P R O C E E D I N G S

1:35 p.m.

MS. WALSH: I'll start off the meeting. Good afternoon. I am Christine Walsh, the Executive Secretary for today's meeting of the Vaccines and Related Biological Products Advisory Committee meeting. I would like to welcome all of you to this meeting of the Advisory Committee.

There is a speakerphone for public participation located here in Conference Room C of Building 29-B on the NIH campus.

This afternoon's teleconference meeting will consist of sessions dealing with presentations and committee discussions that are both open and closed to the public, as described in the Federal Register notice of August 30, 2005.

At this time I would like to introduce the Committee members and ask that they acknowledge by saying "Present" if they can hear me:

The Committee Chair, Dr. Gary D. Overturf, Professor of Pediatrics and Pathology, University of New Mexico Medical Center.

CHAIRMAN OVERTURF: Present.

MS. WALSH: Dr. Monica M. Farley, Profess of Medicine, Emory University School of Medicine.

DR. FARLEY: Present.

MS. WALSH: Dr. Ruth A. Karron, Professor, Johns Hopkins School of Hygiene and Public Health.

DR. KARRON: Present.

MS. WALSH: Dr. Philip S. LaRussa, Professor of Clinical Pediatrics, Columbia University.

DR. LaRUSSA: Present.

MS. WALSH: Dr. David Markovitz, Professor, University of Michigan Medical Center.

DR. MARKOVITZ: Present.

MS. WALSH: Ms. Cindy Lyn Province, Associate Director, Bioethics Center of St. Louis.

MS. PROVINCE: Present.

MS. WALSH: Dr. Steven Self, Professor, Department of Biostatistics, University of Washington.

DR. SELF: Present.

MS. WALSH: Dr. Walter Royal III, Associate Professor, Department of Neurology, University of Maryland School of Medicine.

DR. ROYAL: Present.

MS. WALSH: Absent today is Dr. Bonnie M. Word, Assistant Professor of Pediatrics, Baylor College of Medicine. Dr. Word is in a Hurricane Rita evacuation area south of Houston. Our thoughts are with her, for her family and her family's safety and wellness.

I would like to thank all Committee members for taking the time to join us today. Now I would like to introduce come CBER staff members that will be participating in today's meeting and are currently seated in the room:

Dr. Michael Brennan, Associate Director of Research, Office of Vaccines Research and Review;

Dr. Kathryn Carbone, Associate Director for Research, CBER;

Dr. Norman Baylor, Director, Office of Vaccines Research and Review;

Dr. Jerry Weir, Director, Division of Viral Products;

Dr. Richard Walker, Director, Division of Bacterial Parasitic and Allergenic Products; and

Denise Royster, Committee Management Specialist VRPAC Advisory Committee.

I ask that all our Committee members identify themselves each time they speak. We do have a transcriber present who will need your assistance in order to accurately transcribe all comments to the appropriate Committee member.

I also ask our Committee members not to use cellular phones, since they may add unnecessary background noise to the line. Should during the teleconference a source of noise occur in your office, we would appreciate it if you would use the mute button on your phone, if you have that option. We ask that you do not place us on hold, since many clinical centers have background music that can be distracting to those remaining on the teleconference line.

I would now like to read into public record the conflict of interest statement for this meeting.

The Food and Drug Administration, FDA, is convening today's meeting of the Vaccines and Related Biological Products Advisory Committee under the authority of the Federal Advisory Committee Act, FACA, of 1972. All members of the Committee are Special Government Employees, SGEs, 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 USC 20(a) and 21 USC 355(n)(4) is being provided to participants in today's 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, including but not limited to 18 USC Section 20(a) and 21 USC Section 355(n)(4).

Under 18 USC 20(a), applicable to all government agencies, and 21 (SC 355(n)(4), applicable to certain FDA committees, Congress had authorized FDA to grant waivers to Special Government Employees who have had financial conflicts when it is determined that the agency's need for particular individuals' services outweigh his or her potential financial conflict of interest (Section 20(a) and where participation is necessary to afford essential expertise (Section 355).

Today's agenda includes a review and discussion of the intramural research programs of the Division of Viral Products and the Division of Bacterial Parasitic & Allergenic Products. Based on the agenda, it has been determined that the Committee discussion presents no actual or appearance of a conflict of interest for today's meeting.

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 participants to advise the Committee of any financial relationships that you may have with firms that could be affected by the Committee discussions.

That ends the reading of the conflict of interest statement. Can everyone hear me okay? Okay.

Dr. Overturf, I turn the meeting over to you.

CHAIRMAN OVERTURF: Thank you, Christine. I want to welcome all the members to this meeting which, as Christine Walsh just pointed out, will be to review four laboratories in the FDA CBER program. So we will go ahead and start through the first speaker, which will be Dr. Hana Golding from the Laboratory of Retroviruses.

DR. GOLDING: Can everybody hear me? Okay.

So I am the Chief of the Laboratory of Retrovirus Research in the Division of Viral Products, and the lab is divided into three sections: Section on Retrovirus Pathogenesis, Section of Retroviral Immunology, and Section of Molecular Retrovirology.

Those sections have been actually formed sort of historically back in 1993, and as you will see, some of the activities in the sections sort of crossed paths, and there was a lot of interactions going on between members of the various sections.

In the Section of Retroviral Pathogenesis, include myself as well as Keith Peden and Marina Zaitseva, who is a Senior Staff Fellow who worked with me for the past 12 years, and Dennis Klinman in the Section of Retroviral Immunology, and Arifa Khan is a PI in Molecular Retrovirology.

I would actually start by describing the diversity of the regulatory work that is covered by our laboratory. Since we are responsible for providing all the CMC consultation regarding HIV vaccines, this is the lion's share of the regulatory work in our group; and just to take a tally, since the last site visit our group reviewed more than 50 pre-INDs, 70 original IND submissions, and close to 850 IND amendments.

In addition, members of the group have been providing review regarding BLA and pre-BLA and BLA, usually in support of other laboratories.

So in addition to the immediate responsibilities, we provide expert opinion to other CBER laboratories and divisions on issues related to novel cell substrate, adventitious agent detection, retrovirus contamination, Lentivirus based vectors, plasmid DNA vaccines, and CpG oligonucleotides and other adjuvants.

In addition to the review of the different applications, members of the lab have been involved in multiple presentations to CBER Advisory Committees, and also have been representing CBER and the FDA at the World Health Organization and several other international regulatory authority meetings.

We commonly participate in interagency working groups and have been involved in organization or participation in special workshops on HIV vaccines, plasmid DNA vaccines, and novel cell substrates.

Importantly, during the past four years, several guidance documents have been worked upon by members of our laboratory. All of them have either been finalized or in last stages of finalization. Those included consideration for plasmid DNA vaccines for infectious disease indications that was headed by Dr. Dennis Klinman; characterization and qualification of cell substrates and other biological starting materials for the production of viral vaccines, which was a very important contribution by Dr. Keith Peden and Dr. Khan; and preclinical toxicity assessments of preventive vaccines to support Phase 1 clinical trials. I was involved in the preparation of this guidance.

I would like now to describe very briefly the main research activities in the individual PI's laboratories in support of our regulatory mission. I want just to say in the start that, in addition to the work related directly to the list of regulatory activities, several of us have been paying, or devoting a significant amount of our research toward agents of potential bioterrorism, and that will become evident in the presentation.

So Dr. Dennis Klinman's laboratory was mainly involved in monitoring the safety and regulatory activity of DNA based products. There are many such products that are regulated by CBER. DNA based products include DNA vaccines, synthetic oligonucleotides or ODN; for therapy, immune modulation and adjuvants.

In addition, another aspect of DNA or cellular DNA -- It is existent as a contaminant, unwanted contaminant in a variety of vaccines, as well as other biological products.

So the main achievements -- I think you have the packages. So you can get the details of the research work done, but the main achievements or accomplishments of Dr. Klinman's work is: He discovered and patented a new class of stimulatory CpG ODN that have been under development as vaccine adjuvants, immunoprotective agents and anti-allergens.

In addition, he discovered and patented a new class of suppressive ODN that may be used for prevention or treatment of autoimmune and inflammatory diseases, and he is actively involved in trying to understand the mechanism of action of these ODN.

In my laboratory there are actually three main areas of research that took place in the past four or five years. We continued in our duties on HIV cell entry with emphasis on HIV co-receptor expression and function in primary human cells, which are targets for HIV infection, and also involved in new entry inhibitors targeting the HIV co-receptors or CCR5.

In addition, significant efforts have been conducted in the area of HIV vaccine trials. Specifically, a new HIV EIA was developed for differential diagnosis of HIV infections in the presence of vaccine generated antibodies, and in the counter-terrorism preparedness we were involved in developing new in vitro assays and animal models for evaluation of smallpox vaccines potency and safety.

Back to the HIV EIA, we termed it HIV-SELECTEST, because it is important to emphasis its cell activity. So all uninfected vaccine trial participants score negative in our assay, while all HIV infections are diagnosed early after infection.

This is a very simple and economical test. It can be implemented in sites of future HIV vaccine trials and in blood collection centers around the globe.

In the area of smallpox vaccine evaluation, we developed a reporter gene based vaccinia neutralization assay. Again, it is a high throughput assay that was adopted by an HHS working group to be used in current clinical trials of new smallpox vaccines.

Using this in vitro assay, we continue in multiple collaborative work, among others on the monkeypox primate challenge that will eventually be validated for the "2-animal rule" for licensure of future smallpox vaccines.

We also are working on the development of mouse models for tracking vaccinia dissemination in order to evaluate vaccine safety and post-exposure prophylaxis.

Marina Zaitseva has developed an independent program regarding cellular genes involved in thymic reconstitution and immune modulation. She developed murine models of transient thymic atrophy that included low dose irradiation of single injection with dexamethasone or estrogen, and then used this model to identify salvage mechanisms which are important for thymic regeneration.

Currently, she is extending these studies in irradiated mice to follow reconstitution of T cells in the Gut-associated lymphoid tissues.

I am now moving to the work conducted in the laboratory of Dr. Keith Peden in the Section of Retroviral Pathogenesis. In that lab, there are three major directions. One is safety of tumorigenic cell substrates for vaccine manufacture, SV40 contamination in human vaccines, and HIV co-receptor evolution and pathogenesis.

With regard to the tumorigenic -- to the use of tumorigenic cell substrates, it was important to develop animal models to assess the oncogenic activity of cellular DNA. In order to do that, Dr. Peden, in collaboration with Dr. Andrew Lewis, developed animal model in which a combination of oncogene-expressing plasmids induced tumors primarily in newborn mice.

This animal model is now ready, all the positive controls are in place, and are ready to test molecular DNA from new cell substrates, including tumorigenic cells.

In parallel, efforts are done to actually provide quantitative means to evaluate the risk associated with residual DNA in vaccines produced in mammalian cells. So Dr. Peden has been putting some effort into developing quantitative assays to measure the infectivity of integrated retroviral DNA. This is just as a model system.

That allows him to come up with estimates for safe levels of residual cell substrate DNA in viral vaccines, and we now have the tools to evaluate the removal of cellular DNA. We hope that this kind of studies will be the basis for future FDA recommendations on the safe amount of residual DNA in viral vaccines.

In a separate area, Dr. Keith Peden's lab developed quantitative assays to detect the presence of primate polyomavirus DNA in biological specimens, as well as a single-cycle, reporter-gene based neutralization assay for BKV, JCV and SV40. This will be particularly important in lieu of the recent reports in the past several years that some tumors contain SV40 sequences, and there was the possibility that it was somehow associated with the contaminated polio vaccines of the early Sixties and Fifties.

I would like to then move to Dr. Arifa Khan in the Section of Molecular Retrovirology. Dr. Khan has been focused on several areas: First, Simian Foamy virus transmission studies in order to assess the risk of human infection by SFV-infected blood donors, as well as studies of Simian Foamy Virus replication in order to estimate the potential risk of SFV propagation in simian and human cells used for vaccine manufacturing.

In a separate project, Dr. Khan's laboratory is developing strategies for detection if infectious agents in vaccine cell substrates. That involves quantitative assays for detection of retroviruses, especially QPCR type assays, induction of endogenous retroviruses in cells from different animal species, and the induction of HHV-8 as a model of latent DNA virus.

That is the end of my presentation.

CHAIRMAN OVERTURF: We have a few minutes. This is Dr. Overturf. We have a few more minutes for questions. I would like to ask one question of Dr. Golding.

It seems to me that there are other laboratories that I recall that we have had presented to us that are also looking at adventitious agents in vaccine and vaccine products. You didn't mention in your presentation whether Dr. Peden is collaborating with any of those other laboratories in that effort, or are they working completely independently?

DR. GOLDING: That is a very good question. Actually, there is very extensive interaction which we think is really the strength of our adventitious agent program. There was a very close interaction between Dr. Phil Krause, Keith Peden, Andrew Lewis, who really complement each other in many of the adventitious agents that they are looking at, as well as the assays development, and actually as a team they were able to obtain several important external funding to support this effort.

I think it is really the -- The strength of the program is they are complementary in the interaction between these investigators.

CHAIRMAN OVERTURF: This is Gary Overturf. Are there any other questions from Committee members for Dr. Golding? Okay, hearing no further questions, I think we can proceed to the next presentation, which is on the Laboratory of Immunoregulation, Division of Viral Products, and the overview of the laboratory is going to be presented by Dr. Ira Berkower.

DR. BERKOWER: Yes. Hi. I hope you can all hear me. I appreciate this opportunity this afternoon to describe the research program of the Laboratory of Immunoregulation. The first slide on the handout shows the organization of the laboratory.

We have two principal investigators, Dr. Carol Weiss and myself. Each laboratory has a rather senior microbiologist, technician type, two post-doctoral fellows, and a pre-doctoral student or post-baccalaureate students who have worked on these projects. On this slide I have also included some of our principal collaborators at the NIH and at the Vaccine Research Center of the NIH.

ON my next slide, I show that the Laboratory of Immunoregulation is active in several regulatory areas. These include licensed vaccines. We approved the Hepatitis A/Hepatitis B combined vaccine which has been used subsequently in millions of people around the world.

We participate in clinical trials of new vaccines, and during the period under review we have reviewed over 250 IND documents, many of which were focused on a specialty that we have somehow evolved, which is therapeutic vaccines for HIV infection. Among these, we completed the review of the first large Phase 3 clinical trial of a therapeutic vaccine which involved over 3,000 subjects.

We are also active in the formulation of vaccine policy at the Office level and at the Center level I am the co-chairman of the guidance document for peptides. We worked on an important issue that was presented to your Committee in the past, which was eliminating the risk of BSE somehow creeping into the vaccines that are given to all the children; and I also served, along with Drusilla Burns here, as CBER's representative to the Interagency Committee on Select Agents of Bioterrorism, which helped the CDC implement the new laws on bioterrorism.

For the rest of this, I would just like to focus on our research program. Our research focus is on the factors that affect vaccine potency and efficacy, including the biology of the virus and the immune response of the host.

Our goals in this work are to advance the science of AIDS vaccines, and to improve our expertise so we can add value at each step of the regulatory process.

Now I have divided up the rest of this talk into discussing the work of the Weiss lab and then my own lab. The Weiss lab is focused in HIV vaccines and on smallpox vaccines.

Their HIV work has defined conserved neutralizing determinants in the Envelope gp41 protein that enabled the virus to enter the cell, and they have characterized these envelope structures as immunogens for eliciting broadly neutralizing antibodies.

This is possible, because these conserved structures are shared among many different virus isolates. So antibodies that neutralize one would probably neutralize all, and there are examples of this in the literature. They have elucidated the mechanism of antibody neutralization by targeting these sites, as measured in a variety of neutralization assays.

With regard to smallpox vaccines, they have analyzed the neutralizing antibodies that are elicited by the current vaccine, Dryvax, and they have evaluated the role of these antibodies in a protection assay.

For HIV: For an envelope virus like HIV to enter a cell, it must fuse its lipid envelope with the lipid vi-layer of the cell membrane. This process is a highly evolved function of the virus that proceeds via a fusion intermediate, and it is this fusion intermediate that is the target of a great deal of interest in the field.

It is well known, for example, that peptides corresponding to the fusion proteins can get in there and interfere with the fusion process. But in addition to that, Dr. Weiss showed that two highly conserved sites on the envelope fusion intermediate can be targeted for inhibition.

She has designed a structure-based strategy for raising antibodies to these conserved sites, and evaluated the antibodies for the ability to neutralize the virus, and studied the potential barriers to antibody access -- for example, the transient nature of the fusion intermediate.

In addition, she has subjected the virus to selective pressure and identified envelope mutations and potential resistance mechanisms by which the virus can escape inhibition at these sites.

This work is highly relevant to vaccines. As I mentioned above, by targeting conserved sites on gp41, this work leads to new strategies for developing vaccines that can induce broadly neutralizing antibodies, which are the goal of much current AIDS vaccine research.

They provide new methods for characterizing envelope immunogens, and they explain the mechanism of envelope escape from inhibitors such as enpuvaritype which have been observed in the clinic. This work also increases our expertise on neutralizing assays and on evaluating potential quality of protection.

In the smallpox area, Dr. Weiss demonstrated that a recombinant vaccinial protein called A27 can elicit potent neutralizing and protective antibodies that are measured in a passive protection assay in immunocompromised animals and show protective value by themselves and also, in combination, can augment the protection afforded by vaccinia-immune globulin.

Interestingly, she found that antibodies to this protein are only a minor component of the antibodies that are induced by the current vaccine, suggesting that additional specificities may be available if A27 can be made more immunogenic. By understanding the protective response to Dryvax, we can aid in the development of new vaccines by identifying viral antigens that induce protective antibodies. The immune response can be optimized in these new vaccines and, finally, identifying new targets for antibodies, it can lead to improved therapeutic immunoglobulins, perhaps by augmenting and adding new specificities to VIG, vaccinia immunoglobulin, as we currently have.

Now with regard to my own lab, we have focused on two projects, two areas. One is creating virus-like particles that are rich in gp120, and the second one is exposing conserved sites on gp120 for the induction of neutralizing antibodies.

With regard to the first point, we note that many successful vaccines are virus-like particles. IPV for polio and HBsAg for hepatitis B are two examples where the formation of particles is critical for vaccine potency and efficacy.

We have found that we can enhance HIV vaccine potency by incorporating gp120 or gp41 into virus-like particles. In addition, the HIV envelope has conserved and valuable antigenic determinants. It is well known that the variability of the virus is a huge problem for vaccines.

In addition, it is now known that the envelope protein can migrate between two structural confirmations, which I would describe as the open form and the closed form. In the absence of a figure of this, I would just like to use the analogy of my hand. The palm of my hand is the open form, and the fist is the closed form.

What we have found is ways to modify the envelope to keep it in the open form. This would expose the conserved sites in my palm and favor the induction of cross-reactive neutralizing antibodies. I would like to illustrate these two points in the coming slides.

The next slide shows our strategy for particle formation. We have expressed gp120 in tandem with a carrier protein, HBsAg. As shown in the lower left, HBsAg is an integral membrane protein that incorporates itself into the lipid bi-layer, and in doing so it anchors gp120 to the surface of a lipid; and when enough of these get together, they butt off to form particles and incorporate gp120 into the particles.

The interesting thing about the particles is gp120 is now expressed in its natural milieu at a lipid-water interface. The results that we have obtained with these particles are described on the next slide.

Hybrid proteins assemble efficiently into 20-30 nanometer size particles rich in gp120. The efficiency is greater than 90 percent.

gp120 is in the native conformation, and it changes conformation in response to CD4 binding from the closed form to the open form. I doing so, gp120 on the particles functions just like gp120 on the virus.

With regard to immunogenicity, the particles elicit neutralizing antibodies earlier than native gp120 alone, and the neutralization is more efficient relative the ELISA titers. However, the antibodies are still limited to neutralizing the immunizing strains.

Now since the time of the site visit, we have made a lot of progress on the second part of this. We know that gp120 exists in two conformations, based on X-ray crystallography, for example, and on monoclonal antibody binding. The closed form is found on the virus. The open form occurs after the virus binds CD4 receptor on cells. All gp120 vaccines tested so far have been in the closed form.

What we have done is we have identified five structural sites on the gp120 that changed position as gp120 migrates to the open form, and we have found that removing one of the loops favors the open form and exposes the CD4 binding site for antibody binding.

We have measured increased binding by two different monoclonal antibodies to the CD4 binding site that are favored by this loop deletion. This mutant will allow us, for the first time, to immunize with the open form in order to elicit antibodies to conserve neutralizing sites that are normally hidden.

This antibody research is quite relevant for HIV vaccines. We know that HIV-infected patients make broadly cross-reactive neutralizing antibodies in response to their infection. Monoclonal antibodies, human monoclonal antibodies, derived from these patients target a shared neutralizing determinant on gp120 or on gp41, and they neutralize broadly, despite the variability of the virus.

We also know that a cocktail of these monoclonals gave potent protection in a macaque challenge model, with sterilizing immunity in most cases. And so a vaccine that exposes the functional sites targeted by these antibodies would have the best chance of inducing protective immunity.

A successful AIDS vaccine most likely will elicit both neutralizing antibodies and effector T cells. Antibodies that target essential viral functions, as I have shown here, functions such as receptor binding or membrane fusion, as I described in the first parts, will cross-react broadly among different viruses, because they all have to do this same function. So they all share conserved sequences to perform this function.

Successfully modified forms of gp120, which expose neutralizing determinants, can lead us toward immunogens with enhanced vaccine potencies, and the ability to neutralize broadly.

Studies of viral neutralization will help us, in addition -- neutralization and protection will help us to evaluate new vaccine candidates as they come along and, hopefully, to define the correlates of immunity.

Any questions?

CHAIRMAN OVERTURF: This is Gary Overturf. Are there questions for Dr. Berkower by the Committee members? A fascinating discussion. This is again Dr. Overturf. A fascinating discussion, and I think highly relevant to AIDS vaccine research, Dr. Berkower. I appreciate that very much.

DR. BERKOWER: Thank you very much.

CHAIRMAN OVERTURF: We are getting ourselves a little ahead of time, but feel free to ask questions as we go along. So I will try to ask after each presentation.

The next presentation is by Dr. Drusilla Burns of the Laboratory of Respiratory & Special Pathogens, Division of Bacterial Parasitic & Allergenic Products. Dr. Burns.

DR. BURNS: Yes. Good afternoon. I am the Chief of the Laboratory of Respiratory & Special Pathogens, and I am going to tell you a little bit about that lab today, both our regulatory responsibilities and our research responsibilities.

Before I do, I wanted to give you a little history of this lab as well as Bruce Meade's lab, the Laboratory of Methods Development and Quality Control, that you will hear about next, since we both evolved from the same laboratory, and I think understanding the history will help you better understand the two labs.

As I said, we both -- Both the labs evolved from the Laboratory of Pertussis, which is a laboratory that has been in -- was in existence at this institution since the 1960s. The Laboratory of Pertussis was responsible for regulation of pertussis vaccines, and during the 1980s and most of the 1990s played a very big role in the development, evaluation and licensure of the new acellular pertussis vaccines, and there was quite a bit of activity in that area for that period of time.

In 1996 the first acellular pertussis vaccine was licensed for infants, and by 1998 most, but not all, of the acellular pertussis vaccines have been licensed.

So in 1998 the regulatory activity in this area began to subside somewhat, and we took a close look at the lab and said, well, you know, is there something that we could do that would help the Division and CBER in a better way than just sticking with pertussis vaccines.

There was one obvious area that needed some coverage, and that was looking at the vaccines that involve bioterror agents. In 1998 the anthrax vaccine was -- The military decided to give the anthrax vaccine to every member of the military.

So while the anthrax vaccine hadn't been used much before that, all of a sudden there was a tremendous amount of activity in that area. Of course, as we now know, in 2001 there were the anthrax letters which also put a lot of attention on both anthrax vaccines as well as other vaccines for bioterror agents.

So we felt that it would be best to expand the laboratory to include these vaccines, not only anthrax vaccines but some other vaccines for bioterror agents. So the name of the laboratory was changed in late 1999 to the Laboratory of Respiratory and Special Pathogens.

At that time, we then looked at the people -- the personnel in the lab, and we decided that perhaps we should split the lab into two laboratories, one that would contain the product area specialists or would look at the manufacturing issues and the evaluation of the vaccines, and the other laboratory which would specialize in test development. That laboratory is the laboratory that Bruce is going to tell you about in just a few minutes, and that is the Laboratory of Methods Development and Quality Control.

So now let me focus on the Laboratory of Respiratory and Special Pathogens. It has three principal investigators, each with our own independent research program, myself, Tod Merkel and Karen Meysick.

I will tell you a little bit about the research program in just a few minutes, but first let me focus in on our regulatory activity. We have three areas that we look at primarily. We still look at pertussis vaccines. We also are responsible for anthrax vaccines and the plague vaccines.

As far as pertussis vaccines are concerned, while the activity in that area has subsided since the late 1990s, there is still a considerable amount of activity, and that is we have to monitor and evaluate changes in formulation. This includes major changes in formulation, such as the Tdap vaccines that your Committee heard about in March and which were recently licensed, those vaccines for -- pertussis vaccines for adults and adolescents.

We also look at a number of other combination vaccines that contain pertussis components or major changes in manufacturing such as the removal of thimerosal that occurred a few years ago. Any change in the manufacturing process is reviewed by our laboratory, and we monitor the vaccines on an ongoing basis.

As far as anthrax vaccines are concerned, there is one licensed anthrax vaccine. That is AVA, the vaccine that was given to the military, and we monitor that vaccine and any change in manufacturing of that vaccine we are responsible for evaluating.

In addition, we are assessing the new generation anthrax vaccines that consist of purified single component, the recombinant protective antigen; and importantly, we have been instrumental or taken a lead role within the Center in using the Animal Rule to demonstrate efficacy of these bioterror vaccines.

For those of you who may not be familiar with the Animal Rule, this was instituted a few years ago. There are certain vaccines such as the anthrax vaccine which cannot be feasibly or ethically tested for efficacy in humans. In order to show efficacy of those vaccines, FDA promulgated a rule, a regulation, a few years ago that allows for efficacy testing to be done in animals.

While this sounds very simple, and it sounds like it could be a shortcut to determining efficacy of vaccines, in reality it is quite complex to come up with a really scientifically sound strategy for translating efficacy in animals to humans. That has been a challenge for us and something that we spent a considerable amount of time on.

As far as plague vaccines are concerned, we are responsible for the new generation of plague vaccines, and again the Animal Rule will have to be used to license these vaccines, and we have been working to come up with a sound strategy as far as plague vaccines are concerned.

The division of regulatory work in our laboratory is shown on the next slide. I am responsible for both pertussis and anthrax as well as Tod Merkel and his group. This redundancy is actually done on purpose, because both of these areas have a considerable amount of activity, and we need that sort of redundancy to make sure we have adequate people available at all times to do the regulatory work.

Karen Meysick is responsible for the plague vaccines, and I serve as her back-up when needed.

Our regulatory workload is shown on the next slide. Since 2000, we have reviewed a number of INDs and amendments, as well as BLAs and BLA supplements. Also, as I indicated, we have taken a lead role within the Center on implementation of the Animal Rule. We have held several workshops on the subject. We have given presentations at various places to get the word out, how we are -- our strategy for licensing these vaccines, and have worked closely with other government agencies, especially NIH who is running the program to evaluate the new anthrax and plague vaccines.

So while I have given you some numbers of INDs and BLAs that we have reviewed, I don't think that the numbers are that important, because sometimes you can review something very quickly. Other times, something takes a very, very -- a lot of work. Suffice it to say that each principal investigator in the laboratory spends about one-third to one-half of their time on strictly the regulatory aspects of our work.

Now I would like to switch to the research program and briefly describe the research of each of the individual principal investigators.

First, I have a research program, a small program in both Bordetella pertussis and Bacillus anthracis. While each program is small, I think that it is important to have a program in each of these areas to give the people who are doing the regulation hands-on expertise in those areas, and it also gives us credibility in each of those individual fields.

My program on Bordetella pertussis in both structure/function studies of pertussis toxin and specifically, we focus lately on the studies on the mechanism of action of secretion of pertussis toxin. My program on Bacillus anthracis focuses on the role of surface proteins in virulence.

Tod Merkel's research: Again, he has two areas of research, one on Bacillus anthracis, one on Bordetella pertussis, because he and his group are responsible for both of those areas as far as regulation is concerned.

He has identified important virulence factors in Bacillus anthracis and done a very nice job of developing a mouse aerosol challenge model for inhalation anthrax that has really been an important resource both for our Center as well as a number of members of the academic community. His work on Bordetella pertussis involves characterization of critical virulence regulatory pathways.

Karen Meysick's work is focused on Yersinia, and she is looking at -- She is analyzing a novel type III secretion system of Yersinia, and characterizing the phospholipases of Yersinia that are likely to play an important role in virulence.

She has just started a program on the development of biological assays to demonstrate the correlates of protection for plague vaccines.

Now in the next slide I have listed a couple of specific areas in which research has helped our regulatory mission. It has helped us design release tests for the DTaP vaccines. It helps manufacturers optimize production of pertussis toxin.

The work that Tod has done has provided proof of concept studies that will justify further development of anthrax vaccines and therapeutics. Karen's work is likely to identify new candidate vaccine antigens for plague vaccines, and development of functional assays that can be used to define correlates of protection for plague vaccines.

I think, just important as these more specific areas in which our research has affected our regulatory mission, are sort of less concrete but very important ways in which research helps us to regulation.

First of all, it gives of state of the art knowledge of the areas that we regulate, which are quite technical in nature, and it is really critical to have this knowledge.

It gives us the expertise to best evaluate tests to assess the safety, purity and potency of vaccines. In our own research, we are actually conducting these sorts of assays, and we can evaluate which ones would be best to use to monitor the manufacturing of a vaccine.

As I had indicated, it gives us the expertise to design and evaluate the efficacy studies for vaccines licensed under the Animal Rule, and again we have really played a lead role in setting the strategy for anthrax vaccines, along with people in Bruce's lab, as you will hear about in a few minutes.

It gives us a credibility in the field that we wouldn't otherwise have. We ourselves are peer reviewed not only by the site review, but every time we publish our manuscripts undergo peer review. And most importantly, I think, it gives us a whole different mentality on how to approach things in that we have approached things with a problem solving approach instead of just a problem identifying approach.

So we work very, very closely with the manufacturers whenever a problem arises to try and solve that problem as quickly as possible. Having been in this business for, I think, 20 years or so, I have really seen it work, especially at going through the licensing of the pertussis vaccines. I think having that sort of problem solving approach really cut a significant amount of time off of the licensure of the pertussis vaccines.

So I think I will stop here and take any questions that you might have.

CHAIRMAN OVERTURF: This is Gary Overturf again. Are there questions for Dr. Burns regarding the Laboratory of Respiratory and Special Pathogens? We are crystal clear, Dr. Burns.

DR. BURNS: Okay.

CHAIRMAN OVERTURF: So we are about 15 minutes ahead of time. Is the next speaker here? Dr. Meade?

DR. MEADE: Yes, I am.

CHAIRMAN OVERTURF: Okay. So he will present the Laboratory of Methods Development & Quality Control, Division of Bacterial Parasitic & Allergenic Products. Dr. Meade.

DR. MEADE: Well, thanks. Given this is, I think, a very difficult forum to go into much detail, what I have tried to do is put together a very short talk, giving sort of an overview on both our research and regulatory activities and generally the kinds of problems we approach and the strategies we take for moving forward and taking on projects.

As you will note, Drusilla Burns' lab and our lab -- and we have worked together a lot many years; so you are going to see some parallelism in the way we've put together the talks, but I also want to -- One of the goals is to illustrate, I think, sort of the difference in the approach and how I think they are complementary approaches.

So again, the second slide really just identifies the areas in which we have a role in both the research and regulatory activities in our area. It is really three areas. One is the clinical immunoassay, and that is really what we consider the assays that are used for clinical evaluation, and given that many of the new vaccines, especially in bioterrorism, will be evaluated using animal efficacy models, we include the clinical immunoassay to include those assays that will be used in those relevant efficacy models with the Animal Rule.

We are going to have a major program in product testing and quality control, and another area that we have taken on again recently in the last few years is to work within the Division and, in fact, within the Office of Vaccines on implementation of laboratory quality system for those official testing activities.

Again, I just wanted to highlight that at least our goal of setting up the laboratory is really to be testing specialists and not limit our activities to a given product area, although in reality we haven't gotten very far from our roots due to workload issues, but again I think we have -- I can highlight a little bit where we have moved in some areas.

The next slide just illustrates the current staff in our laboratory. There is five permanent staff, including one other doctoral level investigator, Juan Arciniega, two post-docs who have been with us for about a year and a half, and Sandra Menzies is a permanent member of the lab, who has non-laboratory responsibilities dealing with the quality control activities for the full Division.

The next slide talks briefly of the history, which again I think Drusilla mentioned already. At our last site visit in September '97 we were both -- both Drusilla's section and ours were members of the Laboratory of Pertussis.

Drusilla mentioned that in February '98 we assumed the responsibilities for anthrax vaccines, which came just a couple of months after the Army decided to immunize all the troops, even though there wasn't an adequate supply of vaccines. So it ended up being a major set of activities for our lab for the next several years. Then in October '99 we split into the two labs, as you have heard.

The next slide tries to illustrate, I think, again what I perceive as the difference in perspective and approach between the product area specialist laboratory such as Dr. Burns' laboratory versus our laboratory as testing specialists.

I think that, really, when you think about tests, there's really two types of questions. One is, is it the right test, meaning is it a relevant test that is addressing appropriate characteristics of the product or immune response.

Then there is the other aspect of the test evaluation that deals with, well, is the test right? Is it a reliable test? Is it appropriately controlled, designed, and adequate for the intended purpose? Again, I think, so our view is -- Our approach is to serve as testing specialists and, as it evolves, to work with multiple labs and product specialists within the Division as we evolve. Again, I think they represent different approaches.

Again, just to provide an overview of our activities, again in the regulatory area I'll mention the regulatory review responsibilities, which I would define as non-laboratory regulatory activities. But in the regulatory forum, we also have laboratory activities related to the quality control and product testing activities. The research program which was described -- which was covered under the review, deals with the other laboratory activities, separate from the quality control.

Again, our main projects are still pertussis and anthrax. Due to workload, we have begun to do some work in the laboratory with diphtheria vaccines and review with others.

So I'll do a couple of slides here which will give an overview of the regulatory activities, again just to give an overview. There's review activities related to the licensing which you have heard before from the previous speakers, both at the investigation of new drug applications and biologic license applications. There's post-approval review, which deal with supplements to the license.

Again, our areas primarily are tests assessing manufacturing that measure -- assess manufacturing or clinical response. Again, in review, our primary activities are pertussis and anthrax, but we have also had a role with the other vaccines listed there, diphtheria, cholera, Lyme, malaria and typhoid, again focusing on the testing issues.

Again, with respect to the Animal Rule, we have been involved with that. Again, our expertise is in animal bioassay, and at one level we think the animal efficacy models are just a very sophisticated, well developed animal bioassay. So our many years of experience between Dr. Arciniega and I and others in the lab really has been applied to the standardization and development of the models, again as a bioassay. Also, we have looked at the assays that will be measuring the functioning responses and how you can evaluate whether or not the response in humans is comparable to that in the animals.

I'll just mention some of the other areas of our regulatory activities: The establishment inspections. Again, we typically go out -- Each of us go out once a year for an extended site visit at the establishments.

Again, the other part that we have not mentioned is that we do the lot release for the currently licensed pertussis and anthrax vaccines. Lot releases have not been mentioned.

Every lot of those vaccines that is submitted for commercial distribution has to be released by us based on review of documentation on their manufacturing and testing, which occurs on all lots. We also have the option of testing of samples submitted by the manufacturer, again which is done in our laboratory.

I highlighted just two other aspects of the testing on this slide. One is the -- The other issue is that the testing experience we gain has been very helpful with -- We have been able to stay involved with the international community in harmonization and standardization of product assays, and again we list official testing activities. We have been very active in the initiative to implement a quality system for those activities.

Now let's go on briefly to give an overview of the research activities that were presented at the site visit in more detail.

Again, the two areas we discussed in some detail were -- One is the clinical immunoassay, which I presented, and again I define that as assays used in the clinical evaluation, both in clinical studies and again in animals from the efficacy models for the Animal Rule. Then Dr. Juan Arciniega discussed the activities related to product testing and quality control of products.

Then just to the next slide to give a quick overview on the clinical immunoassay projects: In the area of pertussis vaccine, this has really been a very long standing activity that has gone on for over 15 years in the laboratory. As a program most recently and where we presented at the site visit was the work we have done recently on a serologic diagnosis of pertussis.

Pertussis, as you all know, is a disease that is increasing both in adults, adolescents and in the very young infants, and one of the major limitations is diagnostic tools that can recognize -- help recognize the infection in adults and adolescents.

So we have been working with the CDC for several years now for developing an assay, and in the last year and a half we have made very good progress in developing a test, again done by a post-doc in our lab, Vijay Kadwad, who has been here for about a year and a half, where he has developed a prototype kit which we are ready for some interlaboratory validation studies, moving eventually to clinical assessment.

Again, we have also been involved for several years with statisticians, primarily with the NIH or with CBER statisticians, on statistical ways of approaching statistical evaluation of immunoassay data. Again, the last bullet is safety and immunogenicity of DTaP. Again, this is an ongoing -- was an ongoing long term project with NIH where we worked with them on the clinical assessment of DTaP vaccines, which led again to the licensure and the increased use of the acellular vaccines.

Anthrax vaccines -- we have been, again, very involved with some of the clinical immunoassay development evaluation.

Again, the last summary of the product testing and quality control subjects presented by Dr. Arciniega: In pertussis vaccine -- again, that was very active several years ago where we worked on toxicity and potency testing methods, and in the recent years the emphasis has been on working with the international community at implementing these and standardizing them and harmonizing at the international level.

For the anthrax projects, which has been our more recent emphasis, Dr. Arciniega talked in detail about the anthrax vaccine potency development, which again we view as an essential step in the development of the new generation anthrax vaccines, and we have been increasingly working with the companies and potential companies on those models. Again, we have been working on appropriate standards for those tests, looking at formulation of the vaccine formulation issues, as well as looking at new HPLC based methods for monitoring antigens in in-process product control.

Then we have been working, again, on some international collaborative studies with the diphtheria vaccine.

So I just want to close with the last two slides, again, which will look in some respects very similar to the messages you have heard from the other talks, but again I think this is sort of a summary of our approach.

Again, in terms of the relevance of our research in regulation, again we think it has been very important to have state of the art knowledge on the areas we regulate. The laboratory activities give us firsthand experience for designing and evaluating tests for both product assessment and product quality.

Ongoing efforts: We have been able to work with companies, troubleshooting problems in testing. We have been very active in international harmonization activities and, again as I mentioned earlier, we have used our bioassay experience related to the Animal Rule. And again as Drusilla mentioned, I think the lab activities has given us credibility, and again we have been able to work with a problem solving approach.

So I just wanted to close on the last slide with some very quick examples of what I think has been the impact on the regulatory mission of some of the activities looking over the longer view of the last 10-15 years.

For acellular vaccines, the clinical immunoassay experience we had: We served as basically a national/international reference laboratory where we distributed methods, reagents, provided training as necessary, and actually participated as appropriate with clinical studies.

The potency tests, the mouse immunogenicity potency tests developed here have really served as the basis of the potency test that is now described in WHO guidelines and the monographs of the European Pharmacopoeia.

With respect to the anthrax vaccines, which is more the ongoing, again as I have mentioned, we have applied our bioassay experience to the animal efficacy models. We are working on tests that can used in assessment of potency, and been very active with NIH and others and the companies at optimizing and standardizing assays for clinical and product evaluation.

Again, in the diphtheria vaccine there is a major initiative for developing alternative animal models for assessment of vaccines. So we have been active in some of the international projects.

So again, that is just to provide a couple of examples of some of the impact, we think, of some of our activities, and I will close with that, and certainly respond to any comments or questions.

CHAIRMAN OVERTURF: Gary Overturf again, Chair of the Committee. Are there questions for Dr. Meade? Go ahead and speak up, and please state your name before you ask a question.

Again, there appears to be no questions, Dr. Meade. So I will dismiss you.

It now must be about 2:40 and change on Eastern Standard Time, and we were to proceed to an Open Public Hearing. So I will ask Christine Walsh whether we can proceed to that now or whether we will have to wait until three o'clock.

MS. WALSH: This is Christine. We can proceed.

CHAIRMAN OVERTURF: Okay. Are there persons wishing to speak at the Open Public Hearing? MS. WALSH: I see no response in the room, Dr. Overturf. I just have one comment. I have received one comment from a person who was not able to attend the meeting. The comments have been distributed to Committee members, are attached to the public notebook, and are posted on the FDA website.

I believe there is no one else in the room who would like to address the Committee at this time. So I will turn the meeting back over to you.

CHAIRMAN OVERTURF: I think we can then proceed to the Closed Session at this time.

(Whereupon, the Open Session of the Committee was adjourned at 2:45 p.m.)

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