, and then recently, cord blood. So we have quite a varied portfolio.

The organization of the office is shown here. Dr. Celia Witten is our director. There are three divisions, the Division of Cellular and Gene Therapies; the Division of Human Tissues; and the Division of Clinical Evaluation and Pharmacology/Toxicology. All the laboratories under review today are in the Division of Cellular and Gene Therapies.

Our regulatory activities include not only review of more than 1,350 active INDs and IDEs, with thousands of amendments per year, but a variety of other actions. There are two licensed products and a growing number of IND products that are in advanced stages of testing. We regulate devices under several regulatory mechanisms. We're involved in the tissue regulations, pre-IND meetings, early consultations through pre-IND advice, policy guidance, advisory committee meetings, inspections, site visits, and then enforcement actions and international activities.

I'm only going to very briefly touch on examples of the areas in which we have issued guidance. These include potency testing for cell and gene therapies, therapeutic cancer vaccines, pancreatic islet products, cell therapy for cardiac disease, cord blood, tissue practices, and international harmonization on genomic biomarkers. So the staff is involved in developing policy and writing documents to advise sponsors in these areas.

Then we have partnerships with a variety of other programs and agencies. I won't go through all these, but if you have questions about any of the acronyms, I can let you know. The NIH and CDC, I'm sure you're familiar with.

We participate in ICH, the International Conference on Harmonization, and WHO work. Staff give outreach talks at a variety of venues and conferences, participate and liaison with professional groups, and write manuscripts on regulatory topics as another communication tool.

Now, for such a wide spectrum of products that we regulate in this office, we can't possibly have research on each product. And what we need to do is stay ahead of the curve. If we only address the products and assays of today in our work and our scientific understanding, we will be obsolete immediately. So we have to participate in guiding pre-IND work and preparing the way for anticipated products.

Our products are diverse and rapidly evolving, and they use new regulatory paradigms that are still developing rather than established regulatory paradigms. For that reason, we use the following research strategy: We aim to fill scientific gaps and deal with barriers. We perform studies that are relevant to entire product classes, whereas in some cases, sponsors may study just their individual product. We make our results public and thus accessible to all sponsors with the goal of advancing the entire field. And then we perform periodic horizon scanning to assist in choosing our priorities.

Dr. Puri will describe the scientific areas that are currently emphasized.

Now, Carolyn Wilson already described the fact that our researcher-regulators are integrated; they perform both functions. The red box is only intended to emphasize that the research investigators also themselves perform product review, participate in policy and guidance and these other regulatory activities. They also may have administrative roles within the branch or division. They do their research, write grants, and then, in addition, perform functions in the scientific community such as peer review or assisting at conferences, chairing sessions.

The next slide describes our recruitment of principal investigators. If a scientific gap is identified and we have the resources to initiate a new program, here's how it works: The gaps are identified with input from the entire staff through horizon scanning. A field of expertise is chosen and then endorsed by the center director's office before the recruitment begins. It is an open public recruitment system using a search committee, seminars and interviews.

The recruitments in recent years have been in fields of organ development, proteomics, retrovirology, tissue safety, immunity and tolerance, and then we have a recruitment ongoing right now in the area of IPS cells. Then some have perceived in the past that we recruited mainly from within the FDA or the government. You can see from this list of institutions of the investigators that that was not the case, and the first set of slides you may have received had a picture covering up some words and giving a wrong impression. You now have the correct ones. So our recruiting is open and open to anyone who wishes to apply and is qualified.

Our research management strategy includes the announcement of goals for the office, the annual reporting system that Dr. Wilson described for PIs. This can lead to refocusing an adjustment of their work as the goals change. We analyze productivity and relevance through horizon scanning.

Then I'll mention here that there's an increasing role of targeted intramural funding allocated by proposal writing and peer review. It's not all just a budget through the management structure. We also have an increasing role of applying to other grants, so much more of our funding currently comes from competitive grants than in the past. Then we do tracking of those outside resources received, and our communication tools include work-in-progress seminars, the annual reports, and then an expertise database that's being developed.

The 2009 priorities are listed here. They were the same for 2010. And I have just taken one liberty of changing the word "biomarkers" to "markers" to avoid confusion with clinical biomarkers. I think I won't read through these either, but they are in the area of chemistry, manufacturing and controls, mainly product characterization and methods for characterizing a biological product and predicting its performance; then preclinical and nonclinical models; participation in center, agency and department-wide initiatives; and then a new area that was developed from horizon scanning and a public health problem, namely, improvement of microbial safety for human tissue products. That was the subject of a recruitment based on that need, and the investigator is one that you are reviewing today.

So I want to second the thank you from Dr. Wilson to all of you for spending the time to give us your input. We value it tremendously, and we look forward to your insights.

Any questions?

DR. KWAK: So the question is in regards to the 1350 INDs and IDEs that are active. I wonder if you could put that in context of how that number's been changing over the last few years, what the growth rate is and how that relates to the pressures on the regulators; and so what the workload is on regulators and how that is changing.

DR. EPSTEIN: The workload has certainly been increasing. The number of cellular therapies, gene therapies and all these types of products have been increasing. Then, for example, the area of cord blood is new. Tissues was a new regulatory initiative. So we've had new kinds of jurisdiction given to us, and we have to fulfill those public health responsibilities. So there has been some expansion of the staff. I would say the workloads have gone up. I don't know if anyone else wants to --

DR. WITTEN: Well, I think the number of new INDs per year is more or less the same, but because they deal with the active, the number where we're exercising oversight has gone up.

DR. KWAK: I'm sorry. Say it again. The INDs or IDEs per year is based -- with what?

DR. WILSON: No. She's saying the increase each year, the number of new ones --
DR. WITTEN: Is approximately the same.

DR. WILSON: -- is approximately the same, but the amendment load goes up because the old ones have not been closed down, for the most part. And then we do have these new whole areas such as cord blood.

DR. WITTEN: Yes, so there's some areas --

DR. KWAK: So it's still a feeling that the workload per regulator-reviewer has been going up on a yearly basis and is not being met by recruitment or is the workload about the same?

DR. WITTEN: I think it would be hard to answer that. We've had an increase, also. There is a number of regulatory-reviewers who don't also do research, and that number has increased over the past couple of years. So I don't think that the – I don't think -- we'd have to do an analysis to know that for sure. But my guess is the workload per regulatory researcher has not gone up. We'd have to look at the numbers, but my guess is the numbers would not bear that out.

DR. GERSON: I think these presentations have been very clear. Perhaps we can move on to the branch presentation.

DR. PURI: Okay. So this is Raj Puri. While my presentation is being loaded, I'd like to thank Dr. Gerson and Dr. Kwak and the subcommittee who did the site visit to our lab program and the full committee for your significant effort and your input and your guidance that you provide. We look forward to that.

My first slide lists the project areas that are being undertaken in the division of Cellular and Gene Therapies. As mentioned by Dr. Epstein, I will provide a little bit more on these projects. We have 12 principal investigators in DCGT, and a 13th, which is a person who is inspecting the IPS, and flow cytometric technology is being actively reviewed and will be recruited in the future.

As you can see from this slide the products that our office regulates, we have a number of research programs that include from virology to immunology, cell biology, cancer biology, and various type of biotechnologies, the proteomics program, the CBER program. The major program is within part of my group, the genomics program. In addition, too, you heard from Dr. Epstein that we have created a new tissue safety program in our division, in our branch.

If you move on to the next slide, the next slide tells you the structure of DCGT. There are five branches, branch on the left. Two branches are of the staff, and those branches, cell therapy branch and gene therapy branch, include our full-time review staff. And you heard from Dr. Carolyn Wilson that these folks are involved not only in the daily regulatory review of the files, but they're also involved in the policy development, guidance document development, and a lot of outreach. Our products are very novel, cutting-edge 21st century medicine. It requires a lot of handholding, and many of our sponsors are small companies that require quite a bit of effort from our staff to provide them a feedback to develop good programs.

The branches on the right side and one below, the three branches are listed there, the staff there are research regulators. These staff also do the same thing as on the left side branches. They also do review activities, and other activities related to regulatory efforts about 50 percent of the time. The other 50 percent of the time is spent on the critical path research in advancing and promoting development of these medicines. The box in yellow is the tumor vaccines biotechnology branch, which is being site visited in April and now being reviewed here.

I'll move on to slide number 3 and list the principal investigators that include myself and Dr. Alterman, who's our proteomics expert, and Dr. Shyh-Ching Lo, our tissue safety expert. And I will summarize all of our activities that are being performed in our group.

The previous slide, slide number 3, there are two additional staff, Dr. Rafat Husain and Dr. Bharat Joshi. They are two staff scientists within my group. They also made a scientific presentation at the subcommittee discussions, and these folks are being considered __________ (deleted according to 5 U.S.C. 5522(c)(6), where disclosure would constitute a clearly unwarranted invasion of personal privacy). And Dr. Puri, Dr. Alterman, and Dr. Lo's program is reviewed for the progress support.

Now I will talk about my research program. A large number of products in Office of Cell, Tissue and Gene Therapy involve cancer vaccines and immunotherapy products. Our program is focused towards in trying to address these challenges. As cancer is a complex disease, it is important to identify a target that is especially for cancer and also look at it not in the normal cells.

Often cancer vaccine products are not defined antigens or peptide but a mixture of cells, antigens of gene-modified tumor cells. Therefore, identification of their identity and potency tests, which are critical to our product development, are often challenging.

The animal models for safety and efficacy are important to determine the safety, the starting dose, the frequency of dosing, the dose escalation, and the prediction of response in clinical trials. Identification of appropriate animal models of human disease that may help guide these parameters are also challenging. Similarly, immune biomarkers or other markers of response and safety are there. These biomarkers may predict the clinical outcome, good or bad, and may be identified in completely developed animal studies in early phase clinical trials.

To address these scientific challenges, my research program has three specific programs. The first one is dealing with the identification of tumor-associated cell surface proteins, or antigens, that can not only serve as possible markers for identity and potency, but they also could serve as the target for cancer therapy; the animal models of human cancer to assess to safety and efficacy of tumor-targeted agents, including cancer vaccines, immunotoxins and gene therapy products. And the third program that we work on is characterization of cancer vaccines and embryonic stem cells by genomics technology to identify cancer stem cells and biomarkers of identity and potency and response to cancer vaccines.

These research programs have been developed over the years since the discovery of Th-2 derived cytokine receptors, Interleukin-4, previously on the murine solid tumors. And later we have discovered that receptors are expressed in a variety of different human solid tumors as shown in this slide. And to target this receptor in collaboration with the National Cancer Institute scientist Dr. Ira Pastan, we developed an immunotoxin called Interleukin-4 pseudomonas exotoxin, and this molecule has shown dramatic anti-tumor responses in a variety of tumor models as shown here. The last four years of site visits, we have studied pancreatic ductal adenocarcinoma, biliary ductal cancer, and oral squamous cell carcinoma head and neck.

In late 1990s, a new cytokine was cloned called IL-13. So we were curious that the IL-13 receptors were also present on the solid tumors, and to our pleasant surprise, the IL-13 receptor were identified very highly with renal cell carcinoma. We were first to identify and clone this receptor in cancer cells, and we had looked at a variety of different cancers as shown in this slide. In the last four years, pancreatic ductal adenocarcinoma, pheochromocytoma, brain stem cancer and prostate cancer has found to express large number of these receptors.

Similar to targeting IL-4 receptor, we have developed an immunotoxin called Interleukin-13 pseudomonas cytotoxin. And this molecule, as from our discovery from our lab, has resulted gone all the way to the phase 3 clinical trial for the treatment of malignant brain tumor.

We have developed a large number of animal models in our lab. These are human tumor models as shown on this slide, slide number 7. And some of the tumor models that we have developed, which is a clever approach, of course, as used in the scientific community as well, is implanting the tumor tactically (ph) on the ovarian tumor, pancreatic cancer, for example, with simulation of disease. It allows not only to test in our model agent, which is immunotoxins, but also can be used for the gene therapy as well as cancer vaccines and other approaches.

To summarize our work, we have identified that certain human tumors express high levels of IL-4 receptors and IL-13 receptors in vitro and in vivo and that structure and signal transduction through this receptor is different than that of normal cells. And then IL-13 receptor and IL-4 receptor can be effectively targeted by immunotoxins by themselves or when combined with other agents for cancer. And Dr. Husain in our group presents data in his presentation, showing that case where in pancreatic ductal adenocarcinoma, Interleukin-4 pseudomonas exotoxin effectively synergizes with the approved drug called gemcitabine in making a synergistic anti-tumor effect in the pancreatic cancer model.

In the last four years, we have discovered for the first time that IL-13 receptor alpha 2 chain is involved in cancer invasion and metastasis, and it may serve as a prognostic biomarker of disease. We have collected more than 300 samples from the patients with pancreatic cancer under the IRB-approved and FDA risk-approved protocol, and we are looking at the expression of the IL-13 receptor by amino histochemistry as well as cyto hybridization (ph) to see if there is retrospective correlation with the clinical outcome of the subjects and if it is truly a prognostic biomarker. This is our ongoing future project.

We have also demonstrated for the first time that IL-13 can signal through IL-13 receptor alpha 2 chain. Predominantly, IL-13 signals through IL-13 receptor, utilizing JAK/STAT pathway. But in the cancer cells, we have demonstrated that it does not utilize JAK/STAT pathway; instead, it uses AP-1 pathway. And we have also discovered that in adrenomedullin, a calcitonin-related peptide produced by the adrenal gland up regulated (ph) this receptor. And Dr. Joshi made his presentation at the site visit and subcommittee, and he showed that adrenomedullin not up regulated this receptor in vitro but also in vivo, and it desensitizes to the tumor cells expressing IL-13 receptor to IL-13 immunotoxin.

Lastly, this project is continuing to look at the mechanism of signaling the regulation of these receptors, which is on the tumors cells. As IL-13 receptor alpha 2 chain is a novel tumor antigen, and we have discovered that the cDNA vaccine to IL-13 receptor alpha 2 chain and this paper had just been accepted, which demonstrated that alpha 2 vaccination can prevent and in the therapeutic murine cancer model, it can create an anti-tumor response, providing an immune response, both T cell and B cell responses. And our ongoing work involved in the prime boost strategies and various combinations of the approaches to target cancer as it is being done in many different in those particular studies.

Now I will shift and talk about the work with Dr. Michail Alterman. Michail Alterman is our proteomics expert. He was recruited about five years ago, and this is his second site visit. And Dr. Alterman's laboratory goals involve the development and application of mass spec-based proteomic tools for qualitative and quantitative assessment of cell products, cell substrates, vaccines and discovery of potential biomarkers of cancer.

Dr. Alterman has a number of mission relevant questions that he is trying to address, which predominantly deals with, first, his development of the technology, as proteomics technology is evolving, it is not a mature technology, and utilizing very high throughput technologies of mass spec-based identification or proteins, in addition to applying this technology, not only the safety and assessment of cellular therapy products but also in the cell substrates, which are used to produce cell and gene therapy products, the vaccine, and, finally, also using this technology in assessing the identity and perhaps the quantity of the vaccine components in the flu vaccine.

The specific aim Dr. Alterman had listed in slide number 11, this is specific aim number 1, the use and development of mass spec-based analytic tools for testing biological product quality and identity. Number 2 includes the proteomic cellular molecular signature that might be tested as predictors of therapeutic success and may be developed as biomarkers of safety and effectiveness in preclinical animal models. And his third aim includes the proteomics-based analysis of influenza virus and vaccine products. And within that slide in italics, you might see that Dr. Alterman has listed some of his accomplishments since the last site visit.

So the conclusion for his research program includes that he has identified a new technique of developed a new label-free quantitation technique that can identify two protein bands, which are overlapping with each other. He has identified two prospective protein groups that could be used as a biomarker or markers for the characterization of cell substrates, cell substrate meaning he had used MRC-5 cells, and they're grown in confluent state versus some confluent, the condition which could be growing cells (unclear) and identifying a marker of quality of the cell substrate.

He has begun to actually have some publications in the area of MS-based proteomics methods that can be used to identify and distinguish different influenza variants, or clades, and quantify protein in the flu vaccines and the virus preparations.

The last project that is a part of the DCGT principal investigator 7 PI consortium, he is looking at the proteome of human MSC, which is a multipotent stromal cell, also called as mesenchymal stem cells. And they're trying to identify the similarity of the markers, proteomic markers, in the MSCs from different donors as well as when the MSCs are cultured at different passages, with the eventual goal to identify a marker that can link to the animal model of schemic high limit schemic (unclear) model.

His ongoing projects include the development of new potency and stability assay for flu vaccine and MSC project, as I articulated in the previous slide, to continue to identify the protein signature that can characterize MSCs from multiple donors and identify molecular signature that could be used to discriminate product that produce a desired clinical outcome.

So I'm now going to summarize the efforts for the new tissue safety program that Dr. Shyh-Ching Lo is undertaking. And Dr. Shyh-Ching Lo was recruited about two and a half years ago.

DR. LO: Two years ago.

DR. PURI: He made the correction. It was two years ago, not two and a half. Time has flown.

Dr. Lo is a clinical pathologist, and he was recruited from Armed Force Institute of Pathology to develop a new tissue microbiology lab for the safety of human tissues intended for transplantation.

As discussed by Dr. Wilson and Dr. Epstein, the CBER leadership recognized there is a need for a tissue safety program. In addition to that, the science board also made a recommendation that there is a need for a tissue safety program at the FDA. And here is why, because the large number of tissues and precisely, I think my numbers are about 1.5 million tissues are transplanted in the United States each year. The tissues, being the bones and cartilage and tendons and dura mater and cornea, are implanted within the U.S.

CBER, our office, is responsible to regulate safety of those and also human cells, tissues and cell tissue-based products in order to prevent the spread and transmission of communicated diseases. It also recognized that scientific capability of this program would need to cover a wide spectrum of expertise with very different microbial pathogens that include bacteria, fungi, viruses, protozoa and parasites.

So the specific aim for Dr. Shyh-Ching Lo's program include to establish the required scientific capabilities to directly support regulatory needs for the tissue safety; to adopt a new technology for rapid detection of ID (ph) pathogens with high sensitivity in human tissues being processed for transplantation; and to evaluate innovative methods for effective inactivation of various pathogens while preserving tissue quality for clinical needs; and to explore new scientific approaches, for example, high throughput sequencing or parasequencing or 454 technology for detection and characterization of previously unknown or nearly emerging infectious pathogens that will likely threaten the safety of more tissue graft.

His ongoing work includes establishment of the lab capability of clinical microbial for detection and characterization of microbes with tissue safety concern. He actually has developed the rapid and high sensitive technology for detection of pathogens in tissues intended for transplantation, the technology being real-time qPCR, where a number of genes can be evaluated at the same time.

Dr. Shyh-Ching Lo is developing, in collaboration with the contractor from NCI, a high throughput technology genomic sequencing capability for detection and characterization of previously unknown infectious pathogens and tissue and tissue-based product. And a project that was funded by the Department of Defense, this is the second year of funding, was the identification of biomarkers associated with the injury mechanism in cell tissue and development of injury associated by gene expression microarray technologies.

So to conclude his program, a new tissue microbiology lab has been established under our division. His regulatory oversight is provided by the Division of Human Tissue; the other division in the Office of Cell, Tissue and Gene Therapy. And Dr. Shyh-Ching Lo has been engaged in development of new technologies and evaluation of innovative methods being implemented to guard the safety and quality of tissue intended for transplantation.

At this point, I'd like to say Dr. Shyh-Ching Lo has succeeded publishing a high-profile article in the Proceedings of National Academy of Sciences, a couple months ago, in the identification of genetic sequences of XMRV, which is a xenotopic murine leukemia virus like sequences in the subjects with chronic fatigue syndrome. And Dr. Shyh-Ching Lo is engaged with the NIAID, NIH, CDC, academy institutions, and other colleagues within the other offices in the Center for Biologics in trying to confirm those results and participate in technology and assay development for this field.

I'd like to thank you for your kind attention. And as has been echoed before, I certainly want to also thank you for your efforts, and I look forward to any questions that you have that I can answer.

DR. GERSON: So before we move into the review stage, could I ask if there is a need for questions about the science or the organization that's been presented very effectively?

[No response.]

DR. GERSON: Well, I hope that there's clarity, as we can now move into the next phase. I guess we should ask, and stop for a second, whether public comment or public discussion is needed. If not, we'll move to the closed session.

MS. DAPOLITO: Dr. Gerson, what I'll do is ask if there's anyone in the audience in this room who would like to address the committee at this time.

[No response.]

MS. DAPOLITO: And I see no one wishes to address the committee. So we will take a minute and close the room here on site. If you'll give us just a minute. Thank you.

DR. GERSON: Yes.
(Whereupon, at 3:54 p.m., the open session was concluded.)