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P R O C E E D I N G S

(11:06 a.m.)

MS. DAPOLITO: Okay. Then let's go ahead and get started. Did you have any welcoming remarks?

CHAIRPERSON URBA: Yes, I guess I would just like to thank everyone for taking time out in their schedules to be together with us this morning to go over these site visits, and if you want to go right into the roll call and conflicts of interest, that would be great.

MS. DAPOLITO: Okay. That's what I'll do then.

I'm going to read the conflict of interest statement with the hopes that we'll get another couple of members on board by then.

If you are not talking and could put it on mute, that would be great.

The Food and Drug Administration convenes today's meeting of this 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 members of the committee are special government employees 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 USC Subsection 208 and 21 USC Subsection 355(n)(4), is provided to participants of today's meeting and to the public. FDA determined that members of this Advisory Committee are in compliance with federal ethics and conflict of interest laws, including, but not limited to, 18 USC Section 208 and 21 USC Section 355(n)(4).

Under 18 USC 208, applicable to all government agencies and 21 USC 355(n)(4) applicable to certain FDA committees, Congress has authorized FDA to grant waivers to special government employees who have financial conflicts when it is determined that the agency's need for a particular individual's services outweighs his or her financial conflict of interest -- that's Section 208 -- and where participation is necessary to afford essential expertise, Section 355.

Today's agenda includes a review and discussion of the intramural research programs in the Gene Transfer and Immunogenicity Branch, Office of Cellular Tissue and Gene Therapies, Center for Biologics Evaluation and Research, and in the laboratories of immunology and chemistry and the laboratory of cell biology in the Divisions of Therapeutic Proteins and Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research.

Based on the agenda, it was determined that the committee discussion presents on actual or appearance of a conflict of interest for today's meeting.

Dr. Gunter serves as the industry representative acting on behalf of all related industry and is employed by Hospira, Incorporated.

Industry representatives are not special government employees and do not vote. This conflict of interest statement will be available for review at the registration table.

We would like to remind members that if the discussions involve any other products or firms not already 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 the firms that could be affected by the committee discussions.

Thank you.

So what I'll do is I'll call the roll for the record of the Committee and then we'll introduce the FDA participants, and we will go on to the presentations. I think the members have their slides. They can follow along, and I would remind the presenters to please indicate when you're changing slides for those on the phone.

I'll start by calling roll. Dr. Urba.

CHAIRPERSON URBA: Here.

MS. DAPOLITO: Dr. Calos. Dr. Calos.

PARTICIPANT: She may have her mute on.

MS. DAPOLITO: I know she was here.

DR. CALOS: Oh, wait. Can you hear me?

MS. DAPOLITO: Yes.

DR. CALOS: Okay.

MS. DAPOLITO: Okay. Dr. Chamberlain.

DR. CHAMBERLAIN: Present.

MS. DAPOLITO: All right. Dr. Tomford.

(No response.)

MS. DAPOLITO: Not yet. Dr. Gerson, have you joined us yet? Not yet.

Dr. Guilak.

DR. GUILAK: Here.

MS. DAPOLITO: All right. Dr. Allen.

DR. ALLEN: Present.

MS. DAPOLITO: Dr. Taylor.

DR. TAYLOR: Here.

MS. DAPOLITO: Dr. Kwak.

DR. KWAK: Present.

MS. DAPOLITO: Dr. Chappell. Dr. Chappell, are you there still?

DR. CHAPPELL: Yes.

MS. DAPOLITO: Okay, and Dr. Woo.

DR. WOO: I'm here.

MS. DAPOLITO: All right. Thank you very much.

We'd like to go around the table here on site. On site we do have FDA speakers. We have some audience, and we have a transcriber and a video. We are being videotaped, too, for those on the phone to let you know who we have here.

And we'd like to go around the table now and introduce the FDA participants, and I'll start with Dr. Witten.

DR. WITTEN: Celia Witten, Officer Director of OCTGT.

DR. BLOOM: Eda Bloom, Branch Chief, General Transfer and Immunogenicity Branch, DCGT, OCTGT.

DR. ROSENBERG: Amy Rosenberg, Director, Division of Therapeutic Proteins.

MS. DAPOLITO: Do you want to introduce your lab staff, Amy?

DR. ROSENBERG: They can go ahead.

DR. MAX: Ed Max, DTP.

DR. BERNSTEIN: Ralph Bernstein, DTP.

DR. BEAUCAGE: Serge Beaucage, DPT.

DR. NORCROSS: Mike Norcross, DTP.

DR. WANG: Jinhai Wang, DTP.

DR. CLOUSE: Kathleen Clouse, Director, Division of Monoclonal Antibodies, and Dr. David Frucht will be calling in about 12:10. He was called out of town on an urgent family matter.

DR. SHORES: Elizabeth Shores, Deputy Director of OBP.

DR. KOZLOWSKI: Steve Kozlowski, Director of OBP.

DR. EPSTEIN: Suzanne Epstein, OC Director of Research at OCTGT.

DR. PURI: Raj Puri, Division Director of Division of Gene Therapy, and I have staff here, GTIB. They can introduce themselves.

Carolyn.

DR. WILSON: Carolyn Wilson, GTIB and DCGT.

DR. ARGAW. Takele Argaw, GTIB.

DR. BYRNES: Andrew Byrnes, GTIB.

DR. MARKOVITZ: Nancy Markovitz, GTIB.

MS. DAPOLITO: Okay, all right. Thank you.

Okay. Did someone just join us?

DR. GERSON: Hello.

MS. DAPOLITO: Dr. Gerson?

DR. GERSON: I'm here.

MS. DAPOLITO: Thank you. We just did a roll call and introduced the FDA.

DR. PURI: And Dr. Carbone is on the phone.

MS. DAPOLITO: Yes, and Dr. Carbone is on the phone.

Dr. Carbone, are you ready for your slide presentation?

DR. CARBONE: Certainly am.

MS. DAPOLITO: Okay. We're going to start with Dr. Carbone then.

DR. CARBONE: I'll start with Slide l. We can skip that because that's just my name. What I'd like to talk about is just the Division of CBER today and a little bit about the site visit process, a little bit about critical path, and I'll be brief.

I'm with some people who weren't here for my presentation to the site visit community. I'll just review the highlights with the Committee.

Basically, if you look at the second slide which has the division, the real important points there are two. One is the fact that we actually facilitate development and approval and for all products for the American public, and that we consider international and global health and the public health a real primary goal for this center.

Next slide.

And when I say "biologics," I mean the complex biologics. Of course the OP people have a biologics portfolio as well.

The next slide is a small, brief chart showing the orientation, and the only thing I want to point out here is that there are four offices that participated in the research enterprise, which is a major part of the facilitation effort, and that's the Office of Biostatistics and Epidemiology, Office of Blood Research and Review, Office of Vaccines Research and Review, and this office, the Office of Cellular Tissue and Gene Therapy.

They also have a wonderful engagement in our research management process from the Office of Compliance and Biological Qualities, although they currently do not do research.

The next slide which is Slide 4, just gives you a brief overview of the concept of scientific research in the evaluation process. We all know scientific research from the point of view of product development, both the early discovery phases in the development through clinical trial research.

However, there is an evaluation science which is important, and one of the areas of focus for the FDA and which overall has been somewhat neglected in the massive investment in biotechnology and other kinds of biologics discovery for products.

And so part of our goal is to develop the scientific pools and information we need to regulate on a scientific basis because once we're outside the scientific basis, it becomes the philosophical discussion, and that's where a lot of the problems arise both in the inabilities to predict outcomes in a scientific manner and also disputes regard certain safety issues, et cetera.

The more we know about how to evaluate our products appropriately, the better.

The next slide, Slide 5, just shows that the critical path, which is a portion of the FDA research that applies directly in facilitating the biologics product development, really happens early in the process and involvement in design and discovery is actually quite important. We would like to have particularly the tools to predict clinical efficacy and safety issues actually in the preclinical phase. So that kind of evaluation process in science is extremely important.

Obviously clinical development and improvement in clinical trial development phase is important, but we would prefer products not fail in that stage, in late Phase 3 clinical development. It is a very expensive way to fail. We would like to have better predictors early in the process, and biologics both in OPD and in CBER have led the way in terms of early and frequent interactions with sponsors which are often academia, small biotech, et cetera, because the early interventions often have a huge impact in key products being successful products going downstream.

Next slide, six.

Bottom line is people ask. The first thing I'm ever asked is, "Oh, does FDA do research?"

The second thing that comes out is, "Oh, why does FDA do research?"

And one of the things we'd like to explain is that there are reasons that FDA science is so definitely value added to the process, and that includes the fact that innovators who are people who typically understand product development well; they understand science and have areas of scientific expertise, but they're working for specific products typically in a proprietary setting, and they're discovering their assays, their standards, their methods are not shared with others.

CBER scientists are also one of the few groups that are expert not only in scientific disciplines but in the biological product development. They also have the opportunity to see success and failures and missed opportunities across the board, and therefore, their scientific input and scientific assessments and scientific activities in terms of research and have broad impact in the field and help all products in a particular category to move ahead.

The science, of course, needs to be communicated to be valuable, and CBER guidance documents, other public communications, publications and peer review of the science so that it can be either repeated and others in the scientific community agree with the findings or it can be disputed. It's very important, and so guidance and other documents based on good science makes for better predictive critical path.

And finally, CBER can actually play a convening and coordinating role a disinterested, if you will, from a financial point of view or a non-conflicting party that helps coordinate sponsors and gets scientific questions answered that are going to help cross product category.

Next slide, Slide 7.

I wanted to point out that the CBER researchers that were reviewed here are fairly unique, and OBP and CBER are the two groups that routinely have researchers doing a standard regulatory review. And I've looked at them on this slide, but it's really too much, and this includes both actual being on site in sections, being there as part of experts when our experts go on section, as well as writing guidances, reviewing R&D, et cetera.

So they are fully integrated in the part of the process. In fact, it has always been my belief that CBER researchers, research regulators, in general, identify clear issues that need resolving better because they're actually involved in the regulatory process and see the challenges at the table, if you will.

The next slide is a culture issue that I have tried to promote, which is the discussion that often follows the FDA dose research discussion with "oh, well, I see. NIH does the basic research and you do the applied research."

The bottom line at CBER is one that's mission relevant. It's the research output and how it is applicable to support the complex biological products. It is not whether it is basic. It is not whether it's applied. That really doesn't matter. It's whether it's applicable, and sometimes some of the most major improvements and assistance that CBER scientists have given have been in the basic biochemical arenas.

So we really approach and utilize all kinds of science. The key is how it relates to the product development and approval.

The next slide is basically one slide that summarizes years of work with a variety of research and regulatory science and the quality office, and that includes a curricular pattern where every year the pattern is to review the regulatory and public health portfolio and analyze the regulatory portfolio based on scientific issues and challenges.

We, of course, track very carefully INDs, BLAs based on titles, base on sponsors, but what's done here is to identify the key scientific issues and challenges within those regulatory processes and to formulate a report from in the office.

And that was submitted this year. Research priorities are then developed because once you identify the key scientific challenges, you have to identify those that can be resolved without resources that need urgent resolution, and if you will, maybe then focus on either low hanging fruit where we can have an impact or major public health issues that are so significant that we must work on them.

The offices sends them and provides the center with their research plan and budget which is formulated, and we're currently in that process now for '07 because we're just initiating this formal initiative, and this year we're, if you will, beta testing the process.

But in '06 they submitted research plans and budget. We developed a form that we liked, and it was very informative, and now the process is being repeated. Next year we have the process more on target with timing because it will be the final product in research management.

And then we have, of course, the scientific program review both for performance as well as prioritization and future scientific quality and their plans, and then an annual report is required, and that also is currently in the works.

And then with the Advisory Committee, the first presentation will be involving the response to the office site visit and a discussion of this process for that office, and that will be coming up for OCTGT. The goal here is to have public input responses and to make the planning process and the prioritization process back-and-forth and allow, of course, public input for interested parties.

Next slide is Slide 10.

Basically there are two kinds of things we do here. We either create regulatory pathways where there are few or none, and that's particularly applicable to this office, or in some cases where there is, quote, historical regulatory pathways, such as in vaccines, which oddly enough are really some of our oldest and most established products. We have to improve and update with 21^st century science those regulatory pathways.

As you can see, our portfolio tends to and always has tended to focus on safety, and we do product quality as an issue and product efficacy, but safety is key, particularly because our products are either fairly novel or they're products like vaccines that are administered to healthy people, and therefore, the safety bar is quite high.

Next slide.

Slide 11, I will let you read to yourself, but we also developed this as part of the research management initiative, Guide Principles for Science at CBER, and you will note words like "collaborative," "crosscutting," "multi-disciplinary." Our staff really lead the chase in terms of having that total scientist, the renaissance scientist who really is quite broad in their expertise and quite forward thinking, and yet collaboration is key because science in this world these days is an international and certainly multi-institutional effort, and I'll leave you to read those yourself.

Today, just for a little bit of site visit definitions, I want to sort of give you some CBERese, if you will. Today we have senior investigators, staff scientists that may be already converted staff presenting under review. A converted staff is tenured and, therefore, they're evaluated either for promotion to a higher GS level, for example, or for simple progress.

We have asked the Committee to comment both on their previous performance and on their future plans.

Then we have another category which is being reviewed, which is service fellows, which are considered non-permanent. If you're a non-tenured STEs we have two versions of those. One is the staff fellow or visiting associate, who is evaluated from conversion to staff scientist or support scientist, and let me just say as an aside not necessarily because that individual could not be an independent investigator, but because of financial or budgetary reasons, administrative needs it has been determined that there is not a need for a second independent program in this area.

And so these scientists form part of a team working under a principal investigator and contribute tremendously to the effort, but sometimes the staff scientist designation is clearly an administrative designation because we have very talented staff.

Senior science staff fellows and visiting scientists are also temporary, not permanent MPEs, and those when they come in are considered senior investigator track, and so they're evaluated for conversion to senior investigator and all the things that go with that, including independence, ability to run an independent program, et cetera.

The next slide, 13.

Basically the site visit team is now viewed as the Roman Coliseum, and appropriately what they help us out with is to identify staff that are on track and help as experts in their field given suggestions for improvement. They identify staff that are not on the right track. They help us with prescriptive advice to get the staff on track, which we appreciate.

And so with the non-permanent staff, the fellows, if you will, service fellows, we like to get them reviewed mid-cycle and then once at the end of their seven-year track so that in the mid-cycle review they have a chance to change direction, change course and take the advice of the site visit in order to improve their programs if it's needed.

Next slide is 14.

The site visit report is what we're talking about today. Basically at the end of the review of the team, the oral summaries presented to the research management, and there's an opportunity for discussion and clarification.

A draft report has been written. It has been distributed to the Advisory Committee. The final report is here today to be discussed, and the final approval by the Advisory Committee, and then that report becomes a major document that is used for the promotion or conversion of staff.

And on the next slide you'll see, Slide 15, that that report which is in red, the Advisory Committee approved report at Slide 15 is part of a package that goes forward to the promotions or conversions committee, and that includes other elements, such as curriculum vitae, bibliography, the nominating memorandum from the advisors of that individual. Locations are submitted, words of recommendation. Again, other outside scientific reviews are sought, and that entire package is reviewed by the promotions and evaluation committee, which contains both research and regulatory scientific staff because an entire scientific and regulatory performance review is performed in parallel. Then that committee makes a recommendation. The center director will ultimately decide on the outcome.

The final slide.

I just want to say thank you very much for all of your time and energy and help in this and every site visit that is performed by the Advisory Committee and the site visits because we greatly appreciate it. We would like to recognize the FDA, along with OBPs who participate in this process as having one of the most rigorous and high quality scientific evaluation processes in the FDA.

I just want to thank you and take any questions if you have any.

CHAIRPERSON URBA: Well, thank you, Dr. Carbone.

We left some time after Dr. Witten and Dr. Bloom's presentation for questions. So unless there's some burning question from a Committee member, I would suggest we go on to Dr. Witten's presentation.

DR. CARBONE: Super.

DR. WITTEN: Okay. Thank you.

This is Dr. Witten. Do you have the slides? I'm assuming everyone has the slides in front of them. That's true?

CHAIRPERSON URBA: Yes.

MS. DAPOLITO: That is why you say "change slide."

DR. WITTEN: All right, good. All right. So the topics I'm going to cover -- this is on Slide 2 -- are the mission and organizational structure of research in our office, the Office of Cell Tissue and Gene Therapy; the regulatory scope of our work; and then some highlights of what our research actually covers.

Next slide.

So the mission in OCTGT is to facilitate development of approval and access to safe and effective medical products. Our products are quite innovative. So some of the research that we do is a very cutting edge, not necessarily on the products, but on research on test methods of other tools that might be needed in product evaluation and development.

Next slide.

This slide gives the structure of the office, our office, and as you can see, there's three divisions that actually do regulatory work, and one of those divisions that does lab and other research, that is the Division of Cellular and Gene Therapies. Dr. Puri is the Division Director of that division.

Next slide.

And here on this slide is a scheme describing the organization of that division. So we are today talking about the Gene Transfer and Immunogenicity Branch, which is depicted in this slide.

Next slide.

Okay. So I mentioned that products regulated by our office are quite cutting edge and also diverse. Here is a general overview of the types of products we regulate: cell therapy, gene therapy, tumor vaccines, and immunotherapy, tissue based product, xenotransplantation products, and these aren't mutually exclusive categories. That is, some of the vaccines might also be considered cell and gene therapy, and certainly some of the cell therapies would be considered xenotransplantation products. So it's more of an overview of the technology of our products rather than specific product categories.

Next slide.

On this slide I've listed the regulatory portfolio and activities, and as you can see, we're a very active office in terms of the research that's here. There's over 1,100 active INDs, IDEs, and master files. These are active, meaning there's a number of amendments for these that we have to look at because they're ongoing studies.

There's one licensed product, but there's a number of products that are in Phase 3 or in discussion about Phase 3, and these are some of the regulatory activities that we participate in.

Next slide.

We're relatively small, but our reach is large as I've indicated in the previous slides about the scope of our work. So much of our both regulatory and really our research work, too, is done with partnerships.

And I've listed here some of the types of groups that we partner with, the National Toxicology Program and other organizations, NIH and CDC. We have some specific initiatives with these different agencies, in particularly with NCI. We have a lot of interactions.

We've listed the IOTF Program, but there's others. We had a workshop this year on cancer vaccines that was conducted within NCI. We have a lot of interactions with NIH. The Stem Cell Task Force is only one example.

We have an MOU with MINDS. There are not all of these listed, but it just gives you a flavor of some of the kinds of outreach and interactions we do, and certainly there are international partnerships, ICH and WHO, but as you can imagine, there's a lot of interest in the field, and we do have a fair amount of discussion with our regulatory counterparts and other areas.

Next slide.

Here I've just listed specifically. I have on an earlier slide that we participated in guidance document development. I have in this slide an update and from when. It is the significant guidance documents from this calendar year. You can see that they're fairly significant: a knee cartilage tissue engineering guidance document and one that we worked on together with cancer drugs; the finalization on clinical trial endpoints for cancer drugs and biologics. We also regulate human tissue and finalize the eligibility determination guidance document, which is certainly very important in enhancing tissue safety, and also the core blood guidance document that was discussed at a meeting that was conducted earlier this calendar year was issued indirect this year.

Next slide.

I'm not going to cover the roles and work of the researcher reviewers again sine Kathy Carbone has already gone through it, but I will just echo what she said in that there's a unique role of the researcher reviewers, and both components of their work here are important and are recognized both in terms of the research and the regulatory component, and I think they are very intimately tied together.

Next slide.

So this list of contributions in the research area and the regulatory area, specifically for the branch that we're going to be discussing today since the 2003 site visit, and I know that Dr. Bloom, following me, is going to go into more detail about what her branch does, but you can get the idea from this that not only does the office overall participate in IND review guidance document, regulatory work and active research, but in particular, this branch has been extremely active in all of these areas that I have mentioned.

Next slide. Okay.

So I think also Dr. Carbone did discuss what is the goal of research at FDA or at CBER, and the goal is to stay ahead of the curve as these products and technologies evolve.

So, in particular, in our field we look at the research that's going to address the regulatory needs of tomorrow. We have a good idea of what the anticipated products are based on our regulatory work, and we use that knowledge to feed into some of the objectives of our research program.

Next slide.

So that we do systematically look periodically internally, as Dr. Carbone did mention. There is a system across, you know, CBER to look at what are the critical path issues in these products, and our research is different from what sponsors do. The sponsors will study individual products and have proprietary results, whereas we look at studies relevant to product classes.

So, for example, if a sponsor wants to do toxicology testing of his or her particular product in an area where test methods don't really exist, they have a double challenge where they're developing the test methodology and of developing their product, and then that test methodology is done by them and relevant to what they do. So we try to encourage development of cross-cutting tools, such as test methods, for example, that can be used by anybody and where there could be a greater understanding of these tools, you know, as they are used across the field. People have a greater understanding of what the results mean.

Next slide.

I've listed on this slide our current research areas. This is across the office, and Dr. Bloom will be focusing specifically on the research in that branch.

Next slide.

I just want to mention reference materials are certainly an important part of our research. It's not basic science research in a way developing reference materials, but it's along the lines that I mentioned of assisting the evolution of standardized test methodologies.

Last slide.

And so lastly, I just want to thank everyone for participating in our review program. It's very important to us to make sure that we, you know, are reviewed and that we make sure that we're evolving in both a relevant way regulatorily and that our science continues to be of high quality and we get input from outside as is needed in all scientific endeavors.

And now I'll turn it over to Dr. Bloom.

DR. BLOOM: Thank you.

I'm going to speak with you this morning about the Gene Transfer and Immunogenicity Branch site visit that happened on March 2nd and summarize for you some of the information that was presented at that site visit.

The investigators at the site visit include myself, Dr. Andrew Byrnes, Dr. Suzanne Epstein, Dr. Nancy Markovitz, Dr. Carolyn Wilson, and Dr. Takele Argaw.

I would like to say that while my presentation will focus on the research of this group, I may refer to one of Dr. Witten's slides on the regulatory activities, and you can see that we have a quite substantial role in regulating INDs and the licensed supplements.

Our particular branch regulates samples of all of the types of products that are received in the Division of Cellular and Gene Therapies, including gene therapies, cellular therapies, xenotransplantation products, tumor vaccines and basically the whole nine yards.

So, in general, problems in development of cell and gene therapy products include -- I'm sorry. I'm on the second slide now -- include that there are a lack of preclinical models to predict performance of gene and cellular therapy products in vivo.

There is a potential for transmission of infectious agents to the patient and even beyond, especially for certain xenotransplantation products and certain gene therapy factors. So not all of the products pose this kind of risk, but many of them do.

And, in fact, some of these products were often intended for lengthy or even permanent residents in the recipient, which raises the risk level.

The complications of the product or --excuse me -- manufacture of the products are quite complicated, and the structure of these products are, as you can well appreciate, very, very difficult to describe and quantitate.

So the challenges for the Gene Transfer and Immunogenicity Branch, in particular, include on the next slide now product safety, which is affected by virus containing products. For example, unintended replicating viruses in viral vectors and in xenotransplantation products and other products pose risks not only to the immediate patient receiving these products, but also beyond the patient, and that's an issue of safety.

Some of our products contain intentionally replicating viruses. Generally these are intended to be attenuated or selected in their replication properties, for example, Herpes simplex viruses.

Viral vectors themselves also carry inherent risks, such as toxicity, tumorigenicity and off-target effects. Immunogenicity of these products impacts both safety and efficacy. Immune responses to viruses and transgene products, xenotransplantation and cell therapy products can severely compromise the efficacy, as well as harming, potentially, the recipient.

In addition, many of the products that we regulate rely on immunologic activity for their mode of action, such as tumor vaccines or immunotherapy, documented immunotherapy products.

The Gene Transfer and Immunogenicity Branch now in the next slide addresses these challenges through critical path research. We use multiple viral systems, and we use a flexible system to address immunogenicity in the function of many OCTGT products.

We believe that the predictability in the clinic of these products comes from understanding the fate and effect in vivo from the role of structure and function in product safety and from interaction of these products with the immune system.

Slide 5 is just to tell you that I am about to discuss with you the individual products that were presented at the site visit on March 2nd.

(Pause in proceedings to respond to cell phone interruption.)

DR. BLOOM: So I'm going to do these in alphabetical order by the investigator. The first one is my own, and it is the immunobiology of cellular therapy and xenotransplantation products, especially immunogenicity issues. What this slide shows is that in xenotransplantation, which is obviously transplantation between species, we've shown that immunity includes natural killer cells and T cells, antibody is also known to play a role.

We've also evaluated the role of regulatory T cells and shown that they inhibit CD4 positive T cell responses.

Autologous cellular therapies include primarily those that are expanded, though they don't necessarily have to be, expanded in vitro, and these include as I've said before tumor vaccines and adopting immunotherapies, and they need to be immunologically active, and these include, for example NK cells, T cells, also dendritic cells, among others.

Our transplantation, the immunologic response to these is primarily T cell dependent, and sometimes we have shown that NK cells can play an important role, for example, in the latter case with human embryonic stem cells or their differentiated progeny.

Slide 7 provides one tidbit of data from this program and shows that we have been working with collaborators at NIH to develop a preclinical model in xenotransplantation and we have been using this model to evaluate the potential for regulatory T cell activity in vivo.

The two figures shown show that when baboon CD4 positive, CD25 positive regulatory T cells are expanded, they strongly supplant both the proliferative and cytokine production of the baboon responder effector cells, which are CD4 positive, CD25 negative.

The impact of this program on cell therapy and xenotransplantation products is show in Slide 8 and includes our showing the NK cells must be considered as immune mediators for the rejection of both xenogeneic transplants and certain allogeneic cell therapy products.

We believe that efficacy may be affected by the types of responses of the recipient and the micro environment. We also believe that safety is important because it's important to have an intact immune system in addition.

So while you want to reduce the immune response of these products, you also need an intact immune system to deal with infectious agents.

We hope that these studies of the patient immune responses in vitro may eventually allow us to predict immunity in vivo and can serve as biomarkers of clinical benefit.

The next project on Slide 9 is that of Dr. Andrew Byrnes, and it is the safety and biodistribution of adenoviral vectors. Adenoviral vectors comprise a very large segment of the INDs reviewed in OCTGT, more than 80 active INDs in the United States alone.

Adenoviral vectors have four pharmacokinetics after systemic injection in that they are rapidly cleared by the liver actually, and in efficient therapy may be due also to that as well as to toxicities. Ad. vectors are taken up by Kupffer cells as shown in the bottom of this slide, and as you know, Kupffer cells are in the liver, and that appears to be a very common source of the pharmacokinetics, or Dr. Byrnes has shown this appears to be a good source of pharmacokinetic compromise.

So the next slide suggests how Kupffer cells recognize adenovirus. He has developed a new assay for quantitating the Kupffer cell uptake of adenovirus and has shown its scavenger receptors are important for their uptake of adenovirus, and again, these would impact on the biodistribution and on the efficacy and safety of these products.

So on Slide 11 we summarize the critical path issues in adenoviral gene therapy. Kupffer cells prevent ad. gene therapies from reach its full potential, and its future goals are to understand how Kupffer cells recognize adenovirus and to develop rational strategies to block Kupffer cells in order to enhance the gene delivery and decrease vector toxicity.

The third project beginning with Slide 12 is that of Dr. Suzanne Epstein and involves influenza, which is a serious public health problem. Influenza as we all know can cause very high mortality from seasonal outbreaks, and we're all acutely aware now of the potential for pandemic outbreak in the not unforeseeable future, and vaccine supply may be delayed or inadequate in these cases.

The work in Dr. Epstein's program involves new vaccine technologies that can cross-protect broadly against different, divergent Influenza A subtypes, and part of the impetus from this is that historical data suggests possible cross-protection in the pandemic flu of 1957.

The data shown in Slide 13 show that vaccines may differ in their ability to cross-protect against mismatched influenza subtypes.

So live attenuated virus similar to an available vaccine was not as effective in cross-protection against H5N1, which was used for challenge, as an experimental vaccine which she tested which was based on conserved antigens and uses a DNA prime recombinant ad. boost mechanism.

The implications for the public health and product regulation of this project is shown in Slide 14, and the project addresses DHHS and center-wide priorities on the control of epidemic and pandemic influenza, but also on counter-bioterrorism because influenza is now actually considered a counter-terrorism agent, but it represents a control of emerging infectious disease without having to know which strain is coming. So that's the purpose of the cross-protection.

Finally, safety and efficacy impact in gene therapy is because antibody and T cell responses to viral vectors can block efficacy and cause immunopathology, and flu serves as a model of that.

The next project on Slide 15 is that of Dr. Nancy Markovitz, and it's the identity and safety studies of herpes simplex viruses and vectors.

Replicating viruses used in cancer therapy can contain unrecorded mutations, and this is something that has been very well shown by Dr. Markovitz.

As far as safety is concerned, in contrast to what is frequently reported, Herpes simplex viruses similar to those that are actually used in clinical trials do, indeed, appear to replicate in normal brain cells in mice.

So the next slide shows that what we've already referred to, is that unexpected mutations in herpes simplex virus for clinical use can -- she has detected them. They can be detected. So our 3617 is a parent strain of virus G207, which is used clinically, and R3617 is what Dr. Markovitz has used in her experiments.

Now, sequence analysis has proven that the mobility shift which she sees of the UL3 protein was due to a single based substitution, and that single based substitution resulted in the truncation of the UL protein, demonstrating that unrecorded, unreported mutations can actually have very marked effects on the viral products.

In the third slide of this project, number 17, are figures that show the herpes based virus similar to those. Again, this is the R3617 virus, that it can replicate in cells of normal mouse brains, as you can see by the electromicroscopic picture on the right.

The next set of projects are those of Dr. Carolyn Wilson, and Slide 18 shows a brief introduction to E. bola virus, which is a little different than what you've heard about so far. E. bola virus has a very high fatality rate with rapid disease progress, and there is no proven cure and there is no vaccine available for these viruses.

Infection by the viruses suppress both the innate and adaptive immune responses and, thus, it exacerbates pathogenic outcome. It also prevents the development of protective immune response.

DHHS has designated E. bola virus as a high priority bioterrorist agent.

Dr. Wilson's group has collaborated to produce monoclonal antibodies against specific epitopes of three E. bola virus species and the epitope are conserved between the species. The anti-F88 monoclonal antibodies, as you can see in Slide 19, can neutralize several different strains -- excuse me -- several different viruses. Back up once. I apologize.

Several different monoclonal antibodies against the F88 determinant can neutralize several different strains of E. bola virus. In fact, these monoclonal antibodies that she has produced neutralize better than the 133 3.16 monoclonal antibody, which is typically used in these types of studies.

So the impact of these studies on counter-bioterrorism is that there may be a possibility; it is possible to develop antibodies for passive transfer, and this is done by targeting conserved epitopes. These epitopes, the antibodies against these epitopes can block entry and, therefore, reduce virus burden, and because the epitopes selected are critical for viral entry, one can avoid potential for immune escape mutants.

The broad protection to various filovirus species is an important plus in these studies and in the potential outcome of these studies, and it compliments vaccine strategy in that the development of monoclonal antibodies against E. bola virus may provide immediate protection in the event of an outbreak, where vaccine strategies would be needed prior to an outbreak.

In addition, Dr. Wilson has been working with the National Toxicology Program or NTP in a study for safety assessment of retroviral vectors for the risk of tumorigenicity. You may remember that there were a number of leukemias that developed in children receiving retroviral gene therapy for absence of the Gamma C chain, and so it is important to determine how these types of leukemias could develop, and so the study is to determine the sensitivity of a preclinical model for detecting vector mediated insertional immunogenesis, tumorigenesis, and to examine the impact of the vector backbone, the dose, and enhancer deletion on tumor frequency.

The study will assess retroviral vectors representing three different retroviral genera, including gamma retroviruses, lentiviruses, and spumaviruses or fomivirus.

Now, Dr. Takele Argaw in Dr. Wilson's group has been looking at the porcine endogenous retrovirus, and the reason for that is because porcine endogenous retrovirus occurs, which is present in all porcine cells, is considered to be a risk of xenotransplantation in that it can affect human cells in vitro.

And so what these data show is that Dr. Argaw has been able to identify particular residues that when mutated actually reduce the ability of perv. to infect human cells.

So the regulatory impact of the retrovirus program is that it addresses risk associated with retroviral vectors, including identifying a model to assess insertional mutagenesis from a retroviral vector, and using models to assess the relative risks based on different vector types, dose and structure.

In porcine xenotransplantation, again, a retroviral agent is considered a very serious potential safety risk and Dr. Argaw has identified residues that are required for the transmission of this virus that may allow development of a means to block the infection by the virus and to reduce the risk of transmission.

In summary, the Gene Transfer and Immunogenicity Branch is addressing regulatory challenges using critical path research. We look at gene therapy vector safety, xenotransplantation safety, cellular therapy and xenotransplantation product efficacy and address center-wide and departmental priorities, including pandemic flu and counter-bioterrorism.

Thank you very much.

CHAIRPERSON URBA: Thank you, all the speakers.

And now we have a few moments for questions from any of the Committee members or any of the previous speakers.

(No response.)

CHAIRPERSON URBA: No questions? Okay. Gail, shall we move on to the next part?

MS. DAPOLITO: Yes, we should. We lost Dr. Shores for a second. We're trying to round her up. Give us two seconds.

CHAIRPERSON URBA: Okay.

MS. DAPOLITO: Here she is. Are you ready, Dr. Shores?

DR. SHORES: Got you.

MS. DAPOLITO: Okay.

DR. SHORES: So hello. My name is Elizabeth Shores, and I'm serving sort of as the sherbert because we're switching courses a little bit now and moving not only between offices, but to a different center, the Food and Drug Administration.

And I want to thank you all for participating in this particular meeting and our site visit committee, headed by Dr. Gerson, that was so important for the peer review process that is essential to maintaining our integrity as a research group.

Although I said I'm a sherbert between groups, many of the things are similar between our two groups, and many of the things that Dr. Carbone mentioned are also true for us. So I won't dwell on those, but I think where we are particularly the same is in the way our research interacts with and critically supports our regulatory mission to provide safe and effective drugs to the public.

So by way of quickly introducing OBP, if you turn to the next page OBP, the Office of Biotechnology Products, is part of a super office called the Office of Pharmaceutical Sciences in the Center for Drug Evaluation and Research. The OBP is headed by Steve Kozlowski, and I'm the Deputy, and it's composed of two sister divisions. We're going to be hearing from both those divisions today.

There is the Division of Monoclonal Antibodies, headed by Kathleen Clouse, and this is a group that regulates a variety of different monoclonal antibodies as well as related products, such as Fc fusion proteins.

The sister division is the Division of Therapeutic Proteins headed by Amy Rosenberg, and that group reviews a large number of different therapeutic proteins, enzymes, cytokine growth factors, and toxins.

So we can move to the next page.

So what does OBP do? And we do a great deal of regulatory work, and I won't perseverate on that too much, but we scrutinize a large number of submissions from industry, from pre-INDs, to INDs, to 510(k)s. These eventually hopefully will lead to license applications, such as BLAs, NDAs, PMAs, and we actually have coverage of up to 90 different license applications in OBP right now, which represents about a one-third increase in the last year or year and a half.

And none of these applications are static. Sponsors are constantly tweaking them, and just as science moves forward, so will sponsors move to meet these challenges and tweak their products.

We engage in inspections, and we write guidance documents. We participate in many different meetings both with industry, as well as scientific meetings, and we consult a lot on our areas of immunogenicity.

But what we want to focus on today is a site visit report, and the site visit took place on February 23^rd, and it included David Frucht, Michael Norcross, Serge Beaucage, and Ed Max, and very much appreciate the input on the quality of the research programs that you heard and their mission relevance.

And regarding mission relevance, I'll just quickly say, and this is on Slide 4, there are a number of very important issues that arise in the review of biotechnology products, and I've listed some of these here, and I won't go through them individually really, but to mention that they're made in many different cell substrates. So microbiology is a huge issue. Immunology is a huge issue for these therapeutic proteins both regarding safety, as well as efficacy, and sometimes the mechanism of action isn't even clearly understood, and this is a big issue for us.

And all of these issues are things that we recognize as we review these applications, and these are things that industry doesn't really want to pursue at least in the detail that's needed or they can't pursue.

And so those are the factors that really drive our research, and as we go to the next page, it's why we use this researcher reviewer model, and as does CBER. We have perhaps successfully employed this model, I think, and it means that the very same people that are reviewing documents from industry may have active research programs that are applicable to the products that they're reviewing.

And so our regulatory reviews and identification of problems ends up impacting on our bench research and the types of programs that we follow, and then it sweeps back so that we learn from our research, then feeds into our regulatory review in many different ways, in our interactions with sponsors and in the publication of the guidance documents, and in many ways.

So with the constant challenges posed by biotechnology products, how can you be prepared to deal with the problems that you know exist, as well as to be prepared for the unknown? And to paraphrase something from Louis Pasteur, a prepared mind may be the best way to approach these unknown factors that arise in the future.

So on page 6, you can get an idea of the type of research, broad research programs that OBP supports, and you're going to be hearing from four individual laboratories that are engaged in research in these areas.

In the area of immunity, you're going to be reading and evaluating a report from Ed Max's lab and his colleague Ralph Bernstein that looks at the generation and control of antibody responses and isotype switching. Very important in considering anaphylactic reactions to therapeutic proteins.

On the next page is our programs in microbiology and infection, and you'll be hearing from two investigators in that area. David Frucht, who does critical research on characterization of the anthrax lethal toxin and its role in disease, and it's very important for our ongoing bioterrorism efforts. And you have reviewed the report from Mike Norcross and his colleague Jinhai Wang regarding HIV and the cytokines and chemokines that are involved in its activity.

And then finally, work from Serge Beaucage who has been a mover and shaker in DNA and ODN synthesis for years and his research has recently taken him into the area of looking at interaction with the toll-like receptors, as well as in the last slide, how to make these ODNs better for both the in vivo and in vitro applications.

So I'll stop now and had over to Kathleen Clouse who will discuss David Frucht's work and the Division of Monoclonal Antibodies.

(Pause in proceedings for teleconference interruption.)

DR. CLOUSE: Okay. We were trying to reach Dr. Frucht since we're running a little bit early. So he may call in in the middle of my presentation. So our apologies. We tried to coordinate timing.

MR. FRUCHT: This is David Frucht.

DR. CLOUSE: Hi, David.

Okay. The Division of Monoclonal antibodies, if you look on the second slide, has as its mission to insure that safe and efficacious and high quality monoclonal antibody and related products are available to the American public, and in order to do this, we have to make sure that we maintain and retain a diverse, knowledgeable, and scientifically based and dedicated staff that's actively involved in research and regulatory review and that the research programs are applicable to the regulatory review process.

In the next slide, you can see that as was published in Nature Biotechnology in September 2005, there was a statement made that monoclonal antibodies now comprise the majority of recombinant proteins that are currently in the clinic, with more than 150 products in studies worldwide.

The reality is at present more than 300 novel products are currently under review in our division alone.

The next slide shows you the organization of the Division of Monoclonal Antibodies. As mentioned, I serve as the Director. Dr. Patrick Swann is the Deputy Director. Dr. Swann also serves as the Chief of the Regulatory Science and Policy Branch, where we have at least eight full-time reviewers who have come up through the research laboratories, and we have three major research laboratory groups: the lab of cell biology, for which I'm Chief; the laboratory of immunobiology; and the laboratory of molecular and development immunology.

Being site visited in February was Dr. David Frucht. He is one of the principal investigators in the laboratory of cell biology, and his research emphasis is on counter-bioterrorism with the program dealing directly with anthrax research.

And in the next two slides summarizing some of David's credentials and accomplishments, he's established an independent research program to characterize the activity of anthrax legal toxin both in vitro and in vivo.

From a regulatory standpoint, he reviews products for infectious diseases, and these include antibodies targeting anthrax toxin, which are under consideration for inclusion in the strategic national stockpile under emergency use authorization. So these products have a more rapid development pathway than some of our other products.

He also reviews monoclonal antibodies and related molecules that function as agonists or antagonists for hematologic indications. He participates in pre-approval inspections. He serves on working groups for guidance document development, most notably anthrax therapeutics development and drug-drug interactions.

He serves as a co-chair for the CDER/CBER inter-center biotechnology counter-terrorism working group, and he has served as chair for the CMC session of an FDA sponsored workshop on immune therapies for anthrax infection.

And in the next slide, continuing on, he is Board certified in internal medicine and infectious diseases, hence the nature of his regulatory assignments. He performs weekly clinical rounds at the National Institutes of Health, and he serves on editorial boards for the Journal of Immunology and the Journal of Biological Chemistry.

He's been awarded competitive HHS grants and CBER/FDA grants for counter-bioterrorism research efforts, and his duties as a commissioned officer in the U.S. Public Health Service include being a member of the Incident Response Coordination Team where he's on call every five months for deployment, and he has had six deployments in the past three years.

And he was also selected for the Physicians Professional Advisory Committee to the Surgeon General.

And in the next slide summarizing his research program objectives, first of all, it's to identify the biological markers for the activity of anthrax lethal toxin in humans and in animal models; to assess the biological significance of these markers in the pathology of toxemia and/or anthrax infection; and to establish the scientific basis for the development of more relevant bioassays in order to assess product potency.

And these objectives are important for addressing issues relevant to seeking approval for these products under the animal rule, in other words, where efficacy testing is done in animal models and not in humans.

And in the next slide, the final slide, his research program milestones are best conveyed in the summary of his publications, and you can see they're broken down into categories where he has assessed the effects of anthrax legal toxins on multiple cell populations, including macrophages, human T lymphocytes, B-lymphocytes, and now most recently neutrophils.

So in the first one, he showed that anthrax lethal toxin activates murine macrophages, leading to the release of IL-1 beta and IL-18, and this study was basically performed in order to identify new biomarkers and determine strain susceptibility factors in the models that were used.

The second publication, "Anthrax Lethal Toxin Targets Human T Cells Leading to a Blockade and Proliferation in Cytokine Production," and this was to form the basis for determining the pathogenic mechanism and the basis for new bioassays.

Third, "Anthrax Lethal Toxin Blocks B Cell Proliferation in Immunoglobulin Production." Before B cells were not thought to be that intricately involved or affected by the anthrax lethal toxin, and this provided insight into a pathogenic mechanism and the basis for a new bioassay.

And finally, "Anthrax Lethal Toxin Promotes Super Oxide and Elastase Production in Neutrophils." This is for the identification of potentially more biologically relevant biomarkers for lethal toxin activity.

And with that I think we're due to take any questions you may have for me or for Dr. Shores or for Dr. Frucht on the phone.

CHAIRPERSON URBA: Thank you, Dr. Clouse, and thank you, Dr. Frucht, for being available.

The presentations are now open for any questions from any Committee members.

DR. TAYLOR: I'd like to get a sense of how much time Dr. Frucht actually spends on research.

DR. CARBONE: David.

(No response.)

DR. CARBONE: David spends -- he may have trouble unmuting his phone. We were dealing with that previously.

David spends probably about 40 to 50 percent of his time on research due to regulatory work loads at present.

DR. FRUCHT: Can you hear me?

DR. CARBONE: David, are you there?

DR. FRUCHT: Can you hear me?

DR. CARBONE: Yes.

DR. FRUCHT: Fifty percent, either supervising or performing necessary work. Sorry about that.

MS. DAPOLITO: Dr. Taylor, does that help answer your question?

DR. TAYLOR: Yes. Yes, it does.

And is the goal to maintain a 50-50 divide or do you anticipate as this research takes off you will still have the capacity to do that?

DR. FRUCHT: I anticipate that I'll have the capacity to do the research that I've set out to do spending 50 percent of my time on research and 50 percent of my time doing regulatory work, yes.

DR. TAYLOR: Okay.

DR. FRUCHT: I think the goals that I've set out are reasonable to accomplish in three years. I supervise the lab. Right now I have two other folks. There's another position that will be filled this year probably, and with that support, I think I'll be able to accomplish these goals.

DR. TAYLOR: Thank you.

CHAIRPERSON URBA: Other questions.

DR. CARBONE: This is Kathy Carbone.

I'd just like to make a statement for people within CBER. We do target a goal of about 50-50, 50 percent regulation, 50 percent research. Sometimes it goes up; sometimes it goes down, depending on crises, but we hope the staff can average that.

CHAIRPERSON URBA: Thank you.