UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE

100th MEETING

**OPEN SESSION**

THURSDAY,

SEPTEMBER 23, 2004

The Advisory Committee met at 9:00 a.m. in the Versailles Ballroom of
the Holiday Inn Select, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr.
Gary D. Overturf, Chair, presiding.

[PRESENT]{.underline}:

GARY D. OVERTURF, M.D. Chair

MONICA M. FARLEY, M.D. Member

BRUCE GELLIN, M.D., M.P.H. Temporary Voting Member

RUTH A. KARRON, M.D. Member

DAVID M. MARKOVITZ, M.D. Member

PAMELA McINNES, D.D.S. Temporary Voting Member

STEPHEN PETTEWAY, Jr., Ph.D. Acting Industry Representative

CINDY LYN PROVINCE, R.N., M.S.N. Consumer Representative

WALTER ROYAL III, M.D. Member

DAVID STEPHENS, M.D. Temporary Voting Member

RICHARD WHITLEY, M.D. Member

BONNIE M. WORD, M.D. Member

CHRISTINE WALSH, R.N. Executive Secretary

[FDA REPRESENTATIVES]{.underline}:

JOSEPH TOERNER, M.D., M.P.H.

[SPONSOR REPRESENTATIVES]{.underline}:

COL. DEBORAH BIRX

LTC ARTHUR BROWN

LTC JEROME KIM

PRASERT THONGCHAROEN

SUPACHAI RERKS‑NGARM

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

I-N-D-E-X

[Agenda]{.underline} [Page]{.underline}

Call to Order ‑‑ Dr. Gary Overturf, Chairman 4

Announcements ‑‑ Christine Walsh, R.N., FDA 4

Opening Remarks ‑‑ Dr. Joseph Toerner, FDA 5

Presentation by the Sponsor ‑‑ Office of the 11

Surgeon General

Questions of Clarification from Committee 31

Open Public Hearing 51

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

9:03 a.m.

CHAIRMAN OVERTURF: Good morning. I\'d like to welcome you to the second
day of the Vaccine and Related Biological Products Advisory Committee
meeting. This is an open session, and, first of all, I\'ll turn the
meeting over to Christine Walsh who has some announcements.

MS. WALSH: Good morning. I\'m Christine Walsh, the Executive Secretary
for the Vaccines and Related Biological Products Advisory Committee.
This brief announcement is in addition to the conflict of interest
statement read at the beginning of the meeting on September 22 and will
be part of the public record for the Vaccines and Related Biological
Products Advisory Committee meeting on September 23, 2004.

This announcement addresses conflict of interest for Topic 2. Drs. Bruce
Gellin, Pamela McInnes and David Stephens have been appointed as
temporary voting members for this topic. Dr. Stephen Petteway is
participating as a non-voting industry representative, acting on behalf
of regulated industry. The Food and Drug Administration has approved
waivers under 21 USC 355(n)(4) of Section 505 of the Food and Drug
Administration Modernization Act for Dr. David Stephens. Dr. Steven Self
has recused himself from participating in this discussion. That ends the
reading of the conflict of interest statement.

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

CHAIRMAN OVERTURF: The purpose of this meeting is to review the Thailand
HIV vaccine phase III trial. The trial sponsor being the Office of the
Surgeon General and the U.S. Army. The products are an HIV I recombinant
canarypox-vectored vaccine and a recombinant gp 120 B/E CHO cells with
alum vaccine. And I\'m going to ask, first of all, Dr. Joseph Toerner,
who will be the first presenter, to come to the podium.

DR. TOERNER: Good morning. My name is Joe Toerner. I\'m a Medical
Officer in the Division of Vaccines and related product application at
CBER, and I wanted to welcome you all today to today\'s discussion at
the VRBPAC. In particular, I\'d like to recognize and welcome the
sponsor who has included colleagues from Thailand who will be
participating in today\'s VRBPAC session and would like welcome members
of the public who are here today as well. And as Dr. Overturf had
introduced the topic for today, a discussion of the ALVAC plus AIDSVAX
vaccine regimen, these are preventative HIV vaccines that are based on
Clade E.

You\'ll be hearing more in detail a discussion of the trial to be
presented by the sponsor, but just as a very brief introduction, ALVAC
is a canarypox-vectored vaccine that can be considered the prime in this
vaccine regimen. The AIDSVAX B/E is a gp 120 protein vaccine that can be
considered the boost in this regimen.

Both of these vaccines contain epitopes of HIV that are meant to illicit
a specific immune response against Clade E, which is the specific clade
that circulates widely in Thailand, and that clade has been
recharacterized as a circulating recombinant form.

You have all been reading about this trial in the lay press as well as
in journals. For example, a recent series of articles in the journal
*Science* had aired these differences in the scientific merit of the
study. However, the purpose of today\'s VRBPAC is not to discuss these
differing scientific opinions but to present to the Advisory Committee
an update on the ongoing study, in particular, the decision to allow the
trial to proceed under U.S. IND.

In addition, we wanted to introduce you to some of our regulatory
challenges that we\'re going to be faced with, in particular with this
trial. One of the regulatory challenges that we\'ll be faced with has to
do with the complicated genetic diversity of HIV. HIV can be defined as
clades or subtypes, and that definition is based on differences in the
short sequences of the outer most portion of HIV, the envelope protein.

In addition to clades that have been identified, new circulating
recombinants have been recently identified. And to further complicate
the genetic diversity, formerly recognized clades have been
recharacterized as circulating recombinant forms. And in this particular
case, Clade E has been recharacterized as a circulating recombinant
form.

HIV\'s genetic diversity does represent a potential obstacle in the
development of an HIV vaccine. A recent article in the *New England
Journal of Medicine* had described an individual with a
well-characterized clade of HIV who experienced a new acute retroviral
syndrome associated with a low CD4 cell count and an increasing HIV RNA
that was due to a different clade HIV. In addition, numerous other
articles have described this phenomenon of super infection.

So it calls into question how broad do immunological responses have to
be and how much cross-clade recognition does there have to be with an
HIV vaccine? One current thought is it perhaps is necessary to illicit
an immune response against the outer most portion of HIV, the envelope
protein. And as a consequence, much of HIV vaccine development today is
clade-specific.

This slide is meant to again represent the complicated global diversity
of HIV. You can see that Subtype B is the predominant subtype that
circulates in North America, Europe and Australia. This slide also
highlights the very complicated genetic diversity in Subsaharran Africa.
But I wanted to call your attention to Southeast Asia and Thailand where
Clade E, or what is now recognized as a circulating recombinant form, is
the predominant subtype that circulates in Thailand.

Dr. Jesse Goodman has taken some of our internal discussion regarding
our regulatory challenges in the field of HIV vaccine development and
has presented our internal discussion in a public forum, and I wanted to
share with you a slide that he had presented at a recent conference, at
the International Conference of Drug Regulatory Authorities that
occurred earlier this year.

And in Dr. Goodman\'s slide he had posed the following interesting
issues in HIV vaccine development. And he had asked a rhetorical
question: Is U.S. approval possible for an HIV vaccine that incorporates
only non-U.S.-prevalent clades? And this particular question, if you
will, or this particular point applies directly to today\'s discussion.

Dr. Goodman\'s second bullet point actually raises many issues, but the
main point that I wanted to make from Dr. Goodman\'s second bullet point
is a vaccine that has been demonstrated to have efficacy against Clade
E, how would we view that as a U.S. regulatory agency where we might
consider that to be a vaccine, a very limited efficacy for the U.S.
population? And so that is the type of discussion that Dr. Goodman has
at least presented to the public, and the slide, I think, serves as an
introduction that these are regulatory issues that we\'ll be faced with
in the future.

I wanted to emphasize that this is simply Dr. Goodman\'s slide. These
are not questions that we\'re posing to the Advisory Committee today.
This slide was simply meant to highlight some of our regulatory concerns
that we\'ll be faced with.

So that concludes my introductory comments, and I wanted to turn the
podium over to Colonel Brown, who will be leading the discussion of the
sponsor\'s presentation.

COL. BROWN: Thank you, Dr. Toerner, Mr. Chairman, committee members.
This morning, we\'d like to present to you an update on this trial, and
we\'ll have three speakers presenting. In addition to myself, who will
give you background information and information on the Phase II study,
Professor Prasert is here with us from the National AIDS Commission of
Thailand and will provide a perspective from that organization, and Dr.
Supachai, the principal investigator of the Phase III trial is also with
us, and he will give the actual description of the study design and
current status.

The collaboration that was the basis of this trial goes back a long way.
There\'s a U.S.-Thai Army collaboration in Thailand that\'s more than 40
years old, which has been studying tropical infectious diseases and has
been very involved in vaccine development. And since 1991, a new mission
was added there to work toward a preventive HIV vaccine. And that was an
agreement between our two military organizations. That collaboration has
expanded to include universities in Thailand and vaccine manufacturers
and became more formalized with the creation of the Thai AIDS Vaccine
Evaluation Group, called the TAVEG.

But in parallel with the growth and maturation of that collaboration,
the Thai national authorities have been addressing their own HIV
epidemic and in the early 90s developed a national plan for the control
of HIV, and as part of that have a specific plan for HIV vaccine
development, which was first published in 1993.

So what I\'d like to do is now just present Professor Prasert, who is a
member of the National AIDS Commission and Chairman of the Subcommittee
for HIV Vaccines. And he will share a perspective from that independent
national authority.

DR. PRASERT: Thank you, Art. What I would like to present to you is
about Thailand involvement in HIV vaccine research and development. My
presentation will include Thailand national plan for HIV/AIDS vaccine
development. It will include the government commitment, the technical
and scientific review of protocols and research proposals and
development of infrastructure and training.

The national plan of HIV/AIDS vaccine development and evaluation is
development by Thai Ministry of Public Health and research scientists
from various institutions in Thailand with collaboration with the Global
Program on AIDS of WHO at the time. And this plan has been approved by
the National AIDS Commission and launched in 1993, placing HIV vaccine
research and development on a fast track. The publication on that is in
a Thai version and English version.

The national plan aimed at research and development of safe, effective,
affordable and accessible HIV vaccine for the Thai people at the
earliest possible date. The main objective of the national plan on
HIV/AIDS vaccine are to develop a comprehensive, well-coordinated,
long-term strategy for the evaluation of the safety, immunogenicity and
efficacy of preventive, therapeutic and at the time we also forecast on
perinatal HIV/AIDS vaccine in Thailand, but now it\'s a low priority
now, and to develop and explain the policy and procedure for planning,
implementation, oversight, administration and evaluation of HIV/AIDS
vaccine related with those activities in Thailand, and to facilitate the
conduct of scientifically and ethically appropriate HIV/AIDS vaccine
trial in Thailand.

The infrastructure and research activity that we plan and have been done
in Thailand are to establish virological and immunological HIV
expertise, especially the HIV isolation in Thailand and characterization
of clades and to strengthen critical at laboratory facility for Phase I,
II and III trial; to develop epidemiological and intervention research
studies required for cohort development for clinical trial and to
conduct the social and behavior research of the volunteers and
communities; to establish the appropriate data that has not existed in
my country and we developed this up to international standard and to
develop the National Specimen Repository that we have established before
also.

This is the commitment of the government and support from the
government. The National AIDS Commission is appointed by the cabinet.
This Commission is Chaired by the Prime Minister of Thailand. And under
this umbrella we have several subcommittees appointed by the National
AIDS Commission. And the Subcommittee on HIV/AIDS Vaccine Development is
one among them. And the AIDS Commission appointed the Department of
Disease Control, Ministry of Public Health to be the focal point to
coordinate all of this, but all of these are independent organizations.

The National AIDS Commission established the Subcommittee on HIV/AIDS
Vaccine Development and report back to this independent organization.
And they collect information on HIV/AIDS vaccine development to the AIDS
Vaccine Coordinating Unit of the Ministry of Public Health, and they
also collect information from IRBs, and we have some coordination with
the Ministry of Public Health, but it is an independent body.

The Subcommittee on Vaccine Development is to identify and prioritize
research activities related on HIV/AIDS vaccine evaluation, to provide
coordination to all HIV/AIDS vaccine-related activities in Thailand and
to provide scientific and technical review of all HIV/AIDS
vaccine-related research protocol and proposals. This is the process we
have done in the past and are going now.

The proposal and protocol must be submitted to the Subcommittee of
HIV/AIDS Vaccine Development and Review for technical value before the
research can be implemented. And the Subcommittee ensures that vaccine
protocol meets appropriate regulatory requirements of Thailand and
international. Upon the request of the Ministry of Public Health the
research proposal and protocol would also be reviewed by WHO/UNAIDS
Steering Committee on Vaccine Development and by independent review
group in Thailand and when applicable by other funding agencies and
investigator\'s host institution.

From 1994 to last year, we have reviewed and approved from Phase I,
Phase II and III research proposal on HIV vaccine clinical trial to get
a number and among them who are Phase III clinical trial.

In summary, I would like to present the national plan for HIV/AIDS
vaccine, established in 1993, has led to the development of appropriate
global research, infrastructure and training in various fields. We have
independent scientific and technical reviews and selection of
appropriate vaccine candidates and research proposal and the
Subcommittee has sustained the government support and commitment. Thank
you very much.

COL. BROWN: Now I\'d like to continue with background for the Committee
and then describe the Phase II trial and the process for advancement to
Phase III.

The focus of the collaborative research effort has been to work in a
multidisciplinary way but always focused toward the goal of preventive
vaccine. So there\'s been work in virology, diagnostics, epidemiology,
preventive education and the disease course of HIV in this population.
Consistent with the national plan for vaccine development, there\'s been
a large emphasis on development of infrastructure, both human and
physical and capacity-building.

The candidate vaccines developed have benefited from the industry
partners tailoring these vaccines to the local strains of HIV, which is
predominantly E, as you\'ve heard, but also B is there. And the
vaccines, as you\'ll see, contain components of both these subtypes. The
TAVEG itself has tested four of these candidates that have been shaped
for the viruses in Thailand in a series of Phase I and II trials that
have included more than 700 subjects.

The Phase II trial that I\'ll describe here, which was just published
last month, was led by two principal investigators, Dr. Ponnee and Dr.
Supachai who are here today. The Phase II was a double-blind,
placebo-control trial. The vaccine candidates were modifications of
vaccines that had been made with strictly Clade B products so that the
ALVAC product now has E envelope but still had the B Gag-protease. The
AIDSVAX product is a bivalent B/E with two antigens, monomeric gp 120s.

The immunization regimen was to give the prime, which is the ALVAC, at
four time periods over a six-month period and then give the AIDSVAX as
the boost at the last two immunization visits. There were three study
groups: A placebo group and a group that got a low dose of the booster
vaccine and a group that got a high dose of the booster vaccine. The
subjects in the trial were healthy adult Thais who have non-reactive
results in commercial HIV EIA assays.

One hundred and thirty-three subjects were enrolled into this trial and
122 were vaccinated. In terms of safety and tolerability, there were no
vaccine-related serious adverse events. Reactogenicity assessments
revealed no severe local or systemic reactions. The false positivity
that can be vaccine-induced was monitored, and at the peak time point,
two weeks after the last vaccination, there were 60 percent of
volunteers who had reactivity in a commercial EIA. Only two percent of
those people met the criteria of positivity in Western blot. And the
actual testing algorithm includes nucleic acid testing, and none of
these people had positive nucleic acid tests, and all were shown to be
false positives. There were no intercurrent HIV infections in this group
during the study.

Humoral antibody responses are summarized on this table. The humoral arm
of the immune system has been monitored with three assays: A binding
antibody assay against both gp 120 B and gp 120 E, neutralization assays
that have been set up against matched viruses of B and E Clade and an
antibody-dependent cytotoxicity assay, also against target cells labeled
with B and E gp 120.

The antibody responses, the seroconversions and the magnitude of
responses, were greater in the group with the high-dose boost, and that
was then selected as the combination to move forward to Phase III. The
results in that group, you can see here, for binding antibody range from
96 to 100 percent, with the two antigens. Neutralization ranged from 71
to 98 percent. And antibody-dependent cytotoxicity ranged from 78 to 93
percent.

The cellular arm of the immune system was monitored in two ways: To look
at both CD8 reactivity and CD4 reactivity. The HIV-specific CD8 CTL
activity was assessed using the traditional chromium-release cytolytic
assay. Detection of vaccine-induced activity in this assay was detected
as early as after the second vaccination and was still being detected
for the first time in volunteers at the last study visit, which was six
months after the last vaccination. The cumulative frequency was 23
percent, and cross-clade reactivity was documented. The placebo group
was consistently found to be non-reactive in this assay.

CD4 cell function was assessed using a lymphoproliferation assay to the
two envelope antigens, gp 120 E and gp 120 B, and the responses of
vaccinees were just about 60 percent, as you can see in this table.

So in moving forward to Phase III, there were a number of factors that
were considered. The program made decisions regarding vaccine candidates
that, one, they should induce both arms of the immune system and that
the cellular responses should include both CD4 and CD 8 responses. And,
two, that the candidate vaccines should match as well as possible the
circulating strains of HIV found in the region under study.

The vaccines themselves when tested had to be found safe and well
tolerated. The immunogenicity needed to be comparable to that seen with
the similar candidates that had already been developed with Clade B
constructs and tested more extensively in the U.S. and Europe. And
equally important is a requirement that there had to be a potential
cohort which was well characterized and included information on HIV
incidence and follow-up rates.

So when Phase II studies were ended, the various partners reviewed the
information available and a joint agreement was reached among the U.S.
and Thai government partners, the academic and manufacturing partners. A
protocol was developed, which has been a long process. The final
protocol was actually reviewed by ten different institutional and
regulatory bodies.

The plans for this trial have been presented to a number of advisory
committees. They within Thailand have been presented to the National
AIDS Commission and its subcommittee. Within the U.S., it was presented
to what was formally called the Baltimore Committee. Internationally,
this was presented to UNAIDS, and the plans have been presented at
multiple meetings, including national AIDS meetings in Thailand for both
AIDS, in general, and AIDS vaccines and the International AIDS Congress
in Barcelona where there was an announcement by the partners that this
would move forward.

The sponsorship of this Phase III trial is shared by both the U.S. Army
Office of the Surgeon General and the Division of AIDS at NIH. The Army
is the IND holder for this vaccine combination. The executing authority
for the trial is the Thai Ministry of Public Health. The principal
investigator is Dr. Supachai, and there have been multiple collaborators
‑‑ there are multiple collaborators that are essential to the successful
completion of this large effort.

So, in summary, this Phase III trial is founded upon more than a decade
of preparedness and capacity building, the support of scientific and
clinical data and a unique partnership among academic, governments and
industry.

So I\'d like to now ‑‑ or we would like to now shift and I\'d like to
present Dr. Supachai Rerks-Ngarm, who\'s a Senior Expert in Preventive
Medicine for the Ministry of Public Health of Thailand and the principal
investigator for this trial.

DR. SUPACHAI: Good morning, Mr. Chairman, the committee members, ladies
and gentlemen. I would like to present to you the study design of the
ongoing Phase III trial and the current status.

Our collaborative study has a primary objective to determine whether
immunization with ALVAC HIV vCP 1521 boosted by AIDSVAX B/E gp 120
protects Thai volunteers from HIV infection. And we also have the
secondary objectives to determine the effect of immunization on viral
load and CD4 count after intercurrent infection. Also, we\'d like to
confirm the safety of this vaccine combination. The last secondary
objective is to evaluate whether a patient in this combined vaccine
trial is associated with behavioral change that increasing risk of HIV
infection.

Our study design has a community-based, double-blind, placebo-control
with a vaccine to placebo ratio of one to one. The vaccine schedule is
similar to what Colonel Brown has described as the Phase II trial in
Thailand, which is the ALVAC HIV vCP 1521 at week 0, week 4, week 12 and
week 24, then boost by AIDSVAX B/E at week 12 and week 24. It was
especially slow serology negative and it\'s 20 and 30 years old. Each
individual volunteer will be followed for three years post-vaccination.

This study designed based on the incidents of HIV infection in that
locality of 0.34 per 100 person-years, which is lower of 90 percent
comes in interval of the incidence found in the cohort study. We allowed
the lost to follow up about five percent for six months and we target to
enroll about 16,000 volunteers. With a conservative assumption, we would
have about 90 percent power to detect difference between the vaccine and
possible if efficacy is 50 percent of regular.

Every female volunteer will be tested for pregnancy before the
vaccination. If found positive, the vaccination will be stopped and the
outcome will be follow-up until the female volunteer gives birth. The
reactogenicity will be evaluated for 72 hours after the vaccination. For
the adverse event, it will be assessed and provide risk reduction
education at the vaccine and follow-up visits. And the behavioral risks
will also be assessed at baseline and every six months.

The serology will be tested during screening at week 24 and then every
six months with the standard pre- and post-test counseling. The plasma
will be collected and stored at baseline and every six months the PBMC
also at baseline six, 12 and 42 months. We will utilize our local health
centers to enhance follow-up of each individual volunteer during the
post-immunization phase.

This is a map of Thailand. Our study area located in eastern part of the
country, which covers two provinces, Chon Buri and Rayong, and in each
province we have a study area in four districts ‑‑ four in Chon Buri and
four in Rayong. We used the government facilities in this trial. This is
a picture taken from one of the health centers that served as the
screening sites. All together we have 47 screening sites. Among the 47
screening sites, we have 40 health centers and seven district hospitals.
In each screening site, we have two counselors. In total, we have about
100 counselors. And this is also the picture taken from the district
hospital. We\'re involved with even district hospitals, and in one
district we don\'t have district hospital, so we worked with the city
clinic to serve as a clinical site. So all together we have eight
clinical sites.

In each clinical site, we have ten counselors, two nurse coordinators,
two site physicians, five clinical research coordinators, two pharmacy
nurses and three research assistants. So all together we have about 200
personnel. All together we have about 300 to 400 personnel working for
this trial, which has been carefully selected, and they all have been
trained in advance before the trial has been initiated. They were
trained for the GCP, for the counseling, for the protocol and SOP and
especially trained among the medical site physician and nurse on the
advanced cardiac life support.

This is a picture taken from one of our government facilities. It
belongs to one of the departments in my ministry that have been used as
a trial registry and repository center. These individuals prepare,
process the specimens taken from the field site to be ready to send to
the lab in Bangkok. All specimens will be here. The cap really is to
keep more than 600,000 specimens here.

This is a picture taken inside the core room, which belongs to my
department, the Department of Disease Control, to distribute the EPI
vaccine in the routine service. We use this as a vaccine distribution
center. It\'s located in Chon Buri. In addition to these facilities I
have presented to you, we also ‑‑ in addition to that, we also use
another two facilities which belong to the government as well. One is
the critical, the surgical lab at the Thai Army, which is involved with
the Thai technician and American technician working there. That lab has
been activated by the American College of Pathology. And another
facility is the data management unit, which is located in the faculty of
Department of Medicine, which belongs to the Mahidol University to
manage all the data in the field that has been faxed to that unit.

After training our personnel in all the facilities and refreshing them,
we can initiate our trial on September 29, last year. And the first
volunteer was vaccinated on the 20th of October, last year. We x-ray\'d
our site by using the facility of site-by-site initiations, and we can
have all sites enrolling in February this year.

As of last week, we have almost about 10,000 volunteers screened, and
about almost 6,000 volunteers has been vaccinated. So, by average, right
now we have about 200 volunteers per week. This is the slide showing you
the demographic data of our participants. We have recruited both male
and female with slightly more male, and they come from both provinces,
even from here, they come from other areas. But all of them moving in
these two provinces to work and they plan to live here for longer than
three years.

In terms of educational level, more than 60 percent they finish high
school or higher than that. In terms of occupation among our volunteers,
this represented participation in this area. For the motivation to join
this study, more than 80 percent of our volunteers they said that they
would like to do good to society. And another thing you may notice that
our volunteers can provide more than one answer to the questionnaire.

In terms of citing the study, we have the Pharmacovigilance Committee to
look for the 30 of the volunteers that they will meet regularly, and we
also have the external monitor, which conducted the monitoring against
the TCP by our contractual research organization, and we also have the
Data and Safety Monitoring Board, which is Chaired by Dr. Walter Dowdle,
which includes international membership. The meeting is planned for
every six months. The last meeting was in July, this year.

From that meeting, the Data and Safety Monitoring Board has commended
our team on the professional conduct of trial, and no safety concerns
identified. They advise us to monitor the element very carefully and
recommended the trial to be continued. Thank you very much.

CHAIRMAN OVERTURF: At this time, I can open the floor to the Committee
for any questions requiring clarification. Yes?

DR. MARKOVITZ: I wanted to ask several questions about the data that you
showed concerning the serological response to the vaccine. The first
one, do I understand correctly that the 23 percent CTL response that\'s
over a period of time, so if somebody had a positive CTL response at any
time that it was measured, that\'s included in the 23 percent; is that
correct?

COL. BROWN: Yes, that\'s correct.

DR. MARKOVITZ: And what percent had positive CTL at the end of this
study?

COL. BROWN: I think at a single time point it was five to eight percent.

DR. MARKOVITZ: So pretty low then. Another question I have ‑‑ so for me
I\'m not sure that that\'s really an accurate way to present the data,
because if you just have a positive one time, that\'s not really
showing, I think, in my mind, CTL efficacy of any sort of lasting
variety.

The other point I want to raise, it\'s very clear when you read the
paper in JID, and you presented the same data, about neutralizing
antibody, I think for the uninitiated that\'s not really very ‑‑ you
must include caveats with that. First of all, the 71 percent
neutralizing antibody with Clade E, that\'s for either one of two
strains. That\'s not both strains being neutralized. And, second of all,
both of those strains, as you know, are lab-adapted, and it should be
pointed out, I think, when you present that sort of data that at least
the feeling in the AIDS research world is that lab-adapted does not
count. What counts are primary isolates. So I think it\'s very important
to point that out.

I had one other question, and then I\'ll ask you to respond. The other
question is just ‑‑ I don\'t have a point of view on this next question,
which is why are only two percent of the Western blots positive? I\'m
just mystified about that. I don\'t know if that\'s bad or good or
anything, but it\'s surprising.

COL. BROWN: Because most of the reactivity was against envelope
products.

DR. MARKOVITZ: Oh, I see. So it\'s negative in the sense that you would
see the envelope in the Western but you wouldn\'t see other things?

COL. BROWN: The frequency of indeterminant Western blots is higher.

DR. MARKOVITZ: Higher. Oh, I see.

COL. BROWN: But to meet a criteria of positivity was just two percent.

DR. MARKOVITZ: I see. That makes sense. What about the situation of the
neutralizing antibodies? I might add, do you have any data yet about
neutralizing primary isolates? You must be looking at that in the lab at
some point.

COL. BROWN: Let me ask one of my colleagues, if Dr. Kim might talk about
the actual assays utilized here.

DR. KIM: As I understand it, the question had to do with the 23 percent
cumulative CTL rate. That\'s a standard mechanism for reporting of CTL
rates that are consistent with other trials done by the HIV Vaccine
Trials Network and its predecessor, the AIDS Vaccine Evaluation Group.
At a single time point ‑‑ and we should point out that not only were
there positives throughout the study but there are positives that
continue after two or three years, and there may be people who are
positive at two years who were not necessarily positive during the
study. I think it speaks to the fact that the traditional
chromium-release CTL assay may be at its limit of detection for CTL and
that CTL may be present. In fact, of the people in the study, 90 percent
had CTL on at least two time points.

To address the question about ‑‑

DR. MARKOVITZ: I\'m sorry, how could that be, that 90 percent had it at
two points? But wouldn\'t that have been included? I thought the 23
percent was if you had a positive ‑‑

DR. KIM: At any time.

DR. MARKOVITZ: ‑‑ result at any time.

DR. KIM: Right.

DR. MARKOVITZ: Oh, you mean 90 percent of the 23?

DR. KIM: Yes.

DR. MARKOVITZ: Oh, I see. I\'m sorry.

DR. KIM: And then with regard to the T-cell line adaptation of isolates,
while it is true that the CM244 isolate was, or is, lab-adapted, it was
in fact ‑‑ CM244, and the reason it\'s selected, was that it is a
primary isolate. And so adapting a primary isolate to grow in a standard
CXCR4 positive cell line would be a rather difficult thing. So what we
did was we created a cell line that expressed CCR5 and CXCR4 and adapted
the virus to grow in that specially adapted cell line. What we do know
is that this cell line ‑‑ that these viruses still require CCR5 in order
to enter, so that although they are T-cell line adapted, they retain
many of the characteristics of traditional CCR5-tropic viruses and that
CCR5 is still required as opposed to a standard T-cell adapted
CXCR4-tropic virus.

The neutralizing antibody data that you requested on primary isolates
has been done on some of the isolates, and using a PBMC-derived assay,
we were not able to detect significant quantities. Now, we have to also
recognize a primary isolate neutralizing antibody in a PBMC-based assay.
However, we should point out that as a correlate of protection ‑‑ that
there is no established neutralization correlate of protection and so
that the mere absence of detectable antibody is of unknown significance
at this point.

DR. MARKOVITZ: We have consensus over here. We\'d still rather have it
than not, however.

CHAIRMAN OVERTURF: Are there other questions?

I\'d like to ask one question. You mentioned what the motivation was for
entering the trial, but I wondered if somebody could explain a little
bit what kind of information is given out in terms of an informed
consent kind of involvement?

DR. PONNEE: For the informed consent process, to ensure that all
participants really understood the trial before enrolled, they
understand their role, their right to participate and also it\'s
voluntary. We use various educational tools, for example, videos. We
have two sets of videos, booklets, leaflets. And also, after watching
videos, we will have group discussion and individual discussion. And
before signing consent form, they have to pass comprehension test before
signing the consent form. And in the consent form, we make sure that
they really know the risks and benefits and also freely have a choice to
participate or not participate.

CHAIRMAN OVERTURF: I guess I was kind of concerned about how much of the
science is explained. I assume that if they understand risks and
benefits, part of the risk must be involved in explaining some of the
limited science in lay terms.

DR. PONNEE: Yes. In there, there is an explanation of what\'s a vaccine
and what\'s the preparation of the vaccine.

CHAIRMAN OVERTURF: Dr. Royal?

DR. ROYAL: With the analyses that have been done to date, have you see
any trends with respect to behavioral changes that might be occurring in
the vaccine recipients?

DR. SUPACHAI: In terms of the analysis, we plan to do it next six
months, because we have the baseline information, and then after six
months we collect another data and analyzing trend.

With your permission, I would like to add more information concerning
the information for the volunteer. Actually, it\'s a process of
education. We have the educational activity for the community before
they come to the site. In that educational activity, we include both the
education information and the information about our trial in both
discussion session and role play activities. And when they come to our
site, they will get more information by watching the DVD that will
illustrate everything about the trial, explain to them clearly what is
going to be, what the vaccine means and what will be treated by our
team. And, as Dr. Ponnee said, they have to pass a comprehensive test of
understanding before joining the vaccine study. Thank you, sir.

CHAIRMAN OVERTURF: Were there other questions? Yes, Dr. McInnes?

DR. McINNES: I wonder if ‑‑ I\'m still trying to get a handle on the
immunogenicity profile of the candidates, vaccines and the regimen. And
I wondered if you would perhaps indulge me and go back to your slide on
the antibody responses that showed the binding antibody, the
neutralizing antibody and the ADCC. I\'m still trying to understand your
binding assay and your selection of concentration in your protein.

COL. BROWN: This slide?

DR. McINNES: Yes. Would you mind just going through this a little more
slowly?

COL. BROWN: Well, again, if we\'re going to do methodology, why don\'t I
let Dr. Kim do this? He\'s actually one of the people that carried out
some of this work.

DR. KIM: I\'m sorry, the binding antibody assay actually reflects a
titer compared to an OD control or blank. So, in this case, protein is
bound to a plastic plate and a standard ELISA is done. And so these are
looking at a comparison of pre-to-post and also a blank control to
establish the baseline OD, and then positive responses are considered
things above that baseline.

For neutralizing antibody, all these samples compare pre-immune serum to
post-immune serum and are looking for a 50 percent reduction in P24
production as a result of exposure of the cells and virus to the serum,
comparing pre-serum to post-serum. So anyone with greater than 50
percent reduction pre-to-post was considered our responder.

DR. FARLEY: Can I ask a follow up to that ‑‑ Monica Farley. Is there a
threshold for the ELISA-binding antibody or is it just anything, any
positivity? There\'s no defined threshold for what\'s a significant
level?

DR. KIM: Typically, the binding antibody assays are greater than one to
100 titer.

CHAIRMAN OVERTURF: I\'m sorry, I didn\'t hear what you said completely.
Dr. Kim? Just speak a little more loudly.

DR. KIM: I\'m sorry. The threshold for positivity was one to 100, but,
typically, titers were far in excess of that. So a positive result is
greater than one to 100. and so what you\'re seeing are percent
responders. So a person is a responder if they have a titer greater than
one to 100, realizing that the average titer is higher than that, and
many are in the thousands.

CHAIRMAN OVERTURF: Yes, Dr. Markovitz?

DR. MARKOVITZ: Yes. Jerry, don\'t sit down yet. I have a question, a
follow-up question. I was ruminating on your answer here about the
neutralizing antibody being of unknown significance. There are plenty of
studies of monoclonal antibodies that neutralize HIV that look like
they\'re protective. So while I think that it\'s clear that there\'s no
absolute correlate of immunity for vaccine development, it does seem
like ‑‑ from what I\'ve been able to garner, and I believe that the
feeling in the field is that neutralizing antibodies are actually
important predictors. Of course, nobody really knows but that\'s the
feeling. How would you respond to that, please?

DR. KIM: Absolutely. I think as a person whose lab does neutralizing
antibody, I also feel very strongly that neutralizing antibody will be
important. I think that one of the points that we need to recognize is
that there was an experiment done where you could ‑‑ Dr. Mal Martin and
Riri Shibata had done an experiment where it was possible to transfer
serum and protect against other strains.

I think that the only point that we want to make with regard to T-cell
adapted strains is although the feeling is that they don\'t protect, we
haven\'t formally demonstrated. The study does have the power to detect
or to study this as an immune correlative protection, and I think that
one of the important scientific pieces of information that we would like
to get out of this study in a model of challenge that is purely human,
rather than in a monkey where even under best of circumstances you get
100 percent of really the vaginal SIV challenge. You\'re aiming for 100
percent infection of all the monkeys. That is not an appropriate
challenge, and so we have to realize the constraints of the models as
well.

CHAIRMAN OVERTURF: Dr. Karron?

DR. KARRON: Yes. I was wondering if anyone could comment on the decision
not to include an ALVAC-only arm in this trial?

COL. BROWN: I can give you an initial response. Actually, we, early on,
when the epidemic was going at a much higher rate in Thailand, we had
envisioned a trial that would have multiple arms. It would have an
antibody-alone arm, a CMI-alone arm and a combined arm. And many of the
preparations for trial were going on during that period. But as the
Thais have been successful in limiting or bringing under some control
their own epidemic, the incidence rate has fallen, and the reality has
been that we would have to settle to just one arm. And not knowing what
the correlate of protection is, the programmatic decision was to put
everything on our side that we could and chose to have ‑‑ that we should
try to illicit both arms of the immune system.

CHAIRMAN OVERTURF: Dr. Whitley?

DR. WHITLEY: There\'s been some discussion, obviously, by advisors to
the vaccine trial that Scott Hammer chaired not long ago that addressed
two issues regarding the co-primary endpoints of the clinical trial, and
they were, I think, considered fairly carefully by that group of people,
suggesting that the total sample size of the population be decreased
from 16,000 to 8,000 and that co-primary endpoints be identified.

By me simply doing the math for the clinical trial, if it\'s 200
volunteers a month who were being enrolled rather than screened, if I
understand the slide correctly, it\'s still going to take you four to
five years to complete the clinical trial, recognizing that you need to
recruit 11,000 individuals from where you are at the present time, and
you\'re going to accomplish that, it\'s at least four years, if not five
years. You\'re only acquiring 2,400 patients a year. Two hundred times
12 is ‑‑

COL. BIRX: A week, 200 a week.

DR. WHITLEY: Okay. And they\'re entering the study a week. It begs the
question then, you know, because there\'s been concerns about the design
of the trial that have been alluded to in a variety of communities, is
it not better to accept an enrollment rate of 8,000 with co-primaries to
try and bring the clinical trial to the medical community as quickly as
possible, recognizing that you have a Data Safety and Monitoring Board
and that Data Safety and Monitoring Board can help you monitor the
incidence of disease and can be beneficial in deciding what the final
sample size of the population should be. And I have to be a little
careful because Dr. Self is here, and he was on that committee.

COL. BROWN: Let me try to divide that into at least two responses. On
behalf of the military, our interest is in acquiring a vaccine that
protects against infection acquisition. That\'s our primary objective.
But I think the board you refer to, that working group is an advisory
group to Dave\'s, and I\'d like to ask Dr. Flores if he might comment on
that interaction.

DR. FLORES: Thank you. My name is Jorge Flores. I am with the Division
of AIDS of the NIH. We are, as you\'ve seen in the slides, one of the
partners or collaborators in this enterprise. It is true, the Division
of AIDS asked the AIDS Vaccine Research Working Group that we
established as a technical assessment group to comment on the potential
for increasing the value of the study. And the responses to that request
they provided us ‑‑ included among then what you have mentioned, namely
increasing the evaluation of viral load to make it a co-primary
endpoint. And if that is the case, a corollary to that would be that if
we are going to analyze viral load to primary endpoint, the sample size
of the study could potentially be reduced.

The team, including all the partners, have agreed to the recommendation
of the group, or the AIDS Research Advisory Committee, and are planning
and have already moved towards elevating the analysis of viral load in
this study to the primary analysis. But we\'ll certainly have a series
of consequences ‑‑ and Dr. Self is here, maybe he would like to follow
up as well ‑‑ has a series of consequences in the trial, of course, that
there\'s an increased error rate that is produced just by analyzing both
viral load and impact on acquisition together.

But in addition to that heat that is taken on the sample size by doing
the combined analysis, there are several other reasons why the Division
of AIDS and some of them, actually, were agreed upon by our advisors. I
feel that maintaining the sample size is important. Among them is the
uncertainty the incidence that was originally planned for is maintained
along the study. As you know, Thailand is one of the countries in the
world that has most successfully controlled the epidemics. So we have
some concern that if that incidence is not maintained, the study itself
will suffer.

Another major consideration that we have and that has been discussed
recently, especially at the endpoints meeting where many people in this
room participated, was the need in the field to establish correlations
between viral load as modulated by a vaccine and the potential clinical
benefit that a drop in viral load may imply. That would require
following up volunteers who become infected in a trial like this and
there is a thorough plan to follow the volunteers of this trial who
become infected. That would require also that the number of those
volunteers be sufficient to again establish a viral load, a body
surrogate marker for clinical progression.

CHAIRMAN OVERTURF: Are there further questions from the Committee? Yes?

DR. MARKOVITZ: Well, we have to ask, so forgive me, but I\'d really like
to know in a succinct manner, obviously everybody in the world would
love to see a successful HIV vaccine, and we\'re all ‑‑ whatever the
genesis of this trial is, obviously it would be great if it\'s
effective. But how do you respond to the strong feeling in sort of the
HIV research community that the at least laboratory demonstration for
efficacy is rather minimal with this approach? Why do you think this is
going to work? I know you\'ve been asked this by many people, but I\'d
just like ‑‑ our Committee I think has to hear first hand why you think
this will work.

COL. BROWN: I think I\'ll ask our Program Director, Colonel Birx, to
respond to that.

COL. BIRX: Fundamentally, we don\'t know if it\'s going to work, and
that\'s why we\'ve committed not only the funding but the human
resources and the training and the infrastructure to ask the question in
the best way and most comprehensive way possible and the most rigorous
way so that we\'ll know at the end of the trial does it work or not.

I think we are all struck by the change in the field over the last two
years. The development of these highly new sensitivity assays that are
highly sensitive for both cellular and humoral immunity that didn\'t
compromise specificity, assays that are developed by Merck and by Dades,
through the VRC and their HBTN Network. We\'re very excited about
applying these new techniques to the samples that have already been
previously stored so we can really understand when we\'re moving a
vaccine forward, particularly one that was moved forward under a
chromium-release full functional assays, how the ICS assays that rely on
IL-2 or gamma-interferon relate.

So I think there\'s two aspects of your question. One is to do a
thorough evaluation of these new highly sensitive immunologic techniques
and see how this vaccine stacks up. We know from the LPA data that 60
percent produced IL-2s. So you can imagine in an ICS assay 60 percent
are going to produce IL-2.

So we\'re very excited about looking retrospectively to understand this
vaccine\'s performance in a more comprehensive way, but we\'re also very
interested in looking prospectively at both the parameters for efficacy
and disease progression that will really add value to the field.

So I think this trial will answer a critical military question about
acquisition, and I can\'t minimize that. When a soldier becomes
positive, he\'s non-deployable. So a critical aspect is the acquisition.
But we\'re also very interested in I think the way the Thais have
demonstrated their commitment for the last decade. We\'re very
interested in using this trial in any way possible to bring more
information to the field, and I think this viral load and CD4 in the
context of a health care delivery system that\'s rigorous and
comprehensive will be able to track disease outcomes in all of these
patients. And so that will add value to the field of really documenting
the role of viral load and CD4 and disease outcome.

So I think there\'s tremendous value in the trial. Learning how to
enroll women, learning how to maintain women on trials, I think that\'s
been very successful. And getting those lessons learned to our other
sites in Africa will be critically important for the next efficacy trial
that will have a different immunologic platform and a different profile.
So we\'re excited this is one step forward, but we realize it\'s only
one step, and there may be ten more or 20 more to come. Thank you.

DR. MARKOVITZ: Excuse me, what does ICS stand for? I don\'t know that
terminology.

COL. BIRX: Those are intercellular cytokine assays that are now being
used, developed and studied, both CD4, CD4 memory, CD4 naive and CD4
long-term, functional and memory aspects.

CHAIRMAN OVERTURF: Any further questions? I think we\'re ready to go to
the next agenda item, which is the open public hearing, so I\'ll turn
the meeting briefly over to Christine Walsh.

MS. WALSH: As part of the FDA Advisory Committee meeting procedure, we
are required to hold an open public hearing for those members of the
public who are not on the agenda and would like to make a statement
concerning matters pending before the Committee.

CHAIRMAN OVERTURF: Again, I am required to read into the record the
following: Both the Food and Drug Administration and the public believe
in a transparent process for information gathering and decision making.
To ensure such transparency at the open public hearing session of the
Advisory Committee meeting, the FDA believes that it is important to
understand the context of an individual\'s presentation.

For this reason ‑‑ we lost half the statement. For this reason, the FDA
encourages you, the open public hearing speaker, at the beginning of
your written or oral statement, to advise the Committee of any financial
relationship that you may have with the sponsor, its product and, if
known, its direct competitors. For example, this financial information
may include the sponsor\'s payment of your travel, lodging or other
expenses in connection with the attendance at the meeting. Likewise, FDA
encourages you at the beginning of your statement to advise the
Committee if you do not have any such financial relationships. If you
choose not to address this issue of financial relationships at the
beginning of your statement, it will not preclude you from speaking.

Our first speaker in the public open hearing period is Mr. Richard
Jeffries, who represents the Treatment Action Group.

MR. JEFFRIES: Hi. Good morning. I appreciate the opportunity to speak
briefly to the Committee. We\'ve actually submitted written comments, so
I won\'t send everyone to sleep by reading this verbatim but just try
and touch on some of the main points.

I think to sort of get back to the question this morning about
licensure, one concern for us is this huge trial, from what we
understand, cannot provide data that would lead to licensure, even in
Thailand. And I think just some of the controversy around the trial, I
think, I\'d argue, is to do with the way circumstances have changed
around it. I think the issue of the single-arm design is really critical
and that would have been partly addressed by the HVTN 201 study they
included in ALVAC-only arm that got cancelled. And I think maybe one
lesson for the future here from TAG\'s perspective is that we need to be
able to get advice as circumstances around a trial change. So when those
things happen, when the AIDSVAX trials fail to show efficacy, if there
could have been consultation here and with the AIDS Vaccine Research
Working Group, that might have actually helped kind of amend the trial
and sort of keep it a little bit more relevant.

And I think if you\'re going to commit the kind of resources that are
involved in this trial, you really need to get a clear answer. And if
there is efficacy, which would obviously be great, we\'re not going to
know the contribution of ALVAC versus the contribution of AIDSVAX or
whether AIDSVAX even had a negative effect.

It was interesting to hear that the military\'s primary concern is
acquisition. You know, I think that I hope that that\'s clear to the
participants in this trial, that that\'s the question that\'s being
answered. I think a lot of people have cited altruism as their
motivation for being a part of this trial. I hope they\'re aware that
the focus on acquisition is really based on a priority of the military
and not necessarily the Thai community.

I think I would like to acknowledge that a lot of people have put an
incredible amount of work into this trial and it\'s incredibly easy to
stand and critique it and incredibly difficult to make a vaccine
efficacy trial happen, but I think we just reiterate the point that
better consultation and more independent advice would have been really
helpful.

The other thing we\'ve done in our written comments is just given a
brief outline of our understanding of the AIDS Vaccine Research Working
Group recommendations, but I\'d like to just be clear that that\'s our
understanding. If people have additional questions about it, if we\'ve
made any errors, that\'s our responsibility. And I think maybe if
there\'s another discussion at this Committee, it would be useful to
have a formal presentation by someone from that group.

And I think just to conclude sort of our perspective of the lessons for
the future is that we really need to ‑‑ there\'s a lot of talk recently
about improved collaboration in the HIV vaccine field. I think some
better consensus around the parameters that justify moving forward with
an efficacy trial would be really critical. I think it\'s kind of
notable that the International AIDS Vaccine Initiative have just
announced that they\'ve decided not to go forward with a DNA/MVA vaccine
because the immunogenicity for CTL was around, I think, between ten and
20 percent, which is pretty much what we\'ve seen here with ALVAC, and
yet we\'re doing this huge trial.

And, also, I think we\'d encourage the FDA to take a closer look at the
efficacy trial designs, because we want to keep our eyes on the prize.
And what we want to have is a licensable HIV vaccine. We don\'t want to
be doing efficacy trials that then require another efficacy trial before
we actually get a licensable product. We need to have something out
there to protect people. Thanks very much.

CHAIRMAN OVERTURF: Thank you, Mr. Jeffries. Is there anybody else who
would like to make a presentation during the open public hearing?

Well, then this will be the end of the open session. In 15 minutes, we
will begin our closed session after the break. This session is closed to
the public. We are asking the public to leave the room at this time and
to take all their possessions. Any briefcases, suitcases or personal
belongings left in the room will be placed outside the door before we
begin our closed session.

The press, any media equipment that cannot be removed in the next 15
minutes must have the power turned off. When the closed session is over,
you can then come and remove any remaining equipment.

So at this time, we are about ten minutes ahead of schedule, and we are
scheduled to reconvene at 10:45. Thank you.

(Whereupon, at 10:23 a.m., the VRBPAC Open Session was concluded.)