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:
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:
JOSEPH TOERNER, M.D., M.P.H.
SPONSOR REPRESENTATIVES:
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 Page
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.)