ATDEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ANTIVIRAL DRUGS ADVISORY COMMITTEE
(AVAC) MEETING
Wednesday May 14, 2003
8:00 AM
Holiday Inn
Two Montgomery Village Avenue
Gaithersburg, Maryland
PARTICIPANTS
Roy M. Gulick, M.D.,
M.P.H., Chair
Tara P. Turner, Pharm.D.,
Executive Secretary
MEMBERS:
Courtney V. Fletcher,
Pharm.D., Consumer Representative
Princy N. Kumar, M.D.
Wm. Christopher Mathews,
M.D., M.S.P.H.
Sharilyn K. Stanley, M.D.
(by phone)
Victor G. DeGruttola,
Sc.D.
Janet A. Englund, M.D.
Kenneth E. Sherman, M.D.,
Ph.D.
CONSULTANTS (VOTING):
Douglas G. Fish, M.D.
Mary E. Guinan, M.D.,
Ph.D.
George J. Pazin, M.D.,
M.S.
Linda S. Potter, Dr.P.H.
Ronald G. Washburn, M.D.
GUEST SPEAKER (NON-VOTING):
H. Hunter Handsfield,
M.D.
HHS FEDERAL GUEST (NON-VOTING):
Katherine M. Stone, M.D.
PATIENT REPRESENTATIVE (NON-VOTING):
Charles Ebel
FDA STAFF:
Debra Birnkrant, M.D.
Mark Goldberger, M.D.
Harry Haverkos, M.D.
Fraser Smith, Ph.D.
C O N T E N T S
Call to Order, Roy M. Gulick, M.D., M.P.H. 4
Conflict of Interest Statement, Tara P. Turner, Pharm.D. 6
Opening Remarks, Debra B. Birnkrant, M.D. 11
Public Health Aspects of Genital Herpes,
H. Hunter Handsfield,
M.D. 14
Sponsor Presentation, GlaxoSmithKline:
Introduction, David M.
Cocchetto, Ph.D. 58
Study Design, Methods and
Results,
Stuart M. Harding, M.D. 63
Concluding Remarks,
Clarence L. Young, M.D. 88
FDA Presentation:
Study Design, Dr. Harry
W. Haverkos, M.D. 92
Efficacy Results, Fraser
Smith, Ph.D. 99
Viral Shedding Substudy,
Safety and Behavioral
Results and Conclusions,
Harry W. Haverkos, M.D. 114
Questions from the Committee 126
Open Public Hearing:
James Allen, M.D., MPH,
American Social Health
Association 168
Gray Davis, M.D., HIV
Prevention Trials Network,
Family Health
International 173
H. Hunter Handsfield,
M.D., University of Washington 181
Mark Wasserman, Ph.D.,
HELP of Washington
(read by Roy M. Gulick,
M.D., M.P.H.) 181
Curtis Phinney, HELP of
Washington 183
Charge to the Committee/Questions for Discussion,
Debra B. Birnkrant, M.D. 189
P R O C E E D
I N G S
Call to Order and Introductions
DR.
GULICK: Good morning. I am Roy Gulick, from Cornell University in
New York, and I am pleased to call to order this meeting of the Antiviral Drugs
Advisory Committee today. We will start
with introductions of the committee, and we will start on this side with Mr.
Ebel. So, please state your name and
your affiliation.
MR.
EBEL: My name is Charles Ebel. I am employed by the American Social Health
Association. I have worked in patient advocacy for genital herpes for about
fifteen years.
DR.
STONE: I am Katherine Stone. I am a medical epidemiologist in the Division
of STD Prevention at the CDC, the Centers for Disease Control and Prevention.
DR.
POTTER: Hi. Linda Potter, private consultant--
DR.
GULICK: Sorry, turn the mike on.
DR.
POTTER: There, now it is okay. My area of expertise is primarily compliance
and adherence with regimens.
DR.
GUINAN: I am Mary Guinan, from the
Nevada Public Health Foundation in Carson City, Nevada.
DR.
PAZIN: George Pazin, formerly from
University of Pittsburgh; now at the VA Hospital in Pittsburgh.
DR.
FISH: I am Douglas Fish. I am the Division Head of HIV Medicine at
Albany Medical College, in Albany, New York.
DR.
WASHBURN: Ron Washburn, LSU and
Shreveport VA.
DR.
MATHEWS: Chris Mathews, University of
California, San Diego.
DR.
FLETCHER: Courtney Fletcher, University
of Colorado Health Sciences Center.
DR.
TURNER: Tara Turner, Executive Secretary
for the committee.
DR.
KUMAR: Princy Kumar, Georgetown
University, Washington, D.C.
DR.
SHERMAN: Ken Sherman, University of
Cincinnati and Director of Hepatology and Professor of Medicine.
DR.
DEGRUTTOLA: Victor DeGruttola, Harvard
School of Public Health.
DR.
ENGLUND: I am Janet Englund, pediatric
infectious diseases, University of Washington.
DR.
SMITH: Fraser Smith, Statistical
Reviewer, FDA, CDER.
DR.
HAVERKOS: Harry Haverkos, Medical
Officer, FDA.
DR.
BIRNKRANT: Debbie Birnkrant, Director of
the Division of Antiviral Drug Products, FDA.
DR.
GULICK: One committee member is joining
us by teleconference. Dr. Stanley, can
you hear us?
DR.
STANLEY: I can hear you loud and
clear. Dr. Stanley, from Texas
Department of Health, not in Oklahoma.
[Laughter]
DR.
GULICK: We did wonder about that,
Sharilyn.
DR.
STANLEY: Unfortunately, there are ploys
why I am here and not there, and I wish I were there.
DR.
GULICK: Well, thanks for joining us by
teleconference. Tara Turner will now
read the conflict of interest statement.
Conflict of Interest Statement
DR.
TURNER: The following announcement
addresses the issue of conflict of interest with respect to this meeting and is
made a part of the record to preclude even the appearance of such at this
meeting.
Based
on the submitted agenda and information provided by the participants, the
agency has determined that all reported interests in firms regulated by the
Center for Drug Evaluation and Research present no potential for a conflict of
interest at this meeting with the following exceptions:
Mr.
Charles Ebel will be permitted to participate in the committee's
discussion. He is, however, excluded
from voting.
Dr.
Princy Kumar has been granted a waiver under 21 U.S.C. 344(n)(4) for owning
stock in the sponsor and competitor. The
stock is valued from $5,001 to $25,000.
Dr.
Roy Gulick has been granted a waiver under 18 U.S.C. 208(b)(3) for consulting
to the sponsor on unrelated issues. He
receives less than $10,000 a year.
A
copy of these waiver statements may be obtained by submitting a written request
to the agency's Freedom of Information Office, Room 12A-30 of the Parklawn
Building. The signed disclosure
statements are available for public review at this meeting.
With
respect to FDA's invited guest speakers. there are reported interests that we
believe should be made public to allow the participants to objectively evaluate
their comments:
Dr.
Hunter Handsfield would like to disclose the following interests in
GlaxoSmithKline. His employer, the University of Washington, has received
contract and/or grants from GlaxoSmithKline and he is an investigator on
GlaxoSmithKline sponsored studies. He
receives compensation for serving as a scientific advisor to Glaxo and speaking
fees from agencies that received unrestricted educational grants from Glaxo.
Dr.
Katherine Stone is an employee of the Centers for Disease Control. Dr. Stone is the first author on a scientific
manuscript, with GlaxoSmithKline co-authors, on the results of a Glaxo
acyclovir and valacyclovir pregnancy registry and she served on their advisory
committee for the registry during 1984-1999.
Lastly,
we would also like to note for the record that Dr. Eugene Sun is participating
in this meeting as the acting industry representative, acting on behalf of
regulated industry. Dr. Sun is an
employee of Abbott Laboratories.
In
the event that the discussions involve any other products or firms not already
on the agenda for which FDA participants have a financial interest, the
participants are aware of the need to exclude themselves from such involvement
and their exclusion will be noted for the record.
With
respect to all other participants, we ask in the interest of fairness that they
address any current or previous financial involvement with any firm whose
product they may wish to comment upon.
Thank you.
DR.
GULICK: One clarification on that, Dr.
Sun was unable to be here, on the committee, today. Dr. Katherine McComus, from the University of
Maryland is going to take a minute to tell us about a side project that is
going on today.
DR.
MCCOMUS: Thank you and good
morning. My name is Dr. Katherine
McComus and I am at the University of Maryland.
I am here today to ask your assistance in a survey that I am conducting
with collaborators at the Food and Drug Administration to examine public
attitudes and understanding of the conflict of interest procedures that the FDA
uses to manage and monitor real or potential conflicts of interest of its
advisory committee members. People in
the audience are being asked to complete this questionnaire and members of the
advisory committee are also distributed a questionnaire under a separate
cover. If you have a chance to complete
it today--I realize it is a very busy day, but there is a box outside at the registration
desk and you can drop it in there.
Otherwise, there is a business reply envelope and you can mail it back
to me later.
Your
responses are anonymous. Your
participation is voluntary but your participation is very important to the
reliability and validity of this study.
This study is being conducted across several centers at the FDA and at
multiple advisory committee meetings. We
would like as a high a response rate as possible so that we can accurately
represent your opinions, provide feedback to the Food and Drug Administration
and perhaps improve overall satisfaction with the advisory committee process.
I
will be here today if you have any questions.
Thank you again for your time.
Thank you for the opportunity.
DR.
GULICK: We were advised yesterday that
informed consent is not required for this but that it has been approved by
local IRBs.
We
will now turn to Dr. Debra Birnkrant to make some opening remarks on behalf of
the agency.
Opening Remarks
DR.
BIRNKRANT: Good morning. I would like to welcome back our advisory
committee members and extend a welcome to our guests and consultants this
morning.
[Slide]
Today
we will be discussing the supplemental new drug application 20550 for
valacyclovir for the prevention of the transmission of genital herpes amongst
monogamous heterosexual couples. We are
bringing you this application today because we seek your input in this
discussion, and this is the first time we are being requested to include
wording in labeling "for prevention of sexually transmitted viral
infection." We will also be asking
you to comment on public health implications as well.
[Slide]
Although
Dr. Hunter Handsfield will be presenting an overview of genital herpes this
morning, I wanted to start this morning off with a few comments related to
management of herpes infections, and this is taken from the CDC STD treatment
guidelines, published in the MMWR, May, 2002.
There
are three key principles of management of genital herpes, consistent and
correct use of condoms; counseling and chemotherapy with three approved
antiviral drugs, one of which, valacyclovir, we will be focusing on today.
[Slide]
Valacyclovir
is approved for first, recurrent and suppressive episodes of genital
herpes. These regimens are actually
taken from the CDC guidelines and are slightly different from the labeling of
the product. In addition, we recently
approved valacyclovir for suppressive therapy in HIV-infected subjects with CD4
counts greater than 100.
[Slide]
In
addition to these indications, GlaxoSmithKline studied valacyclovir for the
prevention of transmission of genital herpes amongst monogamous heterosexual
couples in study HS2AB3009. This was a
study in more than 1,400 discordant couples for genital herpes. This sample size was achieved after screening
more than 4,000 discordant couples. It
studied the dose of valacyclovir 500 mg daily for eight months. In this study, which you will hear much more
about later this morning, condom use was encouraged and the primary endpoint
was clinical signs or symptoms of genital herpes plus laboratory confirmation.
[Slide]
The
issues we will be asking you to address this afternoon include the
following: The appropriateness of the
endpoint in the clinical trial and for future clinical trials, as well as the
trial design; the applicability of the results to other populations, given the
restricted patient population that was studied in this clinical trial;
screening issues related to the fact that more than 4,000 couples had to be
screened in order to achieve more than 1,400 couples to enter the clinical
trial; an issue related to the high dropout rate in relation to the event rate
in the clinical study--again, we will be asking you about the impact on public
health guidelines and, as with all antiviral drugs, we will be asking a question
about resistance issues with wider use of valacyclovir.
[Slide]
An
overview of the day is on this slide. As
I mentioned, Dr. Hunter Handsfield will be giving opening remarks with regard
to geital herpes. This will be followed
by the GlaxoSmithKline presentation.
Actually, we may delay clarifying questions until after the FDA
presentation, which will be done by Drs. Harry Haverkos and Fraser Smith. Then there will be a time for questions and
discussion. The open public hearing will
be held this morning, before lunch.
Following lunch we will have a charge to the committee and
questions. Thank you very much.
DR.
GULICK: Thanks, Dr. Birnkrant. We will turn now to our guest speaker, Dr.
Hunter Handsfield, from the University of Washington.
Public Health Aspects of Genital Herpes
DR.
HANDSFIELD: Good morning. Dr. Gulick and colleagues and interested
persons, thank you very much for the invitation to participate in this. I have been looking forward to it with some
enthusiasm. Thanks in particular, Harry
Haverkos, an old friend from his days at the Division of STD Prevention at CDC,
for those of you who are not aware of his background in that arena.
In
the further discussion of conflict of interest, it actually directly relates to
why I am here today in a way. I spent my
career in sexually transmitted diseases, more than a 20-year career in
prevention, epidemiology and so on, predominantly in the bacterial section of
transmitted diseases. I had the
opportunity to take sabbatical leave at CDC in 1997 and 1998, and my sabbatical
was largely supported financially by Glaxo Wellcome and SmithKline
Beacham. My focus in that sabbatical was
to really take the first steps with the Division of STD Prevention to look systematically
at prevention aspects and public health issues concerning the viral STDs other
than HIV and hepatitis, which is not directly the responsibility of the STD
Division. That led me into essentially a
year of delving into the public health aspects of genital herpes in particular.
My
sabbatical was followed, as it happens perhaps as an indirect indicator of
CDC's growing interest in viral STDs, by Dr. John Douglas who spent a similar
year working mostly on human papilloma virus infections and, perhaps not
insignificantly, Dr. Douglas has recently agreed to assume the position of
Director of the Division of STD Prevention, perhaps indirectly reflecting the
level of interest of CDC in looking carefully at the public health aspects of
viral STDs.
My
task this morning I see as sort of to set the context of some thoughts about
the epidemiology of this disease from a public health perspective. It is really a review and I hope there is not
very much new to most of you. In fact,
those of you on the committee who had the time and energy on the airplane
flying in to read GlaxoSmithKline's overview in their application, the
epidemiology data and so on is actually quite excellent and I thought quite
objective, and an excellent summary and so much of what I have to say will
highlight some points that are made there.
It also allows me to gloss over some things because they are clear in
that fashion.
[Slide]
A
simplistic review--I hope everybody knows about the basic biology of these two
viruses. With mucocutaneous infection,
retrograde infection along sensory nerves, latent infection potential for
recurrences--some of the terminology is evolving whether there are true
biological recurrences in terms of viral replication or some level of ongoing
viral replication, things other than replication per se that influence
transmission of virus down nerves, and recurrent mucocutaneous lesions is an
issue that I think is still not totally settled and discussed by people who
study this disease at a laboratory level.
We
have two viruses, cleverly called types 1 and 2. Type 1, as you well know, mostly causes oral
labial disease but does cause high proportions, depending on where you are in
the world and what population, of initial genital herpes. HSV-2, by contrast, is really rare in the
oral area. It is a very rare person
walking around with oral so-called fever blisters that has HSV-2
infection. When oral HSV-2 occurs it is
almost exclusively in either overtly immunodeficient persons, such as persons
with overt AIDS as has recently been published in studies, or in the context of
initial infection when infection was simultaneously acquired in the oral cavity
and the genital area.
The
corollary to that is that of recurrent genital herpes the vast majority is type
2 virus. If you are unlucky enough to
get herpes but lucky enough for it to be HSV-1, and I will show you data on
this, you are far less likely to have recurrent outbreaks of disease and also
less likely to have subclinical shedding of the virus with the potential for
sexual transmission, at least by vaginal intercourse.
[Slide]
It
is not a formally reportable disease.
Indirect methods and sentinel surveillance is required to understand the
frequency of this disease. This data set
is from the National Disease and Therapeutic Index, over three decades, and it
is initial visits to clinicians' offices because of genital herpes. The up and down is a sample size study design
artifact. The upward trend is clear
although, of course, these data don't let you distinguish between increasing
incidence, increasing patient concern and increasing clinician acumen and
diagnosis.
[Slide]
These
data are in the information provided by the sponsor. They simply make the point that genital
herpes is in the middle ground of the annual guesstimated--and I have to say guesstimated
incidence of sexually transmitted diseases.
They suggest at the low end half a million; at the high end, in a recent
analysis, 1.6 million new cases occurring per year in the U.S.
[Slide]
The
prevalence of genital herpes, however, is highest of all STDs. That is because, as the cute saying in the
STD world goes, "what is the difference between herpes and true love? Herpes is forever." Once you get herpes, it stays. So, the seropositivity is an accurate
indication of people who are infected, are believed to remain infected and so
as long as infection is occurring at a rate higher than the rate with which
people with herpes are dying in the population, the disease accumulates. So, we are dealing with something like a
quarter of the U.S. population infected with genital HSV-1 or 2.
[Slide]
I
think everybody in the room is aware of the National Health and Nutrition
Examination Surveys, previously done in discrete cycles called one, two and
three. What is now sometimes being
called cycle four is really what is hoped to be, by the Center, an ongoing
population-based sample. NHANES is a
population-based access to Americans that includes extensive health
questionnaires and also serum banking.
The banked sera from these studies have been looked at for HSV-2
serology and they provide the core information now available on prevalence of
this disease in the U.S.
What
it shows is that from the cycle that had a mid point in 1978 to the cycle that
had a mid point in 1991 there was a 25-30 percent increase in overall
prevalence that occurred in both men and women.
The other point to draw from this slide is that in every survey ever
done, for practical purposes, the prevalence of infection is higher in women
than in men and the incidence of infection when people are followed at risk is
higher in women than in men, probably reflecting differences in anatomy in
terms of the nature of the exposure or the nature of the surfaces exposed to
the virus during intercourse.
[Slide]
Here
is where we come with that number that I showed you on the pyramid. The NHANES II data were around 16 percent
after adjustment for various issues in study design, believed to have increased
to about 22 percent prevalence in 1991, which translated to 45 million
people. The number of persons infected
since 1991 is a little bit conjectural but the estimate supports something in
the range of 5-15 million, depending on which rates of new infection you focus
on.
Some
unknown number of the roughly 50 percent of the U.S. population as adults that
are HSV-1 seropositive have genital as opposed to oral labial infection. It is impossible on a population basis to
know that number very well so I put a double question mark here. I don't know whether it is two million, 10
million or 15 million but it is a lot.
That is where you can come to the conclusion that something like a
quarter to a third of the U.S. population likely is infected.
[Slide]
There
tends to be, I find, in people who are not familiar with this disease and with
sexually transmitted diseases in general a skepticism from time to time about
whether that proportion of the population really acquires an STD. These tend to be looked at with some
emotionality from a lot settings and the concept that many of us get it doesn't
set well with some people psychologically, socially, politically and sometimes
at the gut level. I will just make the
point that human papilloma virus infections is probably acquired by 70 or 80
percent of us but within our first two to four lifetime sexual partners so that
is even a more normative event to acquire HPV.
But
that having been said, what these data show is the seroprevalence in the NHANES
I study of SHV in whites by age. I show
the '78 data because the 1991 data were not analyzed below age 12 or 15 so we
didn't have the data down here. What it
shows is that whereas HSV-1 seroprevalence rises on a more or less linear basis
as age increases, HSV-2 infections are essentially absent before the sexually
active years and the acquisition rate obviously declines to very low levels
after the sexually active years. So,
after someone reaches their late 30s they become, as has been used in the
sexually transmitted disease epidemiology modeling world, sexually dead. So, all of the acquisitions are basically
occurring in the sexually active years.
So, that is just one piece among many of the evidence for those of you
who might be skeptical that, yes, HSV-2 infections are sexually acquired.
[Slide]
Many
of you have seen these data before and in a way, there is this almost too cute
sort of slant to them, but I think they are important to take into
account. This is one question on
health-related random digit dialing survey, conducted by the American Social
Health Association a few years ago, in which a number of health-related
questions were asked. People were sought
who were age 18-40. So, it is the
younger half of the population.
This
is simply one of many questions that was asked.
It is listed verbatim here. I can
read you a list of items--it is exactly the same approach used for political
polling, the same sort of confidence intervals and so on. The sample size is around a thousand. I can read you a list of items that people
may or may not consider traumatic. For
each one, please tell me how traumatic it would be for you personally,
"very," "somewhat," "not very traumatic," or
"not traumatic at all." No
surprise, people said getting HIV or AIDS would be very traumatic. The proportion saying it was very traumatic
was virtually 100 percent. But two-thirds
reported that they would consider it very traumatic if they acquired genital
herpes, and that was more than the proportion than rated it very traumatic to
break up with a significant other, to get fired from a job or to fail a course
in school.
Now,
in a way that is crazy because this is a disease that, although it has its
serious outcomes, the vast majority of infections are, in fact, mild. In fact, they are so mild that the majority
of infections are entirely subclinical.
Many of those can be converted into clinically recognized cases by
proper counseling for people to recognize subtle symptoms. But it is probably not an accurate reflection
of how bad the disease is, but it is a reflection of how people who recently
acquired the disease or are afraid of getting it look at it.
[Slide]
This
slide shows that although you may say, well, that is one data set but that
makes the point of what about others?
This is an entirely separate kind of data set that essentially comes to
the same conclusion.
After
1997 the national STD hotline, conducted by American Social Health Association
on behalf of CDC combined with the national AIDS hotline, so it was a single
hotline so the statistics are a little bit less easy to break out in this
fashion since that time but the last year these data were available, 1997, if
you limit the logged calls in terms of what they are about to disease specific
calls, eliminating non-specific ones--what is an STD; do condoms work,
etc.--and looking at disease-specific calls, herpes generated almost as many
calls as all the rest of these combined.
HPV
and warts was, in the middle 1990s, the most rapidly rising category so it
wouldn't surprise me if more recent data would show these two running more
closely to one another, and who knows which would be first, but the point is
the viral STDs in general and genital herpes in particular generate far more
concern than the traditional bacterial STDs on which I have spent the bulk of
my professional career.
[Slide]
Clinical
spectrum of disease--I hope this is also a review. First episode infection is divided into those
who have true primary infection. These
are people who have never been infected with either HSV-1 or HSV-2 and they
tend to have the clinically most severe disease. I say "tend" because most of these
are subclinical. Even people who are
HSV-2 seropositive and HSV-1 negative, which means when they acquired HSV-2, it
had to be a primary infection--most of those or many of those, in fact, have no
previous diagnosis or symptoms.
That
said, among the people who development symptoms, these tend to be clinically
the most severe. These are the folks who
present with multiple bilateral lesions, systemic symptoms and so on, and a
more prolonged course. Non-primary first
episode infections are people who are infected typically with HSV-2 in the face
of chronic, often undiagnosed and unaware HSV-1 infection, often acquired years
before. These tend on average to be
shifted toward a less severe clinical course and probably more subclinical
infection.
Very
important, many people present and already at the time of presentation have
type specific antibody to the virus type that is causing the acute clinical
syndrome, meaning that they have been infected for at least some weeks and,
statistically, the vast majority have been infected for months or years. That is, they are experiencing the first
clinical outbreak in spite of an infection that was acquired some time
previously. This phenomenon actually
explains a large proportion of the magical transmission theories that we have
all heard about--toilette seats, hot tubs and shared towels--because what it
means is that people who show up with infection who are not currently sexually
active or at risk for an STD because they are in a reliable monogamous setting
and, of course, in that monogamous setting the other possibility is that
transmission only just occurred in a relationship that had been going on for a
substantial period of time. But in both
cases clinicians tend to help patients reach for face-saving explanations that
we now know simply don't occur. So, that
is an important issue to understand from an epidemiology as well as a clinical
management perspective.
Recurrent
infection, of course, by definition is a second or subsequent recurrent
outbreak that is clinically recognized, and most of the important information
in understanding the epidemiology and clinical aspects of this disease in the
past 15 years has been to understand that subclinical infection overlaps all
these categories and is subdivided into those who are truly asymptomatic and
those who have unrecognized disease.
Most are in this category. Data
show that persons who are seropositive and unaware, and even who say they have
had no symptoms, if counseled about even subtle genital symptoms to look for
and then are given a green light to be seen clinically within a day or two as
opposed to an appointment ten days later when symptoms appear, in fact, 60
percent or so appear with symptoms that are culture positive for herpes within
about three months.
[Slide]
Much
of these data, though not exclusively, I owe to my colleagues Anna Wald and
Larry Corey who have made entire careers of studying this disease, and much of
these data come from their facility. So,
this is sort of the plenary study on the recurrence rate of 450-some persons
followed for something over a year on average.
Men had an average of five, women an average of four episodes in the
next year of recurrences. I believe the
true recurrence rate probably is the same in men and women. Carefully counseled people in a herpes
research clinic--men may be able to recognize subtle disease than women because
of anatomical location and visibility.
For a woman it is hard to know perhaps whether a labial itch is a lesion
or not. Almost 40 percent had at least
six recurrences in the next year and a sizeable minority had at least ten
recurrences in the coming year.
I
actually intended to bring a slide, and I guess I just forgot to include it in
my slide set and it wasn't in my laptop, about the natural course over the
years. The same data set has been looked
at to look at recurrences and, actually, over the course of about eight years
and beyond eight years the number of patients followed over time became too
small to draw very many conclusions. But
the average rate of decline was 0.7 to 0.8 recurrences per year.
The
problem with those date is it is not linear, so people probably tend to have
fairly frequent recurrences in the first year.
There is probably usually then some decrement that goes on for many
years. The same pattern appears to apply
for subclinical shedding. So, we have
fairly poor data both for subclinical shedding and for clinical disease beyond
eight to ten years. I think that is an
important thing to keep in the back of our mind. It is true that we don't see very many people
in STD clinics who are, for example, age 50 who say, "I got herpes at age
25 and here I am, 25 years later, still having two or three episodes per
year." But the frequent recurrent
rate and certainly the potential for transmission goes on, as ball park
thinking, for at least a decade and what happens after that is harder to
know. The recurrence rate is much lower
for genital SHV-1.
[Slide]
This
slide shows data on that. These were
presented by Dr. Wald at IDSA a couple of years ago and have just been
published, within the last month. The
bottom line is when you follow HSV-1 infected persons for an average of 2.5
years, 40 percent almost had no recurrences that are clinically recognized; a
third had only one; and only a quarter had four or more. So, it is very different than HSV-2 and the
days to first recurrence are quite prolonged.
As you can see, there is a decrement down to an average of less than one
recurrence per year for many people after the first couple of years. So, the bottom line is that people with this
disease can be told with some assurance that they might have no recurrences
though probably most people have one or two over the next year or two and maybe
very little disease thereafter.
[Slide]
There
is a lot of folklore about triggering recurrent outbreaks. It is interesting that for oral labial
infection with HSV-1 the very fact of the name, cold sore or fever blister,
reflects the role of intercurrent infections in stimulating outbreaks. We certainly know that sunburn or other
actinic injuries can do it. Local trauma
can do it. Ophthalmologists and ENT docs
have learned that people with recurrent oral herpes often are being treated
prophylactically with antiviral drugs at the time of surgery to prevent
postoperative complications. Admittedly,
I don't know the extent to which those procedures have been systematically
documented as effective, but they are believed to be effective by many of those
providers.
In
contrast to folk lore, there aren't very many well documented triggers for
HSV-2. The studies that are weak in this
area but in general those that have attempted to look at diaries of stressful
events plus recurrent outbreaks and overlying objective psychological scoring
methodologies have not been able to show much of a link between the things that
patients often cite, such as stress, diet, menses and that sort of thing. I think it is important to remember the power
of the human mind's capability of linking sequential events in a causal
fashion, and I would ask anybody to contemplate whether it is herpes or
myocardial infarction or a sprained ankle, whether they can look back and say,
"oh, I haven't been stressed at all in the last week."
[Slide]
The
biomedical complications--I stress biomedical because of the psychological
complications I am going to talk about in a little bit--are a separate
category, and I think everybody recognizes the predominant, frequent impact of
this disease. It is psychosocial rather
than purely biomedical although, obviously, they are interacting. But just to remind you of that spectrum, this
is a protean disease that causes more than just the occasional genital
sore. So, localized neuropathic
manifestations, particularly the first set of infection, bladder paralysis,
sphincter incompetence and things like that; meningitis, either acute or
recurrent. For those who don't know, the
historic syndrome of what used to be called Molleret's meningitis or benign
lymphocytic meningitis is, in fact, in at least 80-90 percent of cases
recurrent HSV-2 infection of the central nervous system. HSV-2 as opposed to HSV-1 tends to cause
meningitis. HSV-1 tends to cause
encephalitis. There is a little bit of
overlap but in an immunocompetent patients those distinctions hold fairly
sharply.
Erythema
multiforme, Stevens-Johnson syndrome--it is now known that recurrent erythema
multiforme is in the vast majority of cases a complication of genital HSV-2
infection and preventing erythema multiforme in those cases is highly
successful with suppressant antiviral therapy.
There
is a range of perinatal and maternal morbidity, and Dr. Zane Brown is here and
will undoubtedly address this if he has a chance to make some comments. The non-genital auto-inoculation syndromes,
such as ocular infections and whitlow are an occasional issue, particularly the
first episode disease; chronic, localized disease, in AIDS patients; and I will
talk a little bit more about the HIV transmission issue in just a minute.
[Slide]
In
fact, here is the start of that theme.
Dr. Wald and her colleague, Katie Link, did a masterful review and meta
analysis of the literature, published a year ago in JID, and this is one figure
from that paper. They found, I think it
was, 20 or 30 studies that had looked at the association of HSV-2 infection
with HIV prevalence or incidence, and within that there were nine studies that
were either prospective cohort or nested control studies that had the
opportunity to look at incident HIV infection as a function of preexisting
HSV-2 antibody while also controlling for a variety of all of the things you
would expect would influence it--sexual behavior, intercurrent STDs, and so on,
and so on.
The
results of those nine studies are illustrated here, and the overall
meta-analytic conclusion was that there is, on average, about a two-fold
increase of HIV infection, of incident HIV in the presence of HSV-2 antibody
compared to the absence of HSV-2 antibody after controlling for a number of sexual
partners, frequency of sexual intercourse, use of condoms and other similar
predictors.
[Slide]
These
data are, to me, among the most dramatic.
They are preliminary and remain that way. They come from the Rikai, Uganda study and I
owe Larry Corey thanks for letting me use this slide which he, in turn, got
from Mary Wawar and Tom Quinn and others.
I
am privileged to be reviewing abstracts for the upcoming international society
for SV research meeting that is occurring in Ottawa in July, and I have seen
that these investigators have analyzed these data now with about double the
number of couples reflected and, without betraying the confidence that is
implicit in seeing pre-published work in that context, suffice it to say that
it looks like these earlier results are not going to be undermined in any
important way.
One
hundred seventy-four HIV discordant monogamous couples, followed over time,
looking at the HIV acquisition rate in those couples while those couples kept
diaries of episodes of sexual intercourse, all these people lacked other risks
for HIV, other than their sexual cohabitation.
What this looks at is the risk of HIV seroconversion according to the
viral load, using a particular earlier assay that gave these particular numbers
and looking at that by viral load in the HIV-infected persons per number of
episodes of intercourse over time.
I
think you can see obviously that if the HIV-exposed person, HIV negative
exposed person was HSV-2 seropositive the risk of HIV transmission was
dramatically higher than if that person was HSV negative. In fact, the transmission rate was
statistically similar in a person who was sexually exposed to someone with a
maximal viral load if the exposed person was HIV negative and in someone who
was HSV-2 positive but exposed to someone with an undetectable HIV viral load
by that assay. So, in this subset the
importance of HSV-2 was a stronger predictor of HIV transmission than was HIV
viral load.
[Slide]
So,
I have concluded when I have spoken to practicing clinicians in the past couple
of years that, other things being equal, HSV-2 infected persons have twice the
chance of acquiring HIV on a population basis.
HSV-2 may be the post important STD.
Not that the transmission efficiency for HIV is enhanced as much as it
might be with, say, syphilis but HSV-2 is so much more prevalent in the
population. The population attributable
fraction likely is maximal for this particular disease.
Now,
there is some controversy about when and how type-specific serological testing
should be used as a screening tool in asymptomatic persons. My own feeling is that that debate
unequivocally is over in people at high risk for HIV. We need to know of they are HSV-2 positive
because it may help them understand that they are at double the risk of
acquiring HIV if exposed. I think
understanding this and its implications for the public health aspect may be at
the pinnacle of what we need to be thinking about for this disease and
prevention and, of course, control strategies for it which is, of course, at
the core of why you are here today.
[Slide]
Subclinical
shedding of this virus is extremely common.
It is really unfair to try to summarize essentially your entire career
in a single slide but here it goes. You
can sort of summarize that it is present in people who test themselves every
day for weeks on end. It is present 1-10
percent of the days if you use PCR, up to 30 percent of asymptomatic days in
people with symptomatic recurrent genital herpes. The maximum frequency, the group in the 5-10
percent of the days or 20-30 percent by PCR is in the first year after
acquisition of this disease. It then
declines. But it probably settles by
culture in most people at the rate of roughly 2-3 percent of asymptomatic days
by culture and roughly double that number of days by PCR for at least several
years. The time course is probably
similar to the clinical recurrence rate that we have already discussed. At least 95 percent of the people who are
HSV-2 seropositive have some days when the virus is present in the absence of
both detectable symptoms and things that even a trained observer can recognize
as clinical disease.
Interestingly,
the frequency is just as prevalent in people who are seropositive without
history of clinical disease as it is in people with clinical disease who test
themselves in between symptomatic outbreaks.
Most episodes are symptomatic but unrecognized, although that is a
little bit challenged by evolving data regarding PCR because there are more
people who are PCR positive and culture negative who truly don't have
symptoms. This accounts for most
transmissions. All STDs are transmitted
selectively, like people whose clinical syndrome has shifted toward the
subclinical end. It is sort of a
no-brainer. People with painful genital
sores, genital discharge, lower abdominal pain don't have intercourse as often
as people without those symptoms. That
is not exactly a surprising finding. It
does underlie the importance of why active steps of partner notification are
important for all STDs. Subclinical
shedding is substantially reduced by suppressive antiviral therapy, both in
terms of frequency of shedding and the amount of virus that can be detected
and, as with clinical disease, it is uncommon with genital HSV-1 disease.
[Slide]
Psychosocial
impact--I could spend the whole lecture on that. The fact that there is a psychosocial impact
is at its core one of the reasons why we are all here today, at least some
aspects of it. I would simply summarize
specifically on the transmission issue because your focus is going to be on
what is the impact clinically, public health and psychologically on suppression
of this disease with the goal of preventing transmission.
Every
study of psychosocial impact or every survey of patients, and the quality of
these studies is highly variable; the design is highly variable in terms of
what they did and how they recruited patients or spontaneous respondents to
web-based surveys, for example, are potentially highly biased. Nevertheless, there is great consistency.
Fear
of transmission to partners is consistently among the top three. It is usually number one or two of the stated
sources of concern, anxiety or stress by the patients. Then typically in these studies that
particular issue--"I don't want to infect my partner and I'm afraid that
I'll do it, and I don't know how to prevent that"--is typically cited by a
third to 90 percent of the people participating in these surveys.
[Slide]
Just
as a minor reflection, this is just a single web site. There are many out there. It is called Antopia, and I am not sure where
the name Antopia comes from but Antopia has a "dating service." MPwH I believe means matching partners with
H, H meaning herpes or HPV. This is a
quote from their web site yesterday, quoted to the point even of what is bold
and what is colored in various ways. So,
MPwH is a social resource and dating site for people with herpes and HPV. Right now it is May 13, 2003 and we have
36,000 registered members and 163 are currently logged in. Signing up is free; no obligation; your
privacy and confidentiality are assured.
Simply,
you don't have these sorts of things appearing--even if you make the argument
that the people who participate in them are shifted towards those who are most
concerned and not typical, you have to have lots of people to generate this
sort of business.
[Slide]
I
am not talking about therapy intentionally, except I do want to make the point
that if you clinically suppress recurrent herpetic disease you have a
significant impact to the good on psychological measures. This looked at herpes-related quality of
life, 20 or so questions related to all the things that people with herpes
might be concerned about plus general questions about quality of life that weren't
directly herpes related. Going higher
means that over time you have an improvement in the score, that is, less
psychological stress and improved quality of life. In five different regimens with different
drugs in Dr. Patel's analysis for suppressant antiviral therapy compared to
people on placebo there was a marked improvement in people who had clinical
suppression of HSV compared to people who were on placebo, and over time, if
you note, there is a general upward trend.
The scores continued to improve with time. It was not a transient effect in people on
antiviral therapy.
[Slide]
So,
if people are so concerned about transmission, what are the data on
transmission? Well, there are several
studies out there. I am going to
summarize only one because, (a) it is one I am the most familiar with and, (b)
because it is probably the most comprehensively done one in a prospective
fashion. It also served, I believe, as
part of the genesis of sample size calculations for the study behind the
sponsor's proposal today.
This
was a retrospective--you know, the Chiron vaccine studies have got to be the
most successful scientific outcome of failed research. It generates all kinds of great
analyses. The Chiron vaccine studies of
HSV-2 serum negative persons enrolled monogamous partners of persons with
herpes or STD clinic patients at high risk, 500-and some and almost 2000;
followed them for 18 months with history, exams, HSV serologies, lesion
cultures when lesions appeared; repeated safer sex counseling--we need to keep
it in mind because these studies are shifted toward the null in terms of the
likely transmission rates because of this need.
Outcome
measures--primary measures HSV-2 infection as measured by seroconversion; the
secondary outcomes in this analysis for HSV-1 infection; clinical disease. The vaccine and placebo recipients were
combined because the vaccine didn't work and the results were identical in the
two groups. The acquisition rates were
similar in both studies, with some very minor differences. So, the results in both studies were combined
in Dr. Langenberg's analysis.
[Slide]
In
that data set there were 155 incident HSV-2 infections, giving good numbers to
work with, of which 37 percent were symptomatic and 63 percent were
asymptomatic seroconversions. There were
19 incident HSV-1 infections. The
infection rate per year was five percent, five infections per 100 person years,
that is, five percent of uninfected people acquiring HSV-2 per year,
essentially similar in both the partners study and the STD population study.
As
predicted and as we pointed out earlier in the broad epidemiologic data, women
had a higher risk of acquiring infection than did men. This is an interesting side issue, HSV-1
infection did not change the rate of HIV infection. So, the people who were HSV-1 seropositive at
enrollment and those who were HSV-1 seronegative at enrollment had identical
rates of acquiring HSV-2. It is fascinating
to me, however, that this result is entirely inconsistent with the results from
the now GlaxoSmithKline, then SmithKline Beecham, HSV-2 vaccine studies which
Dr. Stanbury may talk about later, where, with an essentially identical study
design, it in fact was shown that HSV-1 appeared to protect against HSV-2
acquisition--similar design; similar sample size. How that debate as to whether HSV-1 is
protective is going to sort out over time remains a conundrum to me.
[Slide]
Other
results from the studies are that 13 percent of the incident symptomatic
infections were atypical. Trained
observers who are looking to find herpes missed the diagnosis pretty
frequently. In fact, if you jump down
here, missed diagnosis in either direction--thinking it was herpes when it
wasn't or not thinking it was herpes when it was because they presented with
these sorts of things--by the investigators and the clinicians who are highly
trained and experienced in this disease was in the 20 percent range. With other, more recent data, it is even
higher than that. So, it is a disease
that can be difficult to recognize.
Many
of the asymptomatic seroconverters subsequently developed clinically evident
disease. That is truly an
underestimate. Some of these people
seroconverted, for example, at 12 or 13 months in an 18-month study and only
had one more follow-up visits thereafter.
So, over a long period of time this undoubtedly would be greater.
Interestingly,
half the HSV-1 infections were genital, not oral. The incident infection was associated with
young age and women but not in men.
Incident infection was two to three times more common in non-whites than
in whites. That also reflects general
epidemiologic factors that I haven't otherwise discussed. As we said, HSV-1 did not influence
acquisition rate but it did ameliorate incident HSV-2 with more asymptomatic
infections. The study design probably
reduced the actual real-world infection rate because of the need for ongoing
strict safer sex counseling as part of the protocol.
[Slide]
Other
factors in herpes transmission, avoidance of sex if symptomatic I have
highlighted because I am going to briefly mention them. My time is about up and I will be quite quick
at this point. For those of you who are
watching the clock, I apologize.
Other
things that are associated with transmission are that more recent infections
are more transmissible than more prolonged infections. A shorter duration of relationship,
apparently independent of duration of infection, is associated with increased
transmission rates, presumably having to do with such things as frequency of
intercourse and perhaps--who knows?--less judgment in terms of when to have
intercourse in people whose sexual relationships are driven more by passion
than by conscious thought. That is my
hypothesis for that.
Certainly
sexual practices can influence when they interact with virus type; circumcision
status perhaps; pregnancy perhaps; immune deficiency and/or HIV status. There have been either conflicting data or
speculation around these issues without a lot of data so I won't go into them
in any more detail.
[Slide]
There
are two condom studies out there. Both
are also spin-offs from the Chiron vaccine study. Anna published this one a couple of years
ago. It is cited in your handout. Basically, in the monogamous couples of the
Chiron vaccine data set with 25 percent common use used as a cut-off because
that was the median--it was sort of where the natural break point was in terms
of numbers of people available for analysis--clearly reduced transmission from
men to women but there was no evidence of protection of women to men. These data were misinterpreted in some
sources, as you can see, even though this odds ratio makes it look like there
is actual risk of transmission, the broadness of the 90 percent confidence
interval really just tells you the sample size was inadequate to draw
conclusions at all.
[Slide]
This
slide is data that have now been analyzed by Dr. Langenberg and by Dr. Wald,
presented in abstract form and I understand are being prepared for or perhaps
are submitted for publication, looking at the high risk group recruited from
the STD clinic with 18-month follow-up.
In this group the breakpoint in terms of the portion who used condoms
was at a different level. It was
plus/minus 65 percent. But in this
analysis there was demonstrated protection, with a roughly 40 percent reduction
in HSV-2 seroconversion rate in common users versus non-users in exposed men.
[Slide]
So,
in the next slide I draw the conclusion that although it is very hard to study
condom use in a definitive fashion because of the whole nature of how you do
those studies, and so on and so on, I think we can draw the firm conclusion
that condoms are partly effective.
Previous controversy not withstanding, they are probably equally
effective or nearly so for protecting women from male infection and females
from male infection. Of course, condoms
fall down in their efficacy in use effectiveness and overall acceptability. One might guess better performance in female
condom because of greater surface area covered but no data are available.
[Slide]
In
the interest of time I will just say there are good data to support the notion
that couples who are aware of a herpes discordance in a relationship and who
avoid sex when symptoms are present do have lower acquisition in transmission
rates in those relationships.
[Slide]
The
counseling of persons with herpes--these are again from the CDC 2002 treatment
guidelines, with the exception that in terms of what people ought to be
counseled I have inserted in highlight the term antiviral therapy, question
mark, because that is what your focus is going to be today.
[Slide]
My
final slide is simply to make the point that when I wear my public health hat
as someone responsible for SV prevention in a metropolitan area of 1.7 million
people, and with some interest in and work at national and global levels as
well, these are what I think are the six key issues, according to my
lights. Some of you might lump these and
come up with fewer and some might split them and come up with more but it is
not a bad representation of what I think are the core current public health
issues in genital herpes. I have
highlighted the ones that I think have some relationship to your discussions
today.
Preventing
sexual transmission and how to best do it is a core issue. The relationship of HSV-2 to HIV and its
prevention is a core issue. The
under-diagnosis of genital ulcer disease--I would actually say that I think in
terms of under-recognition and under-attention to this disease, I think the
public health community in general is probably more lax than the practicing
community. Few health departments are
paying the attention to this disease that it needs or deserves. The role of and when and how to use
type-specific serological testing is an issue of ongoing debate. I will say I believe it is grossly under-used
but I think that is a core issue.
Under-treatment, leaving aside the transmission issue, is a big issue
that, in turn, relates to clinicians' lack of understanding of the psychosocial
impact and, of course, preventing the single most frequent devastating outcome,
neonatal herpes and attendant maternal morbidity, is the last.
Thank
you very much for your attention.
DR.
GULICK: Thanks for the overview, Dr.
Handsfield. We have time for a couple of
questions, if there are questions, for Dr. Handsfield from committee members. Dr. Mathews?
DR.
MATHEWS: That was a great overview,
Hunter. Is there evidence of uniform
type-specific immunity?
DR.
HANDSFIELD: Well, yes but, first of all,
it does not cross specificity. There is
not cross immunity between HSV-1 and HSV-2.
The general consensus is that it is extraordinarily rare at the clinical
level for people to get ping-ponged, that is, new HSV-2 infections if they are
already HSV-2 seropositive.
Now,
there are no absolutes in biology of medicine and it would be very difficult to
know if, for example, the occasional patient who, three years into a pattern of
recurrences occurring three or four times year, now all of a sudden has six or
eight occurrences a year, did that person get a new infection on top of
it? There is no evidence that that
happens. If it happens it is very rare. We do know from the Chiron and extrapolating
from the GlaxoSmithKline vaccine studies that neutralizing antibody alone does
not provide protection against exogenous infection. But the notion that there is strong
type-specific immunity that involves some combination of cellular and other
mechanisms we don't understand I think is epidemiologically solid, but there
are others in the audience who could probably answer your question with more
scientific precision than I just have.
DR.
GULICK: Dr. Kumar?
DR.
KUMAR: Would you be able to comment on
why it is more common, HSV-2, among African-Americans?
DR.
HANDSFIELD: Yes, I intentionally avoided
that issue because though I think it is epidemiologically interesting, I think
it can be distracting to get too much into racial issues for a whole variety of
reasons that you are very well familiar with.
That said, whatever drove the prevalences to very high rates, after you
adjust for age, sex and geography, fairly consistently African-Americans have
much high HSV-2 seroprevalence rates than do whites, Asians and some other
ethnic groups, and Hispanics and native Americans tend to be in the
middle. Whatever the reason that got it
there, once it gets to that point the average sexually active person is more
likely to encounter an infected person.
So, sustained rates do not imply ongoing levels of sexual risk-taking that
you might assume just that the prevalence is high.
Now,
why they got there to begin with clearly has to do with issues that are fairly
poorly understand by sexual partner networks, partner selection and that sort
of thing. The whole issue of overall
higher HSV rates in African-Americans compared to whites probably relates to
such things as higher mortality rates and higher incarceration rates in
African-Americans that change the male-female ratios in communities and affect
sexual partner networks, and a whole host of other very complex issues. So, that is a fairly inadequate answer but I
think that is about as far as the science allows us to go with it.
DR.
GULICK: Yes, Dr. Guinan?
DR.
GUINAN: I wonder about the source of
asymptomatic shedding. Where have these
cultures been taken? Theoretically, the
virus could shed anywhere along the distribution of the nerve, which is a long
way. Traditionally, you know, the vagina
in women has been cultured and maybe the labia, but in men it is not clear to me
that there are samples taken from suspect areas that might be shedding. Are there well-established negative studies
that it doesn't shed in some places and does in others?
DR.
HANDSFIELD: In the interest of time I
didn't go into the methodology behind those studies. Briefly, what is done is that patients are
trained to self-collect specimens, attempting to get a cervical specimen in
women which really means putting a swab at the end of the finger and attempting
to reach the cervix for at least a high vaginal and introital sweep and
perianal sweep, and those are collected every day and go to the
laboratory. Couriers come and pick them
up, and that sort of thing.
In
men, and Anna, correct me if I am wrong, I think the technique is a swab in the
urethra, under the foreskin or around the glands and up and down the shaft, and
a third swab also perianally. As a side
note, a modest proportion of subclinical shedding in heterosexual men occurs
perianally, having to do undoubtedly with that broad neural distribution that
you suggest.
So,
that is the basic technique. The
frequencies of subclinical shedding tend to be slightly lower in men than in
women, but that is probably an artifact of the notion that, first, cultures may
be less sensitive on dry skin and PCR for that matter and, second, because men
probably recognize subtle lesions more readily than some women do and,
therefore, more men with recurrences classify themselves as symptomatic than
women do.
DR.
GUINAN: Scrotum, for example, might be a
source and, of course, condoms don't cover scrotum so it would make sense that
in asymptomatic--
DR.
HANDSFIELD: Anna, have you tested
scrotum? Is scrotum one of the sites
that you have been surveying?
DR.
WALD: Not routinely.
DR.
HANDSFIELD: Not routinely?
DR.
GULICK: I am sorry, we need you to go to
the mike and identify yourself and answer the question. Thanks.
DR.
WALD: Anna Wald, from the University of
Washington. In men, we have them mostly
swab normal-appearing penile skin for asymptomatic shedding and also the
perianal area. Urethral swabs in general
are negative and we have moved away from those.
We have looked at scrotum in a small number of men and it did not yield
virus, but it was a small sample.
DR.
GULICK: I would like to ask one last
question and then we need to move on. I
was intrigued by your recommendation that people at high risk for HIV actually
have an HSV-2 serology done. Two
questions from that. One, what is the
mechanism of action that increases the acquisition of HIV? Number two, what would you do with that
result practically?
DR.
HANDSFIELD: As far as the first
question, I am not an immunopathologist so I am probably not the best to answer
but I think the general notion is, as you well know, that shedding is
associated with lesions; they are simply not visible in an inflammatory
reaction at the surface, and those inflammatory reactions bring CD4-laden
inflammatory cells to the surface so that there is a biological enhancement of
potential infection above and beyond, and in addition to the potential
mechanical mucosal disruption. I think
there is a general consensus that something like that is going on. Others may elaborate in more detail than I
can.
What
would you do? Well, I guess I would
answer the same way I would answer what do you do with HIV testing and
counseling to begin with. There is a lot
of controversy about how good it is in helping people understand their risk and
helping them prevent transmission. But
what we do know is that it can't hurt.
So, from a public health standpoint, I think it is clear that people who
are HIV susceptible and HSV-2 infected, that some individuals, not all and
maybe not even a high proportion, we don't really know, will, with that
knowledge say--I mean, it will help some people click and the person who is
sort of on the fence about where and how he or she is going to select partners,
whether to use condoms or not, maybe now clicks over and that is the deciding
factor that helps them reduce their risk.
So,
my argument is that it cannot hurt and very likely, on a broad population
level, will help. So, the quick answer
is I would counsel them accordingly about their increased risk and use that to
help them protect themselves.
The
other issue is should HIV-infected people also be tested? That is actually a reasonable issue as
well. Whether those people would be
more efficient HIV transmitters is less clear from the available data. Then the issue is will it help clinicians be
alert for clinical disease that will lower their treatment threshold for
certain syndromes. I think that probably
depends a little bit on the dedication and clinical acumen of that particular
provider as much as anything else.
DR.
GULICK: Thanks. We need to move forward. Thanks again for the presentation. Next up is the presentation by the sponsor,
GlaxoSmithKline. Dr. Cocchetto will be
introducing this.
Sponsor Presentation
Introduction
DR.
COCCHETTO: Good morning, Dr. Gulick, Dr.
Birnkrant, members of the committee, FDA and guests.
[Slide]
On
behalf of GlaxoSmithKline, thank you for the opportunity to share the results
of a major clinical study with valacyclovir, also known as Valtrex. My name is David Cocchetto and I am a member
of the team at GlaxoSmithKline that studied the ability of suppressive therapy
with Valtrex to reduce the frequency of transmission of genital herpes.
[Slide]
Over
the next 45 minutes my colleagues and I will summarize this work. I will briefly summarize the regulatory
history of this study and show the statements that GSK is seeking in product
labeling. Following my introductory
remarks, Dr. Stuart Harding will present the design, methods and results of the
clinical study. Finally, Dr. Clarence
Young will provide concluding remarks.
[Slide]
Dr.
Handsfield has presented an informative overview of genital herpes, including
information on transmission. The current
approaches to reduce transmission of herpes are abstinence, avoidance of sexual
contact during symptomatic episodes of genital herpes, and use of condoms
during sexual contact even if symptoms are absent.
However,
as you have heard, these approaches are incompletely effective. Further, no prophylactic vaccine or topical
microbicide is currently licenses or likely to be registered in the next three
to four years. Therefore, an unmet need
exists for additional approaches to reduce transmission of genital herpes.
[Slide]
Valtrex
is currently approved for use in the United States for several indications, as
listed here. One of the approved uses is
suppression of recurrent episodes of genital herpes. Suppressive therapy with Valtrex was approved
by FDA for immunocompetent individuals in September of 1997, and for patients
with HIV infection in April of 2003.
[Slide]
For
study HS2AB3009, which I will refer to as the 3009 study, GSK and FDA have had
a proactive, constructive dialogue about this study since the topic was first
introduced in 1995. We appreciate the
time and expertise of FDA in providing their guidance on the design of this
study. Extensive feedback was obtained
in a meeting with FDA in September of 1996.
That meeting, as well as subsequent dialogue, enabled GSK to design a
single adequate and well-controlled trial to evaluate Valtrex. Ultimately, the study was completed in March
of 2002, and a supplemental application was submitted on October 31.
In
GSK's pre-study discussions with FDA we received three main items of guidance
regarding the design and conduct of this study, and I will now summarize these
items for you.
[Slide]
FDA's
first item of pre-study guidance pertained to the primary endpoint. FDA advised strongly that the primary
endpoint be acquisition of clinically symptomatic, laboratory-confirmed genital
herpes in the susceptible partner.
Importantly, this primary endpoint is able to demonstrate clinical
benefit to the susceptible partner. FDA
advised that a single large clinical study should yield strong evidence in
order to be convincing. That is, 70-80
percent reduction in transmission. At
GSK, we adopted this primary endpoint and designed the study to detect a 75
percent reduction in transmission of genital herpes.
[Slide]
FDA's
second item of pre-study guidance to GSK was that a robust analysis of clinical
safety is required for Valtrex in this relatively health population receiving
suppressive therapy. We responded to
this advice in the 3009 study itself where we collected clinical safety data
for the 743 source partners receiving Valtrex for eight months. In addition, in other clinical studies of
suppressive they we collected clinical safety data for over 1,500 additional
patients who have received Valtrex for 6-12 months. All of these safety data have been provided
to FDA in previous submissions.
[Slide]
Finally,
FDA emphasized the importance of GSK assessing the efficacy of Valtrex in
addition to current public health recommends for safer sex counseling and use
of condoms. We designed the study to
provide all patients with safer sex counseling and encouraged use of condoms
during all sexual acts. Therefore, our
objective was to demonstrate the incremental benefit of the addition of Valtrex
to safer sex counseling and use of condoms.
In
summary, we designed the 3009 study to incorporate each of FDA's main items of
pre-study guidance to GSK. Subsequent
speakers will present results showing that suppressive therapy with Valtrex is
safe and effective for reduction in transmission of genital herpes.
[Slide]
We
are seeking an addition to the prescription drug labeling for Valtrex based on
the 3009 study. On this slide, in white
text, I am showing the current FDA approved indication statement for genital
herpes. We propose to add the yellow
text based on the 3009 study.
Further,
a description of study 3009 is proposed for the clinical trial section of the
labeling, and this description has been provided in your briefing document.
[Slide]
Let
me move on and introduce Dr. Harding.
Dr. Harding will present a summary of the study design, methods and
results. Thank you.
Study Design, Methods and Results
DR.
HARDING: Thank you, David. Good morning, everyone.
[Slide]
As
Dr. Cocchetto said, I am going to describe to you the conduct and results of
study 3009 but, before doing so, I would like to make some introductory
remarks.
[Slide]
First,
we were set a considerable challenge in being able to demonstrate what was
described as a substantial reduction in transmission between partners, between
70 and 80 percent and with symptomatic clinical disease as the endpoint.
Second,
the study was demanding and personally intrusive for the couples
participating. Furthermore, it was
difficult to find serodiscordant couples who were in a stable
relationship. As a result, it took over
three years to screen and recruit couples, and involved over a hundred sites
internationally.
Finally,
I would like to thank Dr. Larry Corey, of the University of Washington, for
helping us develop a protocol, reviewing the endpoints and interpreting the
results. He served as chairman of the
endpoints committee in his laboratory under the direction of Dr. Rhoda Ashley
Morrow who performed the virology assays.
He and Rhoda are here today and are available as experts to join the
discussions.
What
I will demonstrate to you in the course of this brief overview of the study is
that we achieved our objective with a 75 percent reduction in the transmission
of symptomatic genital herpes.
[Slide]
The
scope of my presentation covers the following topics.
[Slide]
So
let me begin with the rationale for the study.
First, there is the proven efficacy of Valtrex in suppressing the
recurrences of genital herpes. Second,
as you have heard from Dr. Handsfield, shedding of HSV-2 occurs not only around
the time of an episode but in between episodes, such that it is being estimated
that up to 70 percent of transmissions occur in the absence of lesions. It is the virus that is shed that is the
source of transmissible infection. We
also know that Valtrex reduces viral shedding.
Therefore, taking all these points into consideration, it is
hypothesized that daily suppressive therapy with Valtrex will reduce the
frequency of transmission of the herpes virus.
[Slide]
Moving
on to design considerations--
[Slide]
--these
are some of the major factors we considered and I will deal with them one by
one. Before I do so, I would like to
emphasize that a trial design that would allow one to demonstrate reduced
transmission requires stringent criteria to make it both manageable and
interpretable. When we applied these
criteria we found that there was really only one design that allowed us to test
the hypothesis.
First,
the study population actually comprised a couple. Let me orient you straightaway to the concept
of the source partner and the susceptible partner. The source partner had to have recurrent
genital herpes, confirmed by HSV-2 seropositive status and had to be a
candidate for suppressive therapy with Valtrex.
This is an important consideration since we have a unique situation
where one person is treated to potentially benefit another. For this clinical trial we felt there had to
be a potential benefit for the source partner as well. So, it was the source partner who was given
study drug. The susceptible partner had
to have no history of genital herpes and had to be seronegative for HSV-2. It was the susceptible partner who is
monitored for the acquisition of HSV.
In
order for us to study this in as controlled a setting as possible, we
stipulated a monogamous relationship. We
did not want the susceptible partner having sexual contacts with others not on study
drug. To limit the number of variables
we enrolled heterosexual couples only.
[Slide]
As
I just mentioned, the source partner had to be a candidate for suppressive
therapy and was allocated Valtrex or placebo.
We selected source partners with nine or fewer recurrences per year,
which encompasses about 80 percent of those with symptomatic disease and for
whom an approved dose of Valtrex is 500 mg once daily.
As
for the duration of dosing in this study, eight months was chosen based on
several considerations. I have already
mentioned the demanding and personally intrusive nature of the study
procedures. In addition, we were
concerned about a possible increase in partner switching over time and a
reduction in acquisitions with time, as shown in the prior Chiron vaccine
study.
What
we did do to encourage enrollment and provide an ongoing commitment during the
study was to offer open-label Valtrex at the end of the study for a further 12
months. This also gave us the
opportunity to obtain further long-term safety data.
[Slide]
Moving
on to sample size calculations, the transmissibility of HSV-2 is quite
variable. Depending upon the population
studied, the range is somewhere between 1/40 and 1/1,000 or more sexual
contacts. Transmission acquisition has
been reported between 3.5 and 10 percent over the period of a year. Considering that our population might be a
somewhat low risk one and that the study was of only eight months duration, we
estimated that the rate of acquisition in the absence of treatment would be
about three percent. In looking for 75
percent reduction in transmission this would translate to 0.75 percent rate of
Valtrex.
Now,
calculation based on these estimates yielded the number of susceptible partners
acquiring symptomatic clinical disease to be 28 to provide 90 percent power to
differentiate between active and placebo.
Given our assumptions of acquisition rates, we would need 1,500 couples
to be enrolled.
[Slide]
Moving
on to stratification and randomized, we already knew that women were more
susceptible than men in acquiring the disease and it appeared that antibodies
to HSV-1 might afford some degree of protection against acquisition of HSV-2,
especially in women. So, we stratified treatment
based on gender and HSV-1 serostatus of the susceptible partner. Our original intent was to recruit more
female susceptibles in order to capture more cases of transmission, but had to
abandon this due to difficulties in recruiting adequate numbers.
[Slide]
Having
stratified enrollment by gender and serostatus of the susceptible partner, it
was the source partner who was allocated Valtrex or placebo as shown here. I would like to point out that there were
equal numbers of Valtrex and placebo for each block but we didn't require equal
numbers block to block. The centralized
randomized and stratification system was used.
[Slide]
It
was very important that couples understood the principles of how the herpes
virus could be spread and how they could help prevent transmission. This is clearly laid out in a very
informative American Medical Association's educational booklet, "genital
herpes, a patient guide to treatment."
A copy of this booklet was given to each couple. For non-English speaking subjects
translations of this booklet were provided.
[Slide]
In
addition, all were counseled at screening, enrollment and each follow-up visit
on how to practice safer sex. The
principles of safer sex, we emphasized, were to avoid sex whenever the source
partner has signs or symptoms of genital herpes and use condoms for every
sexual contact, whether vaginal, oral or anal.
In
addition to safer sex counseling, source partners were treated if they had an
episode of genital herpes whether they were on active or placebo. Study medication was stopped and they were
given open-label Valtrex, 500 mg twice daily for five days. However, it should be noted that the couples
remained in the study,, with the source partner returning to double-blinded
study medication at the end of the five days.
So,
taking these factors into consideration, we were doing all we could to ensure
prevention of transmission. Any benefit
of Valtrex suppressive therapy would be above and beyond these measures.
[Slide]
Now
moving on to study methods, I have already made mention of some of these in my
introduction. For example, I have
already indicated that this was stratified and randomized, double-blind,
placebo-controlled and that it was carried out in a large number of centers
around the world. In fact 96 centers
contributed couples who participated.
The study population was otherwise healthy and 18 years of age and
older.
[Slide]
For
both partners there was a monthly clinic visit.
For both there was a review of a diary.
For the source partner whether they had had any signs or symptoms of
genital herpes or any adverse events.
For the susceptible partner both any signs and symptoms of genital
herpes and a record of the type and number of sexual contacts and whether
condoms were used. Diary interviews were
performed separately to allow more frank evaluation. Both partners were counseled on safer sex
practices and condoms were offered. The
susceptible partner had a blood draw for serology and the source partner
returned the study drug for drug accountability.
[Slide]
Regardless
of the monthly visits, if a susceptible partner thought they had signs and
symptoms of genital herpes they were to go to the clinic as soon as possible
for examination, swabs and serology. On
days one, five and ten of the suspected episode one swab was taken for culture
and one for PCR. All samples of swabs
and sera were sent to the University of Washington, with the exception of
culture swabs from Canada which were sent to a Canadian lab. If a clinical diagnosis of genital herpes was
suspected, they were given treatment appropriate for an initial episode
according to approved product label.
However, the couple remained in the study until a definitive diagnosis
was made based on the lab tests. If the
diagnosis was confirmed they were considered to have completed the study.
[Slide]
The
primary endpoint was, as agreed with FDA prospectively, the acquisition of
symptomatic genital herpes infection by the susceptible partner. The diagnosis was based on the susceptible
partner having signs and symptoms commensurate with genital herpes confirmed by
one or more laboratory tests, culture, PCR and/or seroconversion. Any positive culture for a primary endpoint
was assessed for sensitivity to acyclovir as transmission of resistant virus
would have been of considerable concern.
Each case where there were signs and symptoms was to be reviewed by an
endpoints committee.
[Slide]
The
endpoints committee was convened at the end of the double-blind portion of the
study when all the laboratory data were available. The purpose was to determine whether each
case met the criteria for being considered a primary endpoint. It is important to note that the committee
remained blinded to treatment during the review process and that the committee
worked to written guidelines and minutes were recorded.
[Slide]
The
secondary endpoints were as described on the next two slides. For the susceptible partner the time to
acquisition of symptomatic infection is another way to look at the primary
endpoint but has the benefit of comparing groups throughout the study and takes
account of duration of study participation.
We were also interested in the proportion of couples with and time to
overall acquisition. This now includes
those who acquired infection without symptoms, as demonstrated by
seroconversion alone, added to those with the primary endpoint.
The
secondary endpoints of the source partner, which formed the basis for our
hypothesis, were the time to first recurrence of genital herpes and the effect
of Valtrex on viral shedding, which was carried out in a substudy and which I
will describe in just a moment.
[Slide]
Other
secondary endpoints are shown here.
First is the proportion of couples with HSV-2 seroconversion. Note that this could have included those with
symptoms or not, and a subset of this which is those with asymptomatic
seroconversion alone. We also planned to
assess any HSV-1 genital acquisitions but there were none. We also looked at the time to first oral
outbreak of herpes in the source partner.
I am not planning to show the results of any of these other endpoints in
my presentation but would direct you to the briefing document which has this
information.
[Slide]
As
I said, the effect of Valtrex on HSV-2 viral shedding was assessed in a
substudy. This involved 89 source
partners from three U.S. sites. The
subjects were still blinded to treatment so may have been on Valtrex or
placebo. Swabs were collected every day
for 60 days for quantitative PCR assay.
[Slide]
Now
for the results which you have all been patiently waiting for. These are presented under three broad
headings, a description of the study couples; the results for the primary
endpoint with subanalyses; and the results for secondary endpoints. I will start with the study couples.
[Slide]
If
you recall, the aim of our program was to enroll 1,500 couples. We enrolled 1498. Of interest is that over 4,000 couples came
forward to take part in the study but more than 2500 were found
ineligible. The most common reason was
that the susceptible partner was already HSV-2 seropositive. Of the couples randomized, 1,484 comprised
the intent-to-treat population, with 743 source subjects randomized to Valtrex
and 741 to placebo.
[Slide]
Now
for subject accountability, 78 percent of the subjects completed the full eight
months in the study and reasons for discontinuation are given in the
table. There were more consents
withdrawn on placebo than on Valtrex, which anecdotally appeared to be due to
recurrences in the source partner, but there were equal numbers lost to
follow-up or dissolution of the relationship.
The other reasons category included relocation, pregnancy, adverse
events and protocol violation.
However,
some data were available from 96 percent of the intent-to-treat population
because all but 58 couples returned for one or more visits and sometimes as
many as six or seven. Having these data
was particularly a value in the time to event analyses.
[Slide]
Recruitment
by region is shown on this slide and shows that over half the couples were from
the U.S.A., with over 60 percent recruited from North America including Canada.
[Slide]
Moving
now to demographics, this set by the stratification variable, gender and HSV-1
serostatus. The majority of susceptible
partners were male, which is in keeping with the higher prevalence of the
infection in women who formed the source.
HSV-1 serostatus, of note almost 70 percent susceptible partners were
already HSV-1 seropositive.
[Slide]
Ages
and race were well matched between groups, with a median age of 34 years and 90
percent of subjects white.
[Slide]
The
Valtrex and placebo groups were also well matched for the items on this slide,
the number of recurrences of genital herpes in the source partner, the duration
of infection in the source partner, the duration of the monogamous relationship
and the frequency of vaginal sexual intercourse. However, about 50 percent, as you can see at
the bottom of the slide, claimed never to have used condoms in the month prior
to randomization.
[Slide]
I
will now deal with the primary endpoint.
What I will do, I will take you through the endpoint evaluations, the
proportion of clinical acquisitions, the time to clinical acquisition and some
subanalyses of this primary endpoint.
[Slide]
First
let me show you how the numbers play out.
Of the original 1,484 couples in the ITT population, 58 never returned,
leaving 1,426 for whom we have data; 71 susceptible partners had some sign or
symptom thought suitable to be put forward for consideration by the endpoints
committee. The remaining 1,355 remained
asymptomatic.
[Slide]
Of
the 71 referred to the endpoints committee, 20 were confirmed as true clinical
acquisitions or primary endpoints, 15 by seroconversion with or without culture
and/or PCR and five by culture or PCR alone.
Fifty-one were rejected. Of
these, the majority had no confirmatory laboratory result. However, there were three symptomatic
subjects who seroconverted but were rejected by the committee. The reasons for rejection for two of them
were that the symptoms were considered unrelated to genital herpes. The third was considered a protocol violator
in that the source subject had only eight doses of study drug. There were also 18 HSV-2 seroconversions from
the asymptomatic group, making a total of 36 seroconversions and 41 overall
acquisitions.
[Slide]
Looking
now at the primary statistical analysis which was a proportions analysis, of
the 20 confirmed primary endpoints, 16 were on placebo and four on
Valtrex. These represent 2.2 percent and
0.5 percent of their respective populations, as shown on this slide. This difference is statistically significant
with a relative risk of 0.25. In other
words, there was a 75 percent reduction in the risk of transmission of genital
herpes when the source partner was on Valtrex compared to placebo. This then met our a priori expectation and
confirmed our result as being both substantial and clinically meaningful.
[Slide]
Looking
at the time to acquisition for these primary endpoints using a Kaplan-Meier
plot, as shown here, again there is a clear and statistically significant
difference between Valtrex and placebo in favor of Valtrex. Of note is that the difference becomes
apparent almost immediately after randomization and that the rates of acquisition
remain linear throughout the study, with no indication of tailing off with
time. I will mention here that we have
viral cultures from ten of the subjects with primary endpoints and all isolates
were sensitive to acyclovir. In other
words, their IC-50 values were below 2 mcg/ml.
[Slide]
I
am now going to show you some subanalyses of the primary endpoint, this one by
gender. As expected, the majority of
acquisitions were in females. There were
12 in total of the 20, this despite the smaller number of female susceptible
partners enrolled in the study. The
difference between males and females was statistically significant but the
difference is in favor of Valtrex regardless of gender.
[Slide]
We
had also expected more acquisitions in HSV-1 seronegative partners but there
wasn't a major difference, as shown here.
The trend was for proportionally more acquisitions in seronegative
subjects but the numbers were small and not significant. However, again differences were observed in
favor of Valtrex regardless of HSV-1 serostatus.
[Slide]
Finally,
here is a display of acquisition by condom use.
The chart here shows the frequency of acquisitions of symptomatic
genital herpes for the placebo group according to whether the median use of
condoms during the study was "never," "sometimes" or
"nearly always." The incidence
reduces from 2.8 percent for those who never used condoms to half that, 1.4
percent, for those who nearly always used them.
[Slide]
Now
I have added the data for Valtrex and the message is the same. Note that there were zero acquisitions in the
sometimes and nearly always categories.
This emphasizes the importance of couples practicing appropriate protective
measures and shows that the benefit of Valtrex is in addition to the practice
of safer sex. In a covariate analysis
the effect of condoms in reducing transmissions approached statistical
significance, with a p value of 0.06.
[Slide]
Now
for the secondary endpoints and I will deal with the following, first I will
look at recurrences in the source partner; then viral shedding from the source
partner in the substudy. If you recall,
the hypothesis was that if we could reduce recurrence and viral shedding we
should also be able to reduce transmissions.
Finally, I will show you the effect of Valtrex on overall
acquisitions. Again to remind you, these
were all HSV-2.
[Slide]
Here
we have a graph of the proportions of source partners for genital herpes
recurrence at eight months, 47 percent for Valtrex and only 13 percent for the
placebo-treated subjects. This is a
highly significant difference and similar to that reported in previous studies.
[Slide]
Now
we have the results from the viral shedding substudy which showed a reduction
in shedding by Valtrex. I will give you
the results for total shedding, which are those obtained from every day of
swabbing which is of 60 days duration.
These included days on which there might have been an outbreak. I will mention results from an analysis when
those days are excluded. Eighty-nine
subjects were enrolled in this substudy and the numbers are somewhat
unbalanced, 50 on placebo and 39 on Valtrex.
This was because randomized to the main study, if you recall, was
centralized, not by site. It was also
dependent upon the source partner's agreement to undergo the extra study
procedures necessary.
The
results were very much as expected from the literature, as we have just heard,
with HSV DNA being detected by PCR on at least one day in over 80 percent of
those on placebo compared with almost 50 percent on Valtrex. HSV DNA was detected in almost 11 percent of
days for those on placebo compared with almost three percent on Valtrex. That is a 73 percent reduction on
Valtrex. The number of DNA copies was
reduced on Valtrex from 4.2 on a log scale to just 1.7. That is greater than 99 percent
reduction. All these differences were
clearly statistically significant.
Very
similar results were obtained if one excludes days when there was an
outbreak. There was still 90-95 percent
reduction in DNA copies/mL on Valtrex compared to placebo.
[Slide]
Just
to remind you before I get to overall acquisitions how that group is
defined. It is those with a primary
endpoint, some confirmed by seroconversion with or without culture and some by
culture or PCR alone, and to those you add those with seroconversion and the
total is 41.
[Slide]
So
here we have the proportion of susceptible partners with overall acquisition of
HSV-2 infection. Twenty-seven of them
were in the placebo group and 14 in the Valtrex group. This represented a relative risk of 0.52 or a
reduction in risk of 48 percent.
[Slide]
The
time to event analysis for this group, shown here, is more powerful
statistically as it adds time of acquisition to the numbers of
acquisitions. The reduction in risk on
Valtrex was, as in the previous slide, 48 percent for the relative risk of
0.52. As with the primary endpoint, the
difference in rate was noted early and remained linear throughout the
study. So, the secondary analyses fully
support our hypothesis and add strength to the primary analyses.
[Slide]
I
will now briefly review the safety results obtained in the study. Remember that these pertain to the source
partner who is receiving Valtrex or placebo.
These results are from the 8-month double-blind portion of the
trial. I will mention results from the
12-month open-label extension at the end.
[Slide]
This
slide summarizes the adverse events reported through the study. As you can see, there is very little
difference between Valtrex and placebo.
None of the serious adverse events was classified as drug related. Discontinuations due to an adverse event were
slightly more frequent on Valtrex but none of these was serious or
unusual. Reasons included headache,
gastrointestinal upset and one case of urticarial rash.
[Slide]
Here
you see a graphical depiction of those adverse events reported by five percent
or more of subjects. The most common
events were headache, upper respiratory and gastrointestinal, and there was
nothing unexpected from previous experience in clinical trials.
[Slide]
Laboratory
tests included those listed above as being of greater potential interest,
reflecting hepatic, renal and hematologic systems, were unremarkable and there
was no indication of any difference between Valtrex and placebo.
[Slide]
Finally,
here is a summary of the data we have up to January 31st of this year from 831
source partners who continued for further 12 months on open-label Valtrex after
the main study had completed. This
represents about 95 percent of those opting to continue to receive drug. The dose of Valtrex was 500 mg once daily as
in the main part of the study.
As
you see, the pattern of events is similar to that reported in the double-blind
phase and, again, we have no new safety signals for what for some of them is
now 20 months of continuous use of Valtrex.
[Slide]
Finally,
in conclusion study 3009 clearly met its objectives. By that, I mean that we set out with a
hypothesis that Valtrex would reduce episodes of recurrent genital herpes in
the source partner and would reduce viral shedding. These would result in a significant reduction
in transmission of genital herpes to an uninfected partner. The study demonstrated this with a reduction
of 75 percent in the acquisition of clinical infection by a susceptible partner
and a 48 percent reduction in overall disease acquisition. This benefit is seen over and above that
afforded by counseling on safer sex practices, the use of condoms and, I should
add, the treatment of outbreaks in the source partner. The safety profile of Valtrex was similar to
that described in the product label which by now has been well characterized.
Thus,
I hope to have demonstrated to you that the data are scientifically sound and
clinically relevant, and that the reduction in transmission of herpes virus to
a partner is an additional benefit of suppressive therapy when combined with
safer sex practices.
Thank
you, and I will now pass it over to Clarence Young to make some concluding
remarks.
Concluding Remarks
DR.
YOUNG: Thank you, Stuart. Good morning, everyone.
[Slide]
My
name is Clarence Young and I direct clinical development activities at
GlaxoSmithKline for anti-infectives. I
have also had the experience in my career of caring for patients with genital
herpes and also counseling these patients.
Dr.
Harding has taken you through the results for study 3009. My task over the next few minutes is just to
summarize what these data mean for both patients as well as healthcare
providers.
[Slide]
First
of all, it is important to note that study 3009 is a landmark study which
provides a new option for the management of patients with genital herpes. As Dr. Handsfield outlined in his talk,
various strategies have been undertaken to prevent the transmission of genital
herpes but to date none of these strategies has been completely effective, and
the availability of a prophylactic vaccine is still several years away.
This
study, 3009, was the first demonstration that an antiviral agent can actually
decrease the transmission of genital herpes between sexual partners. This study also indicated an association
between the reduction in viral shedding and the transmission of genital herpes. These data may be especially relevant for
HSV-2 uninfected women of childbearing potential who are at great risk for
acquisition of genital herpes in the course of pregnancy.
[Slide]
The
benefits of Valtrex therapy that were observed in this study were in addition
to safer sex practices and condom use and the results, as Dr. Harding had
mentioned, are truly unique in that the benefits of Valtrex therapy accrued not
only to the HSV-2 infected source partner with genital herpes who received
Valtrex therapy but also the HSV-2 uninfected susceptible partner who did not
receive Valtrex. These benefits were
without any added risk to the partner who received Valtrex.
The
study, therefore, provides a new option to address what has been shown, and as
you saw earlier in Dr. Handsfield's presentation, to be a major patient concern,
which is transmission of genital herpes.
[Slide]
Now,
GlaxoSmithKline has had a long-standing interest in the education of patients
and families, as well as healthcare providers, regarding genital herpes, its
management and various treatment options.
It is important to ensure that the patients as well as healthcare
providers have a very clear understanding regarding study 3009, how the study
was designed; what the results of the study showed; and what the implications
of these results are to avoid any misinterpretation of the study results. GlaxoSmithKline will work with FDA as well as
with external stakeholders in order to ensure that the benefits of Valtrex
therapy and, more importantly, the benefits of safer sex practices and condom
use are communicated both accurately and effectively.
[Slide]
Since
Valtrex is already available for suppression of genital herpes recurrences, it
is reasonable to ask why additional information is required in the prescribing
information. Well, feedback from healthcare
providers has indicated that the availability of this new indication for
Valtrex will provide another reason for healthcare providers to initiate a
conversation with their patients regarding sexually transmitted diseases and
safer sex practices. Others view this as
another tool in the toolbox which they will use as part of their management
approaches to their patients with genital herpes. Awareness of these data by patients may
influence their decision to actually pursue suppressive therapy. Finally, the availability of labeling will
enable GSK, external stakeholders and patients to have a definitive source of
accurate and balanced information on the results of study 3009 with the
benefits of FDA oversight.
[Slide]
We
cannot say that based on the results of this study the use of Valtrex will
impact in any way the prevalence of HSV-2 infection in the United States, or
that the study addresses all of the questions which one might have regarding
the benefits of Valtrex therapy in special populations. What we can say is that the results from study
3009 clearly provide an opportunity to make a difference in the lives of
patients.
[Slide]
Finally,
GSK would just like to acknowledge the participation by the hundreds of
individuals in this very time consuming and demanding study. We also would like to acknowledge both the
study personnel as well as clinical investigators. Some of them are here with us today. Thank you very much for your attention and
for the opportunity to share the results of study 3009 with you today. Thank you.
DR.
GULICK: Thanks to Drs. Cocchetto,
Harding and Young for the sponsor presentation.
As mentioned earlier, we are going to defer the question and answer
period until after the presentation from the agency, which brings us to our
break. It is 9:55 so we will reconvene
at 10:10.
[Brief
recess]
DR.
GULICK: We will move now to the agency
presentation. We will start out with Dr.
Haverkos.
FDA Presentation
Study Design
DR.
HAVERKOS: Good morning.
[Slide]
I
am Dr. Harry Haverkos. I am the primary
reviewer on the application, and I will be joined by my statistical colleague,
Dr. Smith, in presenting the FDA review.
First
of all, I would like to congratulate the sponsor on conducting this large,
multinational trial, really a landmark study looking at a medication to reduce
sexual transmission of herpes simplex.
[Slide]
Our
presentation will be divided into several areas. I will present some comments on study design
and Dr. Smith will get to present the efficacy results. I will then come back up and discuss a little
bit of the virology, safety and some of the behavioral results. We will then list our conclusions and finally
read for you the questions that we would like the committee to deliberate on
for us.
[Slide]
As
reported before, this application was submitted in October and has an NDA due
date of September. They propose the
dosage of 500 mg a day of valacyclovir to reduce the risk of transmission of
genital herpes with the use of suppressive therapy and safer sex practice.
[Slide]
Valacyclovir
is approved for several indications involving herpes simplex, treatment of
initial genital herpes with one gram b.i.d. for ten days; treatment of
recurrent genital herpes too mg b.i.d. for three days; and as chronic
suppressive therapy of recurrent genital herpes at one gram a day or 500 mg a
day as an alternate dose.
[Slide]
This
single study was submitted. It is
multinational, randomized, double-blind evaluating valacyclovir in HSV-2
discordant monogamous couples. As
mentioned, the sample size sought was 1,500 couples. Over 4,000 were screened and the patients
were randomized to valacyclovir versus placebo for eight months of
therapy. During the study all subjects
were encouraged to use condoms and abstain from sex during any outbreaks.
[Slide]
Inclusion
criteria were gone through before. These
were monogamous heterosexually active couples.
The source partner had to be HSV-2 antibody positive and have clinical
episodes. They excluded patients who had
greater than ten symptomatic recurrences a year. I am concerned about some of the ethics about
not providing suppressive therapy to that group, but it was needed that a
person be a candidate for suppressive therapy.
It was not clearly defined in the protocol but generally is considered
as somewhere between five and six recurrences in a year. The susceptible partner had to be in a
relationship with no other partners, and be HSV-2 antibody negative and report
no clinical herpes outbreaks.
[Slide]
The
primary endpoint has discussed and we will be discussing this point I think
over and over again. It is the
proportion of susceptible partners with a clinical episode confirmed by the
laboratory. The laboratory, of course,
could be by culture, PCR and/or serology.
[Slide]
The
monitoring that occurred during the study is listed on this slide. Safer sex counseling was provided at each
visit. The source partner came in
monthly, and during those monthly visits they reviewed the diary card for any
symptoms or recurrences that the source partner had. If they developed an outbreak they were to
return to the clinic immediately to be evaluated and to be started on therapy.
Susceptible
partners also came back monthly and for those partners two areas were reviewed,
the diary cards of the sexual exposures and practices and also looking for any
signs of herpes in the previous month.
They too were expected to return for any suspect lesion for open-label
therapy.
[Slide]
For
virology, as mentioned, confirmation was defined by either culture, DNA of
suspicious lesions and monthly serologies were followed. Mostly all of the samples were sent to a
single lab in Seattle. However, there
were five cultures that were sent to a lab in Vancouver.
[Slide]
There
were a couple of issues raised I guess by the virologist during our
review. In a study with a fairly small
number of endpoints I think you really want to make sure that you miss one, two
or three endpoints. The samples, as
mentioned, were collected at over 100 sites in more than 20 countries from
around the world and then were transported to Seattle. As mentioned, a few Canadian samples were
sent to Vancouver.
Concerns
are about some protocol violations.
There was failure to report at the first sing of genital herpes so some
cultures were missed. There were a few
samples that were contaminated, a few samples that were lost in transit. Even though herpes is quite a stable virus,
there was some concern raised by our virologist about what effect transit might
have on some of these results.
[Slide]
As
mentioned, there was a long history of discussion between the FDA and the
sponsor. As mentioned, there were three
topics of discussion. I think our three
may be a little different than their three but that probably just reflects more
history. The primary endpoint was one of
the primary areas of discussion, and we will talk about that again on the next
slide.
Source
partner inclusion--again, the study was initially looked at as predominantly a
serologic study, serologic endpoint. But
the FDA wanted really clinical endpoints and so wanted to have the history of
clinical herpes of source partners be candidates for suppressive therapy and
less than ten recurrences in the past year was the agreed upon inclusion
criteria.
There
was some discussion of whether two studies would be better than one. If one studied different populations would it
be easier to interpret the results and write the label? In the end, the company I think decided to do
one large, multinational study.
[Slide]
The
primary endpoint agreed upon is that shown first. We will also be presenting some data on some
secondary endpoints, predominantly the endpoint of HSV-2 seroconversion which
historically was how the study was initially proposed. Finally, acquisition of meeting one or both
of the two endpoints.
I
just want to point out question six is actually going to deal with that issue
so I think it is very important that we understand the different endpoints.
[Slide]
My
last slide before turning it over to Dr. Smith is just to give you a little
history of the study. It was initiated
in February of 1998. As mentioned, over
4,000 couples were screened. There were
a couple of amendments along the way that occurred. Two of them I think may be part of the
discussion. A shedding substudy was
added about six months into the study.
We will look at some of those results.
Then, in May of 2000, because recruitment hadn't quite lived up to
expectations, sites were added outside of North American and Europe to include
Australia. Eastern Europe was added to
those originally recruited from western Europe, and south America. The initial stratification to try to get more
female susceptible partners was waived in order to recruit more couples.
With
that, let me turn the podium over to Dr. Smith who will present the efficacy
results.
Efficacy Results
DR.
SMITH: Thank you.
[Slide]
I
am going to go over the demographic and baseline characteristics and then
primary and secondary results, and robustness of the analyses to discontinuations,
and finally regional differences.
[Slide]
One
thousand four hundred and ninety-eight out of 4,030 screened couples were
randomized. The primary reason for
screening failure was the lack of HSV-2 discordance within couples. So, the susceptible partner was HSV-2
seropositive or had symptoms of it.
[Slide]
Demographic
characteristics were very similar in both treatment groups so I will summarize
them overall. Two-thirds were male and
one-third of the susceptible partners were female. The median age was 35 years; 90 percent of
the susceptible partners were white; five percent Hispanic; three percent
black; one percent Asian and less than one percent other races.
[Slide]
One
percent has sexual relations with other partners in the last three months. The median duration with the source partner
was two years and 22 percent had been treated for an STD.
[Slide]
Ninety-seven
percent had sexual intercourse with the source partner in the last month and
the median number of contacts in the last month was seven.
[Slide]
This
summarizes the condom use for vaginal/anal intercourse at baseline. Approximately 50 percent of the patients had
never used condoms at baseline in both treatment groups. Thirty percent said they nearly always used
condoms and about 20 percent said they sometimes used condoms.
[Slide]
In
terms of HSV-1 status for female susceptible partners at randomization,
approximately 80 percent were positive in both treatment groups. About 20 percent were negative and only two
were atypical.
[Slide]
For
male susceptible partners, slightly less, about 65 percent were positive. About 35 percent were negative and five were
atypical. Again, these were very similar
in both treatment groups.
[Slide]
Now
I will summarize efficacy evaluations.
[Slide]
The
primary analysis looked at clinical evidence of HSV-2 or symptomatic HSV-2
acquisition and 0.5 percent of valacyclovir patients had clinical evidence of
transmission compared to 2.2 percent of the placebo patients. The p value was 0.011 and the odds ratio was
0.24, representing approximately a 75 percent reduction. The 95 percent confidence interval of the
odds ratio went from 0.06 to 0.76.
The
other two selected secondary endpoints are HSV-2 seroconversion and overall
HSV-2 acquisition, which consists of HSV-2 seroconversion or symptomatic HSV-2
acquisition. Some may argue that HSV-2
seroconversion may be a better endpoint because subclinical infections may
become symptomatic HSV-2 later on.
Here
we have 1.6 percent of the valacyclovir patients with HSV-2 seroconversion 3.2
percent of placebo patients. In this
case the odds ratio was 0.49, approximately 50 percent, representing about a 50
percent reduction with valacyclovir treatment.
The p value was 0.06. Similar
results were obtained for overall HSV-2 acquisition. This was primarily driven by the HSV-2
seroconversion results. In this case we
have 1.9 percent of valacyclovir patients compared to 3.6 percent of the
placebo patients. In this case the odds
ratio was 0.5.
[Slide]
This
is what it looks like graphically. We
have a bigger difference for the primary endpoint when you compare placebo
patients to valacyclovir patients.
Again, the odds ratio is approximately 0.25. Here we have about a 50 percent reduction for
these other two selected secondary endpoints, and the p values are of
borderline significance. In these analyses
withdrawals were regarded as being transmission-free.
[Slide]
When
we look at condom use during the study what we have are over 50 percent of the
patients never used condoms during the study compared to 30 percent who nearly
always used condoms in both treatment groups, and about 15 percent who said
they sometimes used condoms. This is
calculated a little differently. In this
case during the study what they have calculated is the median usage over months
one through eight so that basically with nearly always using condoms 90 or more
percent of the patients who nearly always used condoms were classified in this
category. So, this represents greater
than 90 percent usage at baseline or at a particular visit.
However,
because we are using the median to calculate this during the study, it is
possible that at one visit they could have nearly always used condoms; at the
next visit they might never have used condoms; and at the third visit they
might have always used condoms at months one, two and three and, in that case,
the median would have been nearly always used condoms. If they never used condoms, that is really
zero percent of the time. So, in that
case the true median would be about 60 percent rather than 90 percent. So, what we got here during the study is a
little different than what we had at baseline.
In
addition, condom use can fluctuate from month to month and patients who nearly
always used condoms over months one to eight might never have used condoms just
prior to an episode. So, we have to take
all of this in mind and the study wasn't designed specifically to look at
condom use.
[Slide]
Here
we have the primary endpoint separated out by condom usage. On the left-hand side we have valacyclovir
patients. In this case one percent of
the valacyclovir patients who never used condoms had clinical evidence of
transmission compared to 0/91 patients who sometimes used condoms and 0/211 who
nearly always used condoms. We have the
95 percent confidence intervals plotted just to indicate that even though we
didn't observe any events we have a confidence interval here that ranges from
zero percent to over three percent, and here we have more patients so we have a
smaller confidence interval that goes from zero to 1.5 percent.
Then,
when we look at placebo patients we can see that almost three percent of the
patients had clinical evidence if they said they never used condoms through the
majority of the visits during the study compared to two percent who sometimes
used condoms and approximately 1.5 percent who never used condoms. So, we also see a main effect of condom usage
and the more condom usage, the less transmission. The p value for the main effect of treatment,
adjusted for condom usage, was 0.011 and the p value for condom usage was 0.08,
close to significant. Again, keep in
mind that this study was not designed specifically to look at condom use.
[Slide]
To
illustrate the effects in a little more detail we also were looking at overall
acquisition rates in addition to clinical evidence. So, what we have in the dark shaded regions
on the graphs down below is what we saw in the previous slide. Over and above that we have the rates of
overall acquisition which can include either clinical evidence or HSV-2
seropositive incidence rates.
So,
in this case when we look at the lightly shaded regions for valacyclovir we can
see that about two percent who never used condoms had overall acquisition and
over three percent who said they sometimes used condoms, and we have the rates
for nearly always using condoms of approximately two percent--no real trend for
overall acquisition with valacyclovir.
When
we look at placebo patients we do seem to see another decline when we look at
overall acquisition rates, as is the case when we look at the clinical evidence
of transmission. In this case the
clinical endpoint is close to statistically significant. It is hard to read here but it is 0.08 and
for overall acquisition the p value is 0.84.
These p values represent the effect of condom use.
[Slide]
Now
I will talk about the robustness of efficacy analyses to discontinuations.
[Slide]
On
the first slide we have the results for the primary analysis. Shown here are the percentage of patients
with clinical evidence of having HSV-2 transmission. In this case we have withdrawals and the main
point of this slide is to show that the withdrawal rate, which is greater than
20 percent in both treatment groups, is much larger than the percentage of
patients with the primary endpoint.
[Slide]
So,
we wanted to look at reasons for withdrawal.
In this case, the principal reasons include withdrawal of consent, loss
to follow-up, relationship breakup and the partner withdrew. Withdrawal of consent was somewhat higher in
placebo patients than in valacyclovir patients.
It ranged from three to six percent.
Six percent of both treatment groups reported loss to follow-up; five
percent reported a relationship breakup, approximately five percent; and two
percent in both treatment groups had partners who withdrew.
[Slide]
None
of the susceptible partners withdrew to adverse events or lack of
efficacy. Less than one percent of the
source partners withdrew due to adverse events, although it was slightly higher
for valacyclovir, approximately two percent.
Less than one percent of the source partners withdrew due to lack of
efficacy.
[Slide]
So
there were various sensitivity analyses that we used to look at this. One very conservative analysis took all of
the withdrawals and considered them to be treatment failures. In this case, the percentage of withdrawals
far outnumbered the primary endpoint cases.
So, what we have is very little difference between the two treatment
arms. In both cases we have
approximately 22 percent of valacyclovir patients compared to about 24 percent
of placebo patients, and a p value of 0.30.
There is no difference when you include all the withdrawals or
discontinuations and treat them as treatment failures.
So,
what we are getting here are more reasonable estimates when we just include a
small fraction of the withdrawals and treat them as if they were treatment
failures. When we assume that 10 percent
of the discontinuations were treatment failures we see approximately four
percent of placebo patients and we can see approximately three percent of
valacyclovir patients. In this case the
p value is 0.11. When we count five
percent of the discontinuations as treatment failures we see about double the
rate for placebo compared to valacyclovir.
This looks very similar to the HSV-2 seropositive results, and the p
value here again is 0.05 so this is what it takes to reach statistical
significance. In the primary analysis
none of the discontinuations were counted as treatment failures. They were all concluded to be successes so
this is what we see here, with the p value again being 0.011.
The
Kaplan-Meier analysis was 0.008. The
Kaplan-Meier adjusts for the length of follow-up and also it assumes not
informed of censoring. For example, in
Valtrex patients the risk for patients who discontinue is the same as the risk
of transmission for patients who complete the study. The same thing in placebo patients, the risk
for patients who discontinue is the same as the placebo patients who complete
the study.
[Slide]
Now
I would like to talk about regional differences.
[Slide]
We
see a histogram of the different countries, major geographic regions. In this case, the percentage of patients with
a first episode of genital HSV-2 in susceptible partners is plotted and we see
that by far the biggest differences seem to occur in Australia and Canada. These are all placebo patients so we have
almost nine or ten percent of Australian patients and in Canada it is about
three percent, and we have no Valtrex cases except in the U.S. South America has only 43 patients but
eastern Europe and western Europe comprise about 20 percent of the sample and
there are no cases, no patients who had the primary endpoint in all of eastern
and western Europe. The p value for the
effect of geographic region was 0.01.
So, the main effect of geographic region was very significant
statistically.
[Slide]
This
is a backup slide which actually has the numbers of confirmed cases in each
country.
[Slide]
When
we plot the overall acquisition rates we see a similar pattern, with the
highest rates in Australia, followed by Canada.
However, in Europe we do see cases.
In fact, we see more placebo cases in eastern Europe than valacyclovir
cases. In western Europe, it looks like
they are approximately the same. In the
U.S., it looks like the rates ar approximately the same. The U.S. has 803 patients.
This
is a little different because for the clinical evidence in the primary analysis
the U.S. results tended to look approximately the same as the overall analysis
with all countries combined. The other
thing is that in Europe it looks like there are as many cases, roughly as many
cases as there are in the United States. which is very, very different from
what we saw with the primary endpoint.
[Slide]
This
is backup slide, which is in your handout, which has the actual numbers of
patients.
[Slide]
I
looked at several different demographic and other sexual behaviors to see if
that could explain the regional differences.
The only thing I was able to see was that it looks like in eastern
Europe there is a much higher percentage of patients who said they nearly
always used condoms, over 60 percent, compared to all the other geographic
regions where it is just slightly over 20 percent or less than 20 percent. However, it doesn't seem like in eastern
Europe the rates of HSV-2 seroconversions are any lower. Also, the overall acquisition rate in eastern
Europe was similar to the U.S. and western Europe and eastern Europe.
[Slide]
So,
my summary and conclusions are that the percentage of dropouts was over 20
percent, and this was much higher than the percentage of susceptible partners
classified as having clinical evidence of a first episode of genital HSV-2.
The
primary reasons for discontinuation include withdrawal of consent, loss to
follow-up and the ending of relationships.
[Slide]
The
statistical significance of the primary endpoint depends on the assumptions
about how many discontinuations should be counted as treatment failures. This can be statistical significance or it
could also mean clinical significance, i.e., is there a 75 percent reduction,
which is actually harder to achieve than statistical significance.
No
transmissions were reported in Europe where approximately 20 percent of the
patients were enrolled. This rate is
similar to the 20 percent discontinuation rate so it is possible that if there
were no real treatment differences in Europe then we could also do a sensitivity
analysis where we counted those European patients as treatment failures and we
would have an equal amount in both groups, and then we would add that on to the
percentage of discontinuations and we would have less robust analyses.
[Slide]
The
largest treatment effects were observed in Australia and Canada. The U.S. results were similar to the results
for the primary endpoint for all countries combined. The differences between valacyclovir and
placebo were not as significant for HSV-2 seroconversions and overall
acquisitions, particularly in the United States.
[Slide]
Now
I would like to have Dr. Haverkos talk about viral shedding, substudy results,
safety and behavioral results and conclusions.
Viral Shedding Substudy, Safety and
Behavioral
Results and Conclusions
DR.
HAVERKOS: Thank you, Dr. Smith.
[Slide]
First
of all, the viral shedding substudy, 89 patients were recruited and 85 source
patients were followed intensively for two months. As mentioned before, they filled out daily
diary cards recording any signs or symptoms of recurrence. They collected samples at home and did a
self-exam, and then every two weeks came into the clinic for review of the
diaries, clinical exams and additional viral cultures.
[Slide]
I
think that the results shown are supportive of an effect in suppressing
virus. As seen here the valacyclovir
group shed 2.9 percent of the days or cultures taken compared to about 11
percent in the placebo group, and during the times of shedding the valacyclovir
group had lower levels of virus present, about a one log drop.
I
think Dr. Guinan asked some questions earlier about differences, male and
female. I have not seen those results
and maybe the company can address her question in the comment period.
[Slide]
Moving
on to safety, currently the drug has warnings in the label about thrombotic
thrombocytopenic purpura and hematuria syndrome and death that has occurred in
some patients with advanced HIV disease and immunosuppressed for other reasons,
transplant recipients receiving valacyclovir up to eight grams a day. So, there are some significant side effects
seen with this but generally at much higher doses than people are going to
propose to use for this indication.
Adverse events commonly reported with use of valacyclovir include
nausea, headache, vomiting, dizziness and abdominal pain.
[Slide]
Looking
through the data presented, there were no deaths. There were no reports of TTP/HUS in the
study. Twenty-six subjects developed
serious adverse events. There were 17
discontinuations and there were 16 pregnancies, and we are looking at those
last three bullets on the next three slides.
[Slide]
If
you look at the serious adverse events, they are pretty similar between the two
groups. A patient discontinued to
glomerulonephritis was a patient that, right at the beginning of the study,
developed some symptoms of arthralgias that ended up in a diagnosis of lupus
and during that process the patient was discontinued from valacyclovir.
We
have one cancer in each column. We have
an intestinal obstruction attributed to another medication that the patient was
taking. Then we can see some parallels,
some spontaneous abortions; uterine fibroids; Bartholin's cyst infection;
ovarian cyst; a couple of localized infections.
I think one with meningitis came in, was treated with cephtriaxone and
was signed out as a viral meningitis though it was not clear that herpes
cultures were done or herpes was ruled out in that case but the patient's
symptoms resolved over four days and the patient was discharged. There were a couple of orthopedic problems in
each group and then a syncope, a vasovagal attack. So, nothing jumping out that one could
attribute to valacyclovir and serious adverse events.
[Slide]
If
you look at the discontinuations, there were 12 in the valacyclovir group, most
of them for symptoms that were attributed to headache and GI disorders. There were two rashes and two where they had
renal problems, one glomerulonephritis associated with lupus and hematuria that
did not meet any other conditions for TTP and was being worked up for kidney
stone.
[Slide]
As
I mentioned, there were eight pregnancies in both groups. Trying to look at what impact, if any,
valacyclovir might have on these pregnancies, there were four women, source
patients randomized to valacyclovir, two healthy infants were delivered and two
developed spontaneous abortions. There
were seven in the placebo group, as you see here, and three health infants and
three spontaneous and one elective abortion.
There was one susceptible partner who was treated with valacyclovir for
a suspicious HSV initial event who elected abortion, and then there were four
other susceptible partners who did not receive drug and for which data was not
presented.
[Slide]
Moving
on now to the behavioral aspects, just for review, the guidelines put out by
the public health service, specifically the CDC, to manage herpes are quite
extensive. They are included in your
packet. It is mentioned that for
critical management of herpes counseling be done. The goals of counseling are to help patients
cope with infection and to prevent sexual and perinatal transmission. They are encouraged to inform their partner
before initiating a sexual relationship and are reminded that transmission can
occur during asymptomatic periods as well as during outbreaks.
[Slide]
In
addition, partners or couples are encouraged to abstain from sex when lesions
or prodromal symptoms are present. They
are encouraged to use condoms which, when used consistently and correctly, can
reduce the risk, again reemphasizing that sex partners might be infected even
if no symptoms occur, and encouraging testing of partners for herpes.
[Slide]
These
guidelines are pretty much based on a variety of studies from the Seattle
group, including a study in JAMA in 2001 which the authors claim was the first
one to prove that condoms actually prevented transmission or reduced
transmission among HSV partners. This
was a reanalysis of an ineffective vaccine trial, alluded to by Hunter
Handsfield and others earlier, in which over 500 monogamous heterosexual
discordant couples were followed for 18 months.
There was about six percent transmission, and condom use was reported as
protective, interestingly, for women but not for men.
[Slide]
Now
let's look at some of the data. If one
asks how effective was the STD counseling provided in this study, what behavior
change was actually found, as you see here, at baseline about 50 percent of
couples said they never used condoms and in the month prior about a third said
they nearly always used condoms. As
mentioned earlier, when we calculate the nearly always used condoms during the
study, it is based really on a median use of the eight months. So, if a couple reports five months using
condoms all the time and then there is a month or two where they only use it
sometimes or never, they still are classified as nearly always.
But
if you look at the effects of counseling, as you can see, condom use during
vaginal sex actually decreased slightly.
"Nearly always" now is reported by 30 percent of couples, and
a higher percent reported never using condoms.
In oral sex, which was reported by over 70 percent of the partners, only
seven percent in both groups reported nearly always using condoms for oral sex.
I
must say, there is some difficulty interpreting the oral sex data because it is
not clear in the reports in which direction the oral sex occurs. Is it man or woman, woman or man? So, it becomes difficult to know exactly what
exposures, particularly during symptomatic periods, in one of the
partners--whether risk or direct contact was made.
[Slide]
Looking
at some of the behavioral data, as we have mentioned, the condom use collection
or report can best be described as poorly defined. For oral sex I think was even more difficult
to look at the data, particularly if one tries to then look at this issue of
abstinence either of sexual behavior or specifically of oral sexual behavior
during outbreaks. No analysis was
conducted.
I
am always struck as I read these studies of couples by what kind of data we
collect and what we don't collect on couples.
We collect data on duration and whether they have had a history of STD,
but among heterosexual couples we don't have data like on marital status;
whether people are living together; whether or not the couples have any
children, which might give us some better definitions for being able to
decipher who these couples are.
There
was no analysis of the effects of counseling or, you know, how the data were
collected on behaviors by different languages; how a number of these things
were done considering the fact that it was multinational and multilingual, how
different cultures might look at some of these definitions of oral sex or
reporting different behaviors. Finally,
there were a number of missing diaries.
[Slide]
In
summary, I think we think the study was well done and does show that it does
reduce clinical HSV-2 outbreaks among source partners and transmission to
susceptible partners among these couples.
The
viral shedding substudy I think clearly supports that valacyclovir does reduce
transmission among such couples, and no new safety issues were identified to
date in our review.
[Slide]
On
the other hand, if one looks at the efficacy of the counseling and behavioral
interventions, clearly subjects continued not to use condoms during every sex
act, and very little during oral sex acts, and looking over the histories,
there were individuals that did not abstain from sex during symptomatic recurrences
despite counseling monthly. This
behavior area may be an area that we can make some additional progress in, in
addition to what we are finding with the medication.
[Slide]
With
that, let me move on to the questions. I
will just read them briefly. We will
start out with one that, hopefully, will be fairly straightforward, does the
information presented by the applicant support the use of valacyclovir to
reduce the risk of transmission of genital herpes among monogamous heterosexual
couples?
If
you agree with that, we will them move on to the other questions. If you don't, then we will talk about what
additional studies need to be conducted.
[Slide]
After
that one I think we get into some questions on how we are going to use this
drug in practice and how we are going to fit it into public health
guidelines. Does the information
presented support the use of valacyclovir to reduce the risk of transmission of
genital herpes among populations other than monogamous heterosexual couples?
[Slide]
Third
is this issue of screening in 3009. Over
4,000 couples were screened. Only 1,500
were enrolled. Many of them, even though
they didn't know they were infected, were.
So, please discuss the implications of screening susceptible partners
for herpes prior to initiating therapy of the source partner with valacyclovir.
[Slide]
Number
four is a more philosophical question but one I know bothers some people in
public health, what will marketing of valacyclovir for reduction of genital
herpes have on the impact of use of condoms and following other STD guidelines?
[Slide]
Fifth
moves on to another issue which I guess deals with duration of therapy and
resistance. Although patients in the
registrational trial were treated for eight months, it is likely to be used for
longer periods of time. What additional
studies would you suggest to evaluate the potential for longer-term adverse
events, including development of resistance to valacyclovir?
I
guess I would kind of like to add a thought.
When would you consider stopping to use this drug in a
relationship? For example, what if the
relationship breaks down? What if you
get into another partner who is already infected? What if transmission occurs? If you get into a relationship and start this
at age 20 and you stay in that relationship for 50, 60 years, how long should
one continue the medication and should there be some monitoring, or whatever,
in the process?
[Slide]
Finally
the six question, getting back to this issue of the primary endpoint, in future
studies for treatments for herpes simplex what do you recommend that we use as
a clinical endpoint? And, if we have
time, which we probably won't, there is extra credit. One can try to address other STDs because I
know we have other STDs that other manufacturers out there are interested in
looking to see what impact this might have on HIV and other STDs.
So
with that, I will conclude and turn it back over to Dr. Gulick.
DR.
GULICK: You have one more slide, I bet
you.
DR.
HAVERKOS: Excuse me, I am sorry.
[Slide]
Dr.
Smith and I would like to thank the collaborators and those who have provided
us with all materials and told us what to say today. Thank you very much.
DR.
GULICK: Thanks, Dr. Haverkos and Dr.
Smith. Just a brief announcement, Dr.
Handsfield mentioned that he would be willing to share his slides with people. He will post them on the FDA web site and he
is also available if you want to get his e-mail address.
At
this point we are going to go into a question and answer session. Although we just saw the questions reviewed
for the committee, I want to stress that we are going to focus on those during
the afternoon period. The period now for
questions and answers is really questions of content or clarification either
for the sponsor or for the agency and their presentation. Dr. Kumar is jumping right in.
Questions from the Committee
DR.
KUMAR: This is a question for the
sponsor. If I understood the prevalence
rate of herpes in African-Americans, it is about 47 percent, and if we just
take African-American women it is about 55 percent. But the study, if you look at the population
that was enrolled, only three percent were African-Americans. Could you comment on why that was and what
did you, as the sponsor, do to encourage more participation of
African-Americans?
DR.
COCCHETTO: Sure, happy to comment on
that. Let me ask Dr. Young to comment on
that question.
DR.
YOUNG: First of all, as noted in Dr.
Harding's presentation, this study was conducted multinationally so we actually
did have sites that were spread throughout the world. Now, we had selected investigators that were
in the U.S. as well as in Canada and actually did have access to diverse
populations. Although I would
acknowledge that we did enroll the percentages of African-American patients
that you had identified, we had no restrictions on enrollment in terms of
demographics. This is how the data
actually played out. Those are the data.
DR.
KUMAR: Dr. Young, about 860 patients
came from the U.S. sites.
DR.
YOUNG: That is correct.
DR.
KUMAR: If I understood the data.
DR.
YOUNG: That is correct.
DR.
KUMAR: Can I just follow-up?
DR.
GULICK: Yes.
DR.
KUMAR: In the FDA briefing document
there was some mention that some specimens were lost or contaminated. Would you comment on cultures from the
European countries, from West Europe and East Europe? Could you give us a sense of how much of
these specimens were lost or contaminated during transport here?
DR.
COCCHETTO: Sure. We did look carefully at that issue of
handling of specimens. Let me ask Stuart
Harding to comment on that, transport and our accountability for specimens.
DR.
HARDING: Of those cases reviewed by the
endpoints committee, 71 cases, there were six subjects in which there was a
sample, or sometimes more than one sample that was missing or contaminated, or
whatever. But when you consider that for
a suspected cases samples are taken for culture and PCR on days one, five and
ten and serology on day one and ten, and then there is continued follow-up with
serology, we don't think that that would impact the results.
For
your question about transport around the world and particularly from Europe, I
am not aware that there was any problem with that transport. According to Dr. Ashley Morrow the samples
typically arrived in very good condition and chilled. If you need more information I think she
would be pleased to give you some.
DR.
KUMAR: That is fine, I just wanted to
get a feeling for that. Can I ask one
last question?
DR.
GULICK: Sure.
DR.
KUMAR: Again, this is for the
sponsor. Could you comment, on
valacyclovir four patients developed herpes.
Could you give me some sense of their clinical presentation and how long
was the follow-up that you had on those four patients?
DR.
COCCHETTO: Let me just make sure I
understand. You are asking for some
clinical information on the four primary endpoints within the valacyclovir
group?
DR.
KUMAR: And how long they were followed.
DR.
COCCHETTO: And how long they were
followed. Again, I would ask Dr. Harding
to comment.
DR.
HARDING: I can't recall exactly but we
do have the case narratives for each of those four, if you want us to show
them.
DR.
GULICK: Yes.
DR.
HARDING: If we could have those? I can give you some summary details at least
for the demography, and stuff. There
were two male, two female, for example, ages 29-35, all from the U.S.
[Slide]
This
is one of them. I don't know if you want
me to read that or if you can read it from where you are.
DR.
GULICK: Why don't you guide us through
it?
DR.
HARDING: The randomized date was in
October, 1999 and the date of the end clinical endpoint was June, 2000. The subject reported dysuria approximately
four days before noticing a large erythematous papule on her external labia on
June 13, 2000. On exam, four additional
erythematous lesions were identified.
There were confirmatory labs; culture taken on June 15th was positive.
[Slide]
Again,
an American one, as we said.
Randomization May 6, '98 and in August, end of August, subject returned
to the clinic on September 2nd with a suspected genital herpes outbreak. Subject stated that prodromal symptoms
started on August 31st, with lesions appearing on September 2nd. The office visit included tender palpable
lymph nodes in the bilateral groin; fatigue, malaise and general rash. The confirmatory lab, culture and PCR on
September 2nd were negative but the serology became atypical on October 13th
and then converted fully to positive on December 2nd.
[Slide]
Another
one, randomization in June, '98; clinical endpoint December, '98. Subject returned to clinic on December 2nd
with complaints of sore throat, genital tenderness and genital lesion that
started on September 2nd. The
confirmatory labs were both culture and PCR.
[Slide]
The
last one was randomized April 21st. On
April 29th the subject presented at clinic on May 1st, complaining of dysuria
lasting two days. The labia was
erythematous with no discrete lesions and extensive cervicitis. Culture and PCR were positive. In addition, serology on May 20th was
positive. So, these are all fairly
typical primary cases.
DR.
KUMAR: Dr. Harding, I may not have asked
my question clearly. What I wanted to
know is not so much what the clinical presentation was but really what happened
to them. Did they respond to a
treatment? What were they treated with
and did they respond? I recognize that
you had not collected any resistance data.
So, I was just trying clinically to see what happened to these four
patients.
DR.
HARDING: Well, they were all given one
gram twice a day of valacyclovir for ten days.
But at that stage they were free to leave the study if we had the
confirmatory labs.
DR.
KUMAR: Can you give us a sense of
whether they responded to the treatment that was given to them?
DR.
HARDING: Can anyone help me as to
whether we recorded that? I am getting
shakes of the heads. This wasn't an
analysis that we collected.
DR.
GULICK: I guess what you are getting at
is, just because of the issue of resistance, it would be nice to know if they
responded to the therapy and healed the lesions.
DR.
KUMAR: Yes, that is all that I wanted to
know. Is there any sense of what
happened once they got treated, and how quickly did they respond, and any such
information.
DR.
HARDING: Dr. Young has reminded me that
all the isolates were susceptible but, of course, we didn't determine that
until later. But we are not aware of
transmission of resistant isolates in immunocompetent subjects anyway so I
don't think this was a consideration.
DR.
GULICK: So, the short story sounds like
we don't have clinical information available on that.
DR.
HARDING: We don't have that sort of
detail. Obviously, expecting very small
numbers it wouldn't have really helped us over and above all the details we
have on treatment of episodes.
DR.
YOUNG: Just one additional comment, it
is not unusual in our clinical studies on suppression to actually have
individuals who may develop recurrences on active therapy. Typically, when these individuals are actually
treated with what would be considered to be the standard doses they do resolve
their lesions. So, it is really not an
unusual circumstance.
DR.
KUMAR: But we are not sure, Dr. Young.
DR.
YOUNG: Not in this study. I am just making a general comment.
DR.
KUMAR: We do recognize that but I think
particularly for this group of patients that would have been important, with
four patients that got it, it would have added a sense of comfort to clinicians
like me.
DR.
GULICK: Dr. DeGruttola and then Dr.
Sherman.
DR.
DEGRUTTOLA: I have a couple of questions
about the withdrawals first, directed first to the FDA but then also to the
sponsor. As was correctly pointed out,
the analyses are sensitive to assumptions about withdrawals so my first
question is, is there any information about when these withdrawals took
place? Obviously, for those toward the
end of the study the assumptions have less impact on the analyses.
Also,
was there any effort to find out more about who withdrew, not just the reasons
for it but what the characteristics of people who withdrew were, and did those
characteristics predict outcome and differ by treatment arm? Because that would be the case, again--where
the characteristics predict outcome and differ by treatment arm--where the
non-informative censoring assumptions would break down and could have an impact
on the results.
So,
two questions to start. Distribution,
when they took place and who they were.
DR.
SMITH: As far as when they took place,
the applicant has, I believe, a Kaplan-Meier plot about the time to
discontinuation in their package.
Generally, it looked like--
DR.
GULICK: Could you give us the page
number on that?
DR.
SMITH: I can't give you the page number
right away.
DR.
GULICK: Anybody who has the page number
could give it to us.
DR.
COCCHETTO: Page 46.
DR.
GULICK: Thanks.
DR.
DEGRUTTOLA: So, it looks like it is
pretty even over time, except right at the beginning.
DR.
SMITH: Yes, so it looks like it is very
even in terms of time to withdrawal, similar to the proportions analysis. Patients who had unknown outcomes in terms of
the primary endpoint, they tended to withdraw earlier than other patients who
discontinued. We didn't really get into
that, you know, present, absent or unknown, as far as the primary endpoint was
concerned but those patients who were unknown were counted--it was
dichotomized; they were not counted as a separate category.
Basically,
in terms of the types of withdrawals and withdrawal characteristics, I am not
familiar with the withdrawal characteristics.
DR.
GULICK: Does the sponsor want to comment
on this?
DR.
COCCHETTO: Yes. Dr. DeGruttola, we share your curiosity about
the withdrawals, as well as Dr. Smith's, and we did look at those pretty
carefully. If you put up D7, just so
everyone can see the same graphic--
[Slide]
--that
is the Kaplan-Meier plot. Let me ask
Roger Liddle, who is the head of our statistics group for this trial, to make
some comments to address your question, Dr. DeGruttola, from looking at patient
characteristics as well as the time course of discontinuations.
DR.
LIDDLE: Thanks. My name is Roger Liddle. I am vice president of biostatistics and data
management for GlaxoSmithKline. Thanks
for the opportunity to just take a few minutes to cover a couple of
slides. Let me jump to D2.
[Slide]
We
have covered already overall. We see a
very similar discontinuation rate between the two treatment arms, with 22
percent on placebo and 21 percent on Valtrex.
In the bottom part of the slide you see that over the course of time
this is sort of similar, maybe just a quick summary to the slide you have
already seen but if you look at the three-month period, less than three months,
three to six or more than six, there was somewhat of a tendency to withdraw
earlier from the study, but between the two treatment groups the pattern was
very consistent. Let's go to D3, please.
[Slide]
I
think with respect to that, what is the impact and what are the various
analyses, and how dependent are they on the different analysis methods? The key sensitivity analyses that we
performed, one was time to event which certainly has some appeal because we get
to use the data right up until the time of discontinuation. With the as-treated analysis, we really
focused on those patients who completed the entire study. The imputation approach, which was also
referenced in the FDA presentation--here, what we have chosen to do rather than
say 100 percent or five percent or whatever else the discontinuations, here
what we did was we took the placebo rate for transmission and we applied that
rate to the discontinuations. So, if we
saw something between two and three percent on the placebo arm, that would
correspond to four or five additional events.
So, we added those four or five additional events to each treatment
group. So, we sort of imputed the
placebo transmission rate for each of the treatment arms.
In
all three of those cases, the intent-to-treat, the as-treated, the time to
event and that imputation, in all three cases the statistical test was robust
for those and we did see a significant, less than 0.05, p value in all three of
those cases. Let's go quickly, if we
can, to D9.
[Slide]
These
are the p values that I just referenced.
You see the primary analysis was the 0.011 which has been referenced a
couple of times this morning. Time to
event is the 0.008. Perhaps not
surprising, because we are using all the data it does give you a bit more
power. The as-treated analysis was
0.012. If you use that placebo rate, it
came out as somewhere between four and five events. So, we have shown the results both for four
and five events added to the two treatment groups.
In
a sense, this itself is being a little bit conservative because we have ignored
in this imputation approach the fact that we do have some data for those
patients. They did not get the
transmission and we have actually imputed the placebo rate as if it was the
entire eight months. If you actually
said, well, they were on average in the study for three months and used a sort
of time-dependent transmission rate it would be more like three events. So, again, it would still be
significant. So, in this sense it is
perfectly appropriate to look at a variety of the sensitivity analyses but in
this case they were all robust to that.
I
think the question about was there information in those discontinuations, I
have one additional slide I would like you to talk you through very briefly,
slide D27.
[Slide]
This
is actually fairly recent work. We,
obviously, were still trying to understand if there was information in these
discontinuations. What we have done is
we took a variety of baseline characteristics that are listed over on the
left-hand side of this, and we have looked at them to see if they were
predictive of discontinuation. There,
what you will see is that the first five were not predictive of discontinuation
and, therefore, would not likely drive some bias because of the discontinuations. So, we sort of didn't worry about those.
The
four at the bottom were of some concern but then, of course, the next question
is are they predictive of primary outcome?
If they are unrelated to the primary outcome, and the HSV-1 for the
susceptible partner was not predictive of the primary outcome, again we don't
see that as a concern.
That
still leaves us with three baseline characteristics that were potentially of
interest and could conceivably result in some bias in the results. For two of those, the country where we
analyzed it as U.S. versus noon-U.S., and the duration of relationship--as I
said, they were somewhat related to discontinuation and they were somewhat
predictive of the primary outcome, with U.S. being more likely to transmit and
shorter relationships being more likely to transmit but, in fact, there was not
evidence of a differential rate in the discontinuation. So, while that may have had some effect on
the overall transmission rate, it should not have a bias in favor or against
one treatment arm versus the other.
That
leaves us really with one variable which was potentially of interest and could
have had some bias. That was the
duration of the HSV-2 in the source partner.
But in this case it is interesting to note that because Valtrex was
associated--sorry, let me get this straight--this does imply a potential bias
against Valtrex and for placebo. The
reason for that is that HSV-2 infection is correlated with clinical acquisition. The duration of the HSV-2 infection is
correlated with clinical acquisition and is also correlated with a higher discontinuation
rate for the placebo arm. So, if in fact
that baseline characteristic, if there is information there, it means that
placebo patients were a bit more likely to drop out and were more likely to
have been transmitters. Therefore, at
least based on this analysis that we went through in some detail, we felt there
were no red flags or cause for concern based on a fairly comprehensive look at
baseline characteristics. Thank you for
your patience.
DR.
DEGRUTTOLA: Thank you very much, that
was very helpful and very useful. I have
a couple more questions. One is to the
agency, given the fact that, as Dr. Liddle just mentioned, at least in the
Kaplan-Meier analysis you can use the information up until the time the subject
discontinues, why were the primary analyses that you presented based on odds
ratios rather than the time to event analyses, and could you comment on the
appropriateness of the time to event analyses, given that in some cases--I
think in all cases there was a higher degree of statistical significance, not
greatly but it was greater?
DR.
SMITH: We found that the Kaplan-Meier
analysis was slightly more powerful but we didn't find a tremendous deal of
difference between the two approaches and since the primary analysis was done
on the proportions we just tried to look at the proportions that correspond to
the primary analysis. But we would
expect similar sensitivity for the Kaplan-Meier analysis if you counted
withdrawals randomly.
The
other problem with the Kaplan-Meier analysis is it depends on which withdrawals
from, say, the five percent you choose as failures.
DR.
GULICK: Can you speak up a little bit?
DR.
SMITH: Sorry. If you choose five percent of the
discontinuations and treat them as failures, then you have a little bit of a
problem where they are all going to have different failure times. So, it depends on which ones you randomly
choose.
DR.
DEGRUTTOLA: I agree, if you were going
to do sensitivity analyses you might want to make different kinds of
assumptions, or would have to make different kinds of assumptions. But it sounds as if in general you considered
the Kaplan-Meier analyses appropriate and informative even though all of them
have issues with withdrawals.
Dr.
Smith presented analyses showing that there was a significant geographic effect
on the risk of developing the endpoint.
But was there was there an analysis done of the impact of geographic
region on the treatment effect?
DR.
SMITH: Yes, we did analyses looking at
treatment by geographic region interactions.
In that case we didn't find any statistical significance so it was
mainly the main effect of geographic region regardless of which treatment they
were on.
DR.
DEGRUTTOLA: And one final question just
to clarify, for the primary analyses patients were followed after drug
discontinuation and included in analyses and then intent-to-treat ways. Is that correct?
DR.
SMITH: Patients were followed for eight
months, the duration of the double-blind study.
After that we didn't look at events after eight months because all the
patients were put on open-label treatment.
DR.
DEGRUTTOLA: But if there were treatment
discontinuations prior to eight months, were those patients no longer followed?
DR.
SMITH: They were no longer followed, to
my recollection, after they discontinued from the study.
DR.
DEGRUTTOLA: Could they
discontinue--maybe this is a question for the sponsor, could patients
discontinue treatment but continue to be followed in the study? Or, once they discontinued treatment was
follow-up discontinued?
DR.
HARDING: Obviously, the typical case was
when they discontinued they were not followed.
There was a small number of subjects who did remain with follow-up. In fact, we tried to get serology after
discontinuation where possible.
DR.
DEGRUTTOLA: And is that true for
partners as well, if they changed partners or treatments that they were no
longer followed?
DR.
HARDING: If the susceptible partner
changed partners, yes, there were some instances where they continued but,
according to the protocol, they should have discontinued because they are no
longer monogamous.
DR.
GULICK: Dr. Sherman and Dr. Fish.
DR.
SHERMAN: Thanks you. Two points of information just to help
clarify some things for myself, for the sponsor, can you explain why in your
design you limited the number of episodes permitted per year to nine or less?
DR.
COCCHETTO: Sure. The regimen of Valtrex evaluated in this
trial is currently approved for suppressive therapy for patients with nine or
fewer recurrences per year. So, in order
to be able to compare a single regimen of Valtrex versus placebo we focused on
that group of patients.
DR.
SHERMAN: Wouldn't you have had a
somewhat higher yield in patients that presumably shed higher levels of virus?
DR.
COCCHETTO: Let me ask Dr. Harding to
comment on the proportion of patients who have those particular histories of
recurrences.
DR.
HARDING: As I said in my presentation,
the vast majority, about eight percent of subjects, do have nine or fewer
recurrences so this was the predominant population. But we did have two other considerations as
to why we didn't choose people with ten or more recurrences. One was the fact that they would be more likely
to actually want treatment as opposed to have the possibility of placebo so it
was bordering on whether this was ethical.
The other is that if they had such frequent recurrences they may be more
easily able to discern whether they were on active or placebo and, therefore,
break the blind because it would be pretty obvious if they started taking
Valtrex.
DR.
SHERMAN: Okay. The second question relates to actually one
of the slides that Dr. Handsfield showed in his discussion of the sexual dead
zone after about age 40. If the rate of
transmission is about 2.5-3.0 percent per year in untreated patients, how come
we don't see in stable monogamous couples continued effect of infection on and
on and on because it is going to take many, many years, 30 years or more, at
that rate to continue to completely infect the stable partner population? This question is relevant to how long does
one ultimately continue treatment. Is
there a time period where pretty much the risk of transmission ends?
DR.
HANDSFIELD: I am not sure we know
definitive answers to those questions. I
have given you the clues that one might suspect that subclinical shedding
because symptomatic recurrences probably wane over long periods of time, after
several years, and it is a fair assumption that subclinical shedding may as
well. So, a longer duration relationship
may become less risky from that standpoint over time. That is hypothetical; it hasn't been
sufficiently studied.
There
has also been speculation, and Dr. Corey or others can answer this part better
than I can, about whether there might be some level of non-measurable immunity,
that is, not measured by current approaches to antibody levels or perhaps even
cell-mediated immunity, but, nevertheless, as has been analogous and suspected
for some HIV cases, low level exposures might, in fact, result in some level of
protection that is not detectable by those methods, which also might be
expected to have its effect in couples over time. So the exact physiologic explanation for the
epidemiologic observations I think is not something we have definitive answers
for, but that is my epidemiologist's response but perhaps others have comments
on it.
DR.
SHERMAN: But would it be fair to say,
and perhaps a representative of the sponsor can answer this, that at some point
it doesn't appear that suppressive treatment may, in fact, be indicated?
DR.
HANDSFIELD: I will comment, if I can
continue, and then I will sit down. I
think that begins to get to issues that are not yet on the table but clearly
will be, and that is, what are some of the extrapolations that can or should be
made from a public health standpoint?
The notion that viral shedding is the most common in the first months to
a year or two after acquisition, therefore, differential benefit might be seen
in people with shorter-term relationships and/or more recent acquisitions I
think is certainly the implication of what you are asking and I think that is
potentially a valid implication. That
doesn't, however, undermine the high value, regardless of the public health benefits,
in those individuals who have ongoing relationships who are looking for that
level of assurance or protection that they may want over a long period of time.
DR.
GULICK: Let me caution us not to get
into the discussion period just yet and let's stick to questions of
clarification at this time. We have
plenty of time to grapple with some of the questions a little bit later
on. Dr. Corey, do you want to add
something?
DR.
COREY: If I might comment, it is a great
question but, you know, you are asking about an area in any infectious disease
and especially for genital herpes and we actually don't know a lot of
information about the exact issues of transmission. As an anecdotal case, both in the Chiron
study and this study, we have had people who have had in monogamous
relationships for greater than eight years and ten years who actually
transmitted on study at that period of time.
So, for a long duration. Yet,
when you look at relative risk factors, certainly shortness of the relationship
increases the relative risk by, let's say, a factor of 2.5 to 3. And, duration of genital herpes, long
duration, decreases the risk factors.
Now,
how much of that is due to biological factors that relate to frequency of
subclinical shedding that decreases over time; how much of it relates to
behavioral factors that are associated with sexual practices that go with
duration of relationships, and how much is the other new factor which is
essentially innate resistance, just like in HIV
where there has been among high exposed seronegative men and women
T-cell immunity associated with no seroconversion? Chris Posavad, from our group, has recently
reported that now with some HSV seronegatives.
So,
on a population basis we have a complex interplay here that we actually can't
really play out in a definitive way from a counseling point of view,
unfortunately, at least in my opinion.
DR.
GULICK: Additional questions of
clarification? Dr. Fish and then Dr.
Englund.
DR.
FISH: I have three questions, if I
may. Understanding that the primary
endpoint related to genital HSV-2, and on slide 28 you mentioned it was
culture, PCR or serology that was utilized, I thought I heard the sponsor say
that there were no cases of HSV-1. Is
that correct?
DR.
COCCHETTO: That is correct.
DR.
FISH: And how is that known?
DR.
GULICK: Sorry, we need people to go to
the mike to answer.
DR.
HARDING: There were no primary
acquisitions of HSV-1 genital herpes in the susceptible partners. There were four asymptomatic seroconversions. Does that answer the question?
DR.
FISH: So, no clinical endpoints but four
seroconversions to HSV?
DR.
HARDING: Yes. The serodiscordancy for HSV-1 was only 13
percent where, of course, it was 100 percent for HSV-2. So, although nowadays a fair number of
primary acquisitions of genital herpes are HSV-1, I think because the gradient,
if you like, was much smaller in our study we didn't actually have one but we
did look for it.
DR.
GULICK: Can people hear in the back of
the room? All speakers, please speak
loudly and into the mikes.
DR.
FISH: The second question relates to the
counseling design. Was there a specific
script given to the investigators in terms of counseling about condom use, or
was this left to investigator discretion?
DR.
HARDING: There was no specific
script. They all had the American
Medical Association booklet, which was state-of-the art at that time,
1997. They were instructed in the
protocol and at investigator meetings to make sure that people could recognize
the signs and symptoms because that obviously is a big feature, and then the
abstinence and the condom use. The fact
that counseling was given was checked off in the CRF so at each visit they had
to verify that they had done that.
DR.
FISH: Thank you. Then a last question for the agency, there
were approximately 25 percent fewer primary endpoints than anticipated, 20/28
that they thought one might see in the 1500 who were entered. Can you comment in terms of how this might
affect, if at all, the robustness of the analysis?
DR.
SMITH: Well, given more endpoints, the
analysis, had there been the same difference between the two treatment groups,
would have been more robust to discontinuations because there were so many more
discontinuations than endpoints. That is
why we had a lot of trouble with the sensitivity because of the fact that the
discontinuations just swamped the treatment effect.
DR.
GULICK: Dr. Englund?
DR.
ENGLUND: I have some questions about the
seroconversions as the secondary endpoint, and specifically on slide A44 for
the sponsor, because in fact serology was an entry point for the study, I am
interested in these 36 seroconversions as a secondary endpoint. Did those include the patients that were
culture and/or PCR positive that were serology negative at the time, perhaps of
a timing issue? In other words, do the
seroconversions include all those that had symptomatic clinical disease
documented by other laboratory parameters?
DR.
HARDING: Perhaps if we have slide A44 it
would be helpful.
[Slide]
So,
you have your 36 seroconversions and, as you see, 15 were from the primary
endpoint. The culture or PCR came first
but seroconversion was detected later.
For the five that were determined to be endpoint based on culture or
PCR, three of them left the study there and then and there was no adequate
duration of follow-up for seroconversion but, obviously, we would have expected
them to convert given time. Then, there
were the three seropositives from the cases referred to the endpoints but
without culture or PCR positives.
So,
the overall acquisitions is probably the best endpoint to look at as a
secondary endpoint compared with the primary because that now includes the
cultures or PCRs taken at the time. It
wasn't that patients were always followed for long enough to ascertain seroconversion. Does that answer your question?
DR.
ENGLUND: Well, it does because one of
the questions when you are looking at the secondary endpoint is that you want
to make sure that you aren't missing any, and you are saying you probably
aren't but you don't have the data on several patients.
DR.
HARDING: That is why I included the
overall acquisitions because that includes not only the seroconversions but
those for which we have culture and PCR.
If you just look at seroconversions, you may have missed some who
withdrew from the study having had a positive culture.
DR.
ENGLUND: I have another question in
which perhaps you might be interested.
This is regarding resistance and I would just like to ask perhaps one of
our other experts here, but to my knowledge there has never been resistant HSV
transmitted from an immunocompetent person to another immunocompetent person,
whether it is HSV-1 or HSV-2. Is that
correct?
DR.
HARDING: That is my understanding.
DR.
GULICK: Dr. Mathews?
DR.
MATHEWS: I wanted to return briefly to
the issue that Dr. DeGruttola raised about whether there was a differential
dropout because there were a couple of other risk factors that I didn't see on
the slide that probably are relevant, and those are whether the dropout was differential
by condom use, either at baseline or on study, and also by the reported
frequency of intercourse. Do you have
any analyses that looked at those factors?
DR.
COCCHETTO: I am looking to my colleagues
to see if one of them can help us with that.
Roger?
DR.
LIDDLE: I may be able to answer but it
won't be totally satisfying. I think in
the analysis that I presented we were looking at baseline characteristics. We were trying to understand what differences
in the patient population when they walked in the door could drive some bias
induced both by the differential dropout rate and some effect on overall
acquisition. So, we were not looking at
variables that we were monitoring during the study, such as the condom use
during the study or the frequency of sexual activity during the study.
DR.
MATHEWS: Well, you probably have the
data, right? I mean, the effect size for
condom use in one of the analyses you presented was a relative risk reduction
of about 0.5 so it is not a trivial protective factor. So, I would suggest those be looked at by the
agency as well as the sponsor.
Secondly,
dealing with the point Dr. Sherman made about how long the period of risk might
last, you might have some data in this trial by looking at what happened to the
effect size for the treatment by antecedent duration of the partnership,
recognizing that there were not a lot of endpoints but if you even made one cut
point in the duration of the partnership was there modification of the
magnitude of the effect?
DR.
LIDDLE: We did look at the duration of
the relationship and there was some impact.
The shorter duration of relationship was associated with an increased
chance of discontinuation and was associated with an increased chance of our
primary outcome of transmission.
DR.
MATHEWS: So, if you were to estimate the
relative risk reduction for those who had, say, partnerships of two years or
greater versus less than two years, those kinds of analyses, was there evidence
of an effect size difference?
DR.
LIDDLE: We did not calculate relative
risk factors so I actually can't comment on how big a difference that was. There was somewhat of a relationship; I don't
think it was huge. Can anybody help me
with that?
DR.
COCCHETTO: Dr. Wald is pressing to
comment.
DR.
GULICK: Please state your name and your
affiliation.
DR.
WALD: Anna Wald, University of
Washington. Although short duration of
relationship was a risk factor for HSV-2 acquisition in this study, there was
no interaction between the valacyclovir effect and the short duration of
relationship.
DR.
LIDDLE: This is Roger Liddle again, if I
can just follow-up, I think the relative risk was a factor of about 2.5 so it
was a fairly significant change, duration of relationship related to
acquisition rate, the relative risk was a factor of 2.5.
DR.
MATHEWS: I would suspect you didn't have
a large power to detect an interaction given the number of events.
DR.
LIDDLE: I am sure that is true.
DR.
MATHEWS: One last question relates to
the condom use. Dr. Haverkos showed us
cross-sectional data on the frequency of reported condom use before starting
the study and on study. It might be
helpful to know cross tabulation. For
example, the people who were never using condoms before the study, what
proportion of them started using them?
The analyses you showed were just cross-sectional and didn't show a lot
of change, but was there mobility when you look within subjects across time?
DR.
SMITH: I think we looked at that and we
didn't see that much of a difference. I
can't remember if we have it on a backup slide but we could maybe look for
that, if we have it.
DR.
MATHEWS: This will come up later in the
discussion but if, in a setting like this where there was a conscious intent to
educate and encourage condom use, you really don't see any effect it raises
questions about, if the indication is granted, how effective any educational
programs along with it will be.
DR.
GULICK: Let's hold that thought for the
discussion but that is an important point.
DR.
COCCHETTO: Can I add something to that?
DR.
GULICK: Let's actually not add anything
at this point in the interest of time.
This is one of the questions we will be facing in the afternoon so let's
not.
DR.
COCCHETTO: Let me just say we have
looked at those data.
DR.
GULICK: Okay, thanks. Dr. Potter?
DR.
POTTER: Yes, actually I was concerned
about the fact that there were 4,000 people, there were attempts to recruit
4,000 with 1,500 actually included. It
was mentioned that for most of them it was because the partner was already
seropositive. But I wanted to know about
the rest of that group. You know, what
proportion was because they were already seropositive? What were the reasons for refusal? Because this would reflect the typical user
as opposed to the more perfect user that takes part in a study like this.
DR.
GULICK: So, the causes of screen
failures, the proportions?
DR.
POTTER: Yes.
DR.
HARDING: What I said was that the most
common reason was the lack of serodiscordancy.
In fact, overall it was about 30, 34 percent so it wasn't the majority. As the study went on and recruitment got more
difficult, more advertising was done and people came forward, thinking that
they might want to participate in the study or they might just want a free
serology test. So, there was about
another 20 percent and the source partner was not confirmed to have HSV-2 by
serology. That has not accounted for
about 54 percent of the subjects. I
think there was another big chunk, probably about 30 percent, who, when they
found out what was required of this study with all this personal, intrusive
stuff and the duration of the study, they refused to participate. In fact, there were three sorts of major
reasons, not just lack of discordance.
DR.
POTTER: My real question was about that
last group. If they were the people who
would have had more trouble complying with the regimen, you wouldn't have data
on that I guess. And, the same thing happens
later--I am not sure of the direct link here but track of compliance with the
Valtrex itself during the course of the study.
In other words, if people refused to participate, was there a proportion
that refused because they thought they couldn't follow the regimen that
carefully and then, during the study was there track of compliance to see how
forgiving the method is? Does that make
any sense?
DR.
GULICK: Dr. Cocchetto?
DR.
COCCHETTO: I think so. You can help me further. On the first part of your question, at the
point of screening where couples were considering the trial they considered the
entirety of the trial. So, they would
include consideration of their ability to adhere over an eight-month,
double-blind period to study medication, as well as the need for monthly
follow-up visits, laboratory specimens and so on. We don't have specific data on which component
of that drove their decision-making.
Anecdotally, as Dr. Harding has said, the personal intrusiveness seems
to be the dominant factor pre-study.
During the study we did use a straightforward table count methodology to
track medication compliance and we could share that with you perhaps this
afternoon.
DR.
POTTER: Thank you.
DR.
GULICK: Yes, Dr. Guinan?
DR.
GUINAN: Thank you. I would like to see gender stratification
breakdown on the substudy on viral shedding and the results. Thank you.
DR.
GULICK: Was that clear?
DR.
HARDING: We have not done that analysis
as yet.
DR.
GULICK: Other members of the committee
who haven't had a chance to ask questions who would like to? Dr. Fletcher?
DR.
FLETCHER: I have two that I think are
quick. First, the say, at least in the
sponsor's briefing booklet, that amendment IV is presented, it says the sample
size was revised in order to observe 28 confirmed endpoints. As I read it, and I think this kind of follows
Dr. Fisher's comment, I was expecting to see 28 endpoints and there are
not. So, was there agreement between the
sponsor and the agency that there did not have to be 28 endpoints?
DR.
HARDING: Yes, the protocol started off
with 1,500 but actually, strictly speaking statistically, it is the endpoints
that matter and, therefore, I think the protocol was amended to reflect that
degree of finesse. What happened in
practice was we were having considerable difficulty enrolling subjects, as you
have heard, and then in May of 2001 we had achieved 23 possible endpoints
because, obviously, there was ongoing review as faxes came in, information and
so on. So, giving the sites sort of six
weeks to complete their period between screening and enrollment, and then
another eight months for subjects we reckoned we would probably achieve over
that sort of ten-month period another five endpoints because that was our
estimated rate, and it turned out that we had about 1,500 couples; we
anticipated 28 endpoints but we didn't achieve them.
DR.
FLETCHER: Then my second question, again
just to make sure I am clear, what the sponsor is requesting on the dosing is
no statement regarding duration so 500 mg once daily but nothing on the
duration of therapy. Is that correct?
DR.
COCCHETTO: In our proposed labeling for
duration it is quite explicit about the nature of the 3009 study in stating
that the study was conducted for an eight-month, double-blind period. We have also proposed a statement elsewhere
in the labeling to be clear that efficacy beyond that eight-month duration has
not been demonstrated.
DR.
GULICK: Are there other members of the
committee who haven't had a chance to ask questions--I will come back to you,
Dr. Guinan--who would like to ask questions?
[No
response]
I
have a few and then I will come back to you.
One of my questions concerns the endpoint committee. I am trying to get a feeling for actually how
the cases were evaluated in terms of what was available to the endpoint
committee--history, pictures, what kinds of things were looked at?
DR.
COCCHETTO: We are fortunate to have Dr.
Corey here who chaired the endpoint committee.
I will ask Dr. Corey to comment.
DR.
GULICK: Great!
DR.
COREY: As Dr. Harding said, there was
both real-time monitoring and then a formal evaluation at the end of the
endpoint committee. The charts were all
reviewed for any clinical signs and symptoms of genital herpes. All the laboratory data from the cultures and
PCRs were made available and a serial line listing on each individual case was
given on the serologies. So, the
endpoint committee did all these evaluations in a blinded fashion. The definitions, of course, were agreed upon
prior to the onset of the study. We
actually reviewed the definitions before our formal endpoint meeting and agreed
there would be laboratory confirmation that would be critical, essentially
necessary to require a case, and the focus was were the signs and symptoms
compatible with genital herpes from the narrative as it relates to the finding? Was it conceivable that these signs and
symptoms were related to the laboratory confirmation of the test?
Of
all the endpoints, actually there was really 100 percent unanimity on the
endpoint committee on all except one endpoint, which we ended up classifying as
an asymptomatic acquisition in a case that clearly had HSV-2 seroconversion,
had some very vague symptoms and signs that were related to the general area
that were prolonged itching that the majority of the members felt could not be
associated convincingly enough at the time of the signs and symptoms with the
seroconversion to be called a clinical endpoint. It certainly was a total overall
acquisition. That was the only endpoint
that had any dispute or difference among the six members of the endpoint
committee.
DR.
GULICK: Just so I understand, the
investigator would do a clinical evaluation; write up a history of what went
on; serologic testing would be done; and then the endpoint committee would
receive--
DR.
COREY: That, as well as the fact that
there was 100 percent monitoring by the sponsor on those narratives. So, the narratives were really confirmed not
only by the investigator but by the monitoring.
They were written up and the narratives were made available with all the
laboratory testing, as well as what the clinician diagnosed and whether
medication was dispensed for an incident case.
DR.
GULICK: As I understand, of the 51
endpoints that were rejected, in all but three it was because the serologic
test was negative?
DR.
COREY: Correct.
DR.
GULICK: We heard about the other three
and why they were different.
DR.
COREY: Correct.
DR.
GULICK: Thanks. My next question is about resistance. Did I understand correctly that ten viral
isolates were available to be tested for resistance? Yes.
DR.
GULICK: So, it was from the source
patient obviously, and that is pretty much the extent of the resistance
information that is available?
DR.
COCCHETTO: Well, let's clarify that
further. Dr. Harding, do you want to
comment on those ten specifically?
DR.
HARDING: There were ten cultures from
the susceptible--
DR.
GULICK: Susceptible?
DR.
HARDING: And one from Canada which is
currently being tested for resistance.
DR.
GULICK: And no evidence of resistance in
any of those cases?
DR.
HARDING: Not at all.
DR.
GULICK: Then, one question for the
agency. Reading through the background
material, apparently the agency initially suggested that two studies would be
preferred. What we have seen here is one
large study. I wonder if you could
comment on the discrepancy between those two recommendations.
DR.
BIRNKRANT: I believe the original
recommendation for more than one study was to be able to capture a more diverse
patient population, and it was left to the applicant to decide whether to do
one or two trials.
DR.
GULICK: Thanks. Dr. Guinan, I am going to go back to
you. I bet I got your question, didn't
I? Anyone else who hasn't had a chance
to ask a question? Dr. Stanley, I have
forgotten you.
DR.
STANLEY: No, you all have clarified all
the questions I had.
DR.
GULICK: Super! We will have additional time for questions in
the afternoon. At this point I would
like to go to the open public hearing part of the agenda. We have four people who have signed up
previously to speak at the open public hearing, actually five. The first one is Dr. James Allen who is from
the American Social Health Association.
Open Public Hearing
DR.
ALLEN: Thank you, Mr. Chairman. I am James Allen, President and CEO for the
American Social Health Association, also known as ASHA. We appreciate the opportunity to comment on
approval of valacyclovir suppressive therapy to reduce the risk of transmission
of genital herpes. ASHA is a nonprofit
organization that has focused on education and prevention of sexually
transmitted diseases since 1914.
We
have operated a National Herpes Resource Center for the last 24 years. Through this center and our associated
services, such as the National Herpes Hotline, the National STD Hotline,
Internet-based services, local support groups and involvement with an
international patient advocacy movement, we interact with tens of thousands of
people affected by herpes every year.
Because of this background and the work that we do, ASHA would like to
address the issue of preventive antiviral therapy to reduce the risk of
transmission of genital herpes from a patient advocacy perspective.
Our
comments today reflect our strong history of patient advocacy and the
information and concerns we have gleaned from contact with people living with
herpes. ASHA fully supports approval of
the GlaxoSmithKline application for valacyclovir suppressive therapy in
reducing the risk of transmission of genital herpes.
As
a prelude to this statement, ASHA discloses that we have received charitable
grants from GlaxoSmithKline, as well as from other pharmaceutical companies, to
support our herpes educational activities and resources. These monies have been provided for specific
activities to be conducted by ASHA such as operation of the Hotline or Resource
Center or convening of a scientific meeting, but we have not used these funds
for promotion, either directly or indirectly, of products or services related
to the pharmaceutical companies providing this support. The message and information provided by ASHA
are determined by an independent scientific and medical review and are not
related in any way to funding from specific manufacturers.
One
of the most prominent concerns expressed repeatedly to ASHA by people with
genital herpes and their uninfected partners is the risk of transmission. Quite apart from the physical aspects of
recurring signs and symptoms, genital herpes can create continuing anxiety and
psychological distress. From a patient
perspective, it is extremely difficult to adjust to the uncertainty of this
infection--the fact that one might be infectious to others even at times when
no signs or symptoms are present.
Affected people and their partners want to know what they can do, what
preventive steps they can take. Unfortunately,
the options for reducing risk have been limited. An effective vaccine for the herpes simplex
virus does not exist and prevention alternatives for this chronic, lifelong
infection are not perfect or reliable.
ASHA
encourages infected persons and their partners to consider any and all of the
options available. We advice infected
people to disclose this information to their partner, to have open
communication and discussions, and to abstain from sexual contact if symptoms
or signs of infection are present. Each
of these has an important place in the prevention message. ASHA promotes consistent and proper condom
use as well, with the important caveats that condoms should not be relied upon
during symptomatic periods and that condoms are never 100 percent effective.
Clearly,
however, more choices are needed. People
with genital herpes have long wanted to know whether antiviral medications
would be helpful in reducing risk of transplantation, and for years we have
informed them we have no data. The
results of the herpes suppression transplantation study, which you have heard
today and that was presented by Dr. Lawrence Corey of the University of
Washington at the Interscience Conference on Antimicrobial Agents and
Chemotherapy in September, 2002, however, provide convincing evidence that
suppressive therapy is effective at reducing both the frequency of clinical
recurrences and the risk of transmission of infection to an uninfected
partner. This information significantly
substantiates the claim that reducing the risk of herpes transmission should be
a labeled indication for valacyclovir.
Such a step will give physicians and people with genital herpes another
option to consider as a risk reduction method.
In
conclusion, ASHA believes that people with genital herpes and their partners
should have more information about risk reduction options, beginning with the
counseling they receive from their healthcare providers, and they need more
choices to consider when faced with the need to reduce to a minimum any risk of
transplantation of herpes infection to a partner. Given the information currently available,
ASHA urges the Food and Drug Administration to approve the GlaxoSmithKline
application for valacyclovir as suppressive therapy to reduce the risk of
transplantation of genital herpes. Thank
you.
DR.
GULICK: Thank you very much. Next is Mr. Gray Davis who is Director of the
HIV Prevention Trials Network. Oh, I am
sorry, that is clearly a grave error, Ms. Gray Davis, Dr. Gray Davis. Thank you.
DR.
DAVIS: You will get it right soon!
DR.
GULICK: Thank you.
DR.
DAVIS: I guess we have established that
my name is Gray Davis and I am the Director of HIV Prevention Trials for Family
Health International. I am here today
not as a representative of any organization but as a private citizen with a
background in the field.
GlaxoSmithKline
did not ask me to come, nor are they supporting my attendance in any way, nor
were they informed that I would be here.
In the past I worked for Burroughs Welcome Company and then for Glaxo
Welcome as the international project leader for acyclovir, which is the parent
compound to valacyclovir.
I
am here to talk about the importance of prevention. Managing an epidemic requires more than just
having an effective treatment for outbreaks.
It requires prevention interventions, diagnostic tools and counseling
techniques. Given that at least 11
million people got infected with HSV-2 between 1980 and 1990, and since little
has changed in the way we manage this disease, we are likely to see another 15
million people infected between 1990 and 2000.
This is of particular concern since, as with other STDs, women are more
severely affected and bear the burden of some of the more devastating outcomes
of genital herpes.
Today
we have an opportunity to have a major impact on the transmission of this
infection. By approving Valtrex for
prevention of transmission you will give clinicians one of the much needed
tools to combat this disease. Provision
of an effective prevention strategy will empower people, especially women, to
make decisions and take control of their lives.
Women can encourage their partners to wear condoms but they can't always
enforce that. This will be an
intervention with equal opportunity for everyone.
The
availability of Valtrex will substantially enhance the provider options on how
to control this disease. The very act of
writing a prescription will provide a window of opportunity for counseling. Patients can be encouraged to talk to their
partners, to use condoms, to avoid sex during an outbreak, and to take daily
therapy. Each of these strategies are
complementary and provide additional tools in the toolbox for prevention. None should be considered exclusive of the
others.
Why
has genital herpes gotten so out of control?
Perhaps because it is an STD we are uncomfortable talking about it. Both clinicians and patients may be reluctant
to bring up the subject because society has labeled people with STDs as somehow
dirty, or stupid, or deserving of what they got. Why would you want to talk about something
like that?
Clinicians
have said that the reason they didn't want to bring up the subject of herpes
was because they knew the patient would get upset about it; they didn't know
what to tell the patient; and they weren't confident of the test. After all, 50 percent of the time cultures
are falsely negative. Once diagnosed,
there wasn't much they could do for the patient anyway. So, rather than bring up the subject, they
elected not to talk about it. Why tell
the patient that they have a disease they don't know they have? However, how can you control an epidemic if
80-90 percent of the people who are infected don't know that they are infected?
Today
we have many of the needed interventions to reduce the spread of this
infection. Reliable, accurate diagnostic
tests that can identify infected individuals are now available. Clinicians can accurately diagnose patients
in their office using a diagnostic test as well as by drawing blood to send to
a central lab for both diagnosis of HSV-1 or HSV-2. Thus, accurate diagnostic tests are now
available to everyone.
We
also know what to say once a patient is diagnosed. Hotlines, written materials and web sites are
available to both clinicians and patients to help them understand the disease
and to provide accurate, non-judgmental information. As you heard earlier from Dr. Allen, the
American Social Health Association has a hotline available five days a week
from 9:00 a.m. to 7:00 p.m. This hotline
is free of charge and is an excellent resource for both clinicians and for
people with herpes. Clinicians can now
refer their patients who need more lengthy consultation to a reliable source
for information, and patients have a place to call for anonymous accurate
information. The counselors at ASHA will
spend as much time as needed to provide the best support for the caller. Written materials provided by ASHA and other
organizations are also available.
Lastly,
information is available on the web for anyone who wants to know more about
this disease. The American Herpes
Foundation and the American Medical Association have information and CME
courses for clinicians. Another site,
herpesdiagnosis.com, provides information for both clinicians and patients on
how to diagnose and manage this disease.
It also provides check lists for the clinicians regarding what to tell
the patient, and for the patient regarding what questions to ask the clinician.
So,
now we can accurately diagnose this infection and we can accurately provide
counseling to the patient. The next step
is to provide a therapeutic intervention.
The availability of Valtrex for reduction in transmission enhances our
armamentarium for the control of this disease.
As stated earlier, it is just another tool in the clinician's
toolbox. We can now accurately identify
those infected. We can educate about the
natural history of the disease. We can
teach patients to recognize recurrences.
We can help them find ways to talk to their partners. We can instruct them to wear condoms, and we
can offer an easy daily therapy to reduce transmission.
Whenever
the FDA is asked to approve a drug they have to weigh the benefits of therapy
against the potential toxicities. Rarely
is there a case in which the benefits of therapy so far outweigh the potential
risks. Valtrex has an impressive safety
profile which makes your decision today much easier. You can concentrate on whether or not the
benefits of this medication warrant its approval.
Some
decision-makers seem to think that herpes is a benign infection with no severe
sequelae. However, as with much of the
history of herpes infections, the more we know about this disease the more we
are surprised to find out how our beliefs are wrong. Neonatal herpes affects one in 3,000 births
in the United States. That is about four
babies a day. The best way to prevent
neonatal herpes is by preventing the mother from becoming infected in the first
place.
As
Dr. Handsfield presented earlier this morning, there is also the link with both
transmission and acquisition of HIV. If
we have learned anything from our African friends, it should be the lessons
learned from herpes. In countries most
severely affected by HIV, the herpes epidemic predated the emergence of
HIV. In each of the countries in which
we know the seroprevalence of herpes infections, the higher the seroprevalence
of HSV, the higher the seroprevalence of HIV.
Needless to say, we need to do everything within our means to prevent
these infections.
Finally,
the investigators, the company and, most importantly, the patient should be
commended for undertaking this trial. I
am currently trying to do similar prevention trials for HIV. It is extremely difficult to get patients to
participate in transmission studies.
Identifying discordant couples and getting them to agree to participate
in a placebo-controlled trial is a challenge.
People are uncomfortable acknowledging that their relationship has
placed them at risk of acquiring a sexually transmitted disease. Many people, while being aware of the risk on
a certain level, have a hard time acknowledging it by actually participating in
a trial. Other patients, when hearing
the rationale for the study, decide to just start taking the medication. Why risk getting randomized to a
placebo? All these challenges were met
and overcome by perseverance, innovative recruitment strategies and dedicated
participants. They should be commended
for conducting such a challenging study.
So,
today you have the opportunity to do something to empower patients and
clinicians to help control this epidemic.
You have the ability to empower people, especially women, to take
control of their sexual health, and you have the ability to approve a medication
that is both safe and effective for the prevention of transmission of herpes
infections. All the decisions in your
life should be this clear!
DR.
GULICK: Thank you, Dr. Davis. Nest is Dr. Hunter Handsfield from the
University of Washington.
DR.
HANDSFIELD: Thank you. I put my name in as a place holder in case
there were issues that came up that I thought were particularly important that
didn't arise, and that hasn't happened.
In
the interest of disclosure, I will say that as a public health official
responsible for a large HSV control program, I support the application on both
clinical and public health grounds, and I think it is also fair to point out
that Dr. Haverkos and others at the agency were aware of that support when they
invited me to speak this morning. Thank
you.
DR.
GULICK: Thank you, Dr. Handsfield. The fourth person to sign up is Mark
Wasserman, who is the co-leader of HELP of Washington. He is unable to be here today but has a
written statement that was made available to members of the committee and it is
at the registration table as well. It is
not very long, perhaps I will just read through it briefly:
Subject: Submission for FDA hearing on Valtrex
supplemental new drug application. This
letter for consideration by the FDA advisory committee is to support the GSK
application for Valtrex suppressive therapy to reduce the risk of transmission
of genital herpes.
For
the past 20 years, I have been a member and leader of the Washington area
herpes support group, HELP of Washington.
In that capacity, I have heard the personal stories of thousands of
people with herpes who have participated in our meetings.
It
may be difficult for someone without herpes to grasp the shock, anger,
depression, fear and loneliness that a person with the virus may well
experience. One of the most often stated
sources of this emotional anguish is the fear of spreading the disease to a
sexual partner during the most intimate act of human nature. Even after people with herpes have overcome
the initial emotional distress that accompanies a diagnosis of herpes, many
continue to have difficulty carrying on a normal social life because of this
fear of transmission.
Fortunately,
the new research showing that daily use of Valtrex significantly reduces the
risk of transmission has given hope and encouragement to our members. For many, this information has helped them
better deal with emotional problems of living, dating, telling and loving with
herpes. For many uninfected partners of
our members, the new has meant that they too can more easily accept having
intimate relations with someone with herpes.
It
is important that the results of this research reach a much wider audience of
people with herpes and their medical practitioners. FDA approval of the supplemental new drug
application would help achieve that goal.
Finally,
from a public health medical perspective, it is important to curtail the spread
of herpes. The new research shows that
Valtrex helps achieve that goal. Both in
the interest of reducing the spread of this disease and reducing the
debilitating emotional distress that often accompanies the disease, HELP of
Washington strongly urges the cm to approve the supplemental new drug
application for Valtrex. It is signed
Mark Wasserman.
Our
last person to sign up to speak at the open public hearing is Curtis Phinney,
also from HELP of Washington. I hope
that you weren't planning to read the letter that I just read.
MR.
PHINNEY: No, Mark had the easy
part. My name is Curtis Phinney and I am
a consumer advocate for people with viral STIs other than AIDS and HIV, loosely
under the auspices of HELP of Washington, DC.
I
am currently speaking on an ad hoc basis at the Johns Hopkins University,
Bloomberg School of Public Health in a nursing preceptorship program there,
administered under the auspices of Keith Aimmerman and Dr. Ann Rampalo.
When
I speak to people outside of the consumer group I always like to say that I
have five things that are important about genital herpes. That is, genital herpes is chronic,
contagious, preventable, treatable, and I think perhaps most importantly very
serious. I think that there are two
things that are relevant to the committee here this afternoon that may not be
intuitive to people outside of the consumer population, and one of those has
been touched on already, and that is one of the primary concerns of newly
diagnosed consumers, people who join the club, if you will, is the risk of
transmission to an uninfected partner.
This causes a tremendous amount of psychosocial morbidity associated
with the condition, not only the possibility of infecting a current partner,
but also adding to the complexity of attracting and retaining new partners.
The
other thing that I think has been touched on earlier is that there has been
very little available, other than counseling, in terms of direct chemotherapy
intervention for people with herpes that will aid in the dynamics of
disclosure. People are not open and
honest about having this condition. I
came to the realization a decade ago that dishonesty and denial were important
factors in the transmission of this condition.
That is one of the reasons that I chose to break my anonymity with
regard to my serostatus. It is my
opinion that being able to offer people with this condition a tool that will
prevent or reduce the possibility of transmission to an uninfected partner
could have a profound positive influence on the dynamics of disclosure and help
not only to dispel the stigma but to also give people a toe-hold in initiating
an extremely difficult conversation, laying themselves vulnerable to somebody
that they are nervous in the presence of anyway, and being able to say that
this treatment will reduce the possibility of getting involved with me having a
negative influence on your health.
Finally,
I would just like to close, I have a short paper out in the lobby on the impact
of prophylactic treatments for people with HSV and HPV, and also contact
information is included in that package as well. That is really all I have this
afternoon. Thanks very much.
DR.
GULICK: Thank you. That concludes the people that signed up to
speak at the open public hearing. Is
there anyone else who did not sign up who would like to make a statement at
this time?
[No
response]
Then
we will close the open public part of this meeting, which brings us to
lunch. It is 12:20. We will reconvene at 1:15.
[Whereupon,
at 12:20 p.m., the proceedings were recessed for lunch to reconvene at 1:15
p.m.]
- - -
A F T E R N O O N P R O C E
E D I N G S
DR.
GULICK: We will reconvene. Welcome back from lunch. Just a reminder both for the committee and
people observing, there are the surveys about conflict of interest, if you
could complete them and either mail them back in, or there is a box at the
registration desk, that would be appreciated.
We
left one unanswered question at the end of lunch, which was posed by Dr. Potter
about the compliance on the study. So,
if we could take a look at those data.
DR.
COCCHETTO: Sure. Dr. Potter, I asked Dr. Roger Liddle to look
at that and we want to focus initially on the information that we have on
source partner compliance among the primary endpoints and also the overall
acquisitions.
DR.
LIDDLE: Could you bring up slide E23?
[Slide]
This
just shows us the compliance rates for the primary endpoints, for the primary
infection transmissions. Obviously, more
interest is on the Valtrex side. Three
of the four transmissions on active treatment were in the greater than or equal
to 95 percent compliance. There was one
that was lower but it was in the 80, 85 percent range. The other slide that might be of interest
would be E37.
[Slide]
If
you are looking at overall acquisition, the same sort of information for all
acquisitions, again, there was one patient where I think we actually had some
missing data. If the treatment stop date
is missing, then we sort of don't have the denominator to calculate the
compliance figure. So, I think the one
that shows up there is less than 80, a case where we had missing treatment stop
date, but overall the compliance was pretty good among the endpoints so there
is no strong signal there.
DR.
POTTER: What about overall?
DR.
LIDDLE: Overall? Let's pull up S5.
[Slide]
It
is a little harder to look at this slide but I think here, if you look under
placebo down to greater than or equal to 80 percent compliance, you will see 91
percent. The same figure for Valtrex is
93 percent. The only thing sort of
disturbing I guess about this slide is there are 40, 41 patients listed under
zero with the asterisk. What happened
here is there were patients for whom we had no stop date and, therefore, it is
really missing so that zero really includes these patients for whom we didn't
have a good compliance figure because we didn't know on what date the treatment
was stopped.
DR.
GULICK: This information is based on
pill counts? Is that correct?
DR.
LIDDLE: Yes, that is correct.
DR.
GULICK: Great, thank you. We will turn now to Dr. Birnkrant for the
charge to the committee.
Charge to the Committee/Questions for
Discussion
DR.
BIRNKRANT: Well, this afternoon we are
looking for a discussion by the committee on the interpretation of the results
presented this morning. We are
particularly interested in the relevance of the endpoint and the impact of the
dropout rate on the trial results.
In
addition, we are very interested in the applicability of the data to other
populations. We are looking for comments
with regard to screening as well.
Lastly,
we are looking for the committee's interpretation of the data and the impact on
public health with regard to condom use and abstinence during outbreaks. So, I
think we can turn to the first question at this point.
DR.
GULICK: So, the first question for the
committee to consider is does the information presented by the applicant
support the use of valacyclovir to reduce the risk of transmission of genital
herpes among monogamous heterosexual couples?
Let's have some discussion about the information that we saw today in
terms of safety and efficacy, and some other issues that people might want to
raise. We will start with Dr. Pazin.
DR.
PAZIN: I am very impressed by the data
that was presented this morning and that we had previously been given. I think it is a very, very well done study. There are a couple of comments I would like
to make. For instance, Dr. Smith sort of
alluded strongly to the people that are dropouts and I think for anyone who has
ever done one of these studies with genital herpes a 20 percent dropout from
1,400 couples is actually a pretty small dropout. I am not troubled by that at all.
I
am a little bothered by the data about Australia and Canada. It was so swayed towards the efficacy of
valacyclovir that you can't help but wonder what if that group had not been
included, would the numbers still be statistically significant? They wouldn't be as significant as they are,
clearly.
The
second comment I want to make is that I have always been impressed by the
scientific validity of many of these studies sponsored by industry basically,
and I think this is another good example.
It is a very, very well done study and I think perhaps the collaboration
with the FDA helped that along. I am not
as equally impressed by the marketing people from companies and I think I would
caution them that everything I got said that it reduces transmission and I
think that that is pretty well borne out.
I think they like to use the words prevents transmission and I think
that is a term that often conveys 100 percent or effective in preventing
transmission. When you say effective, it
sounds like it is 100 percent. I would
say that the committee ought to caution the company to say that it is partially
effective or partially preventive or, as they have said in the materials we
have gotten, that it reduces transmission.
The
third comment I would like to comment on is something I just found out
yesterday. I happen to stop by our
pharmacy and I inquired as to the cost of acyclovir and the cost of
valacyclovir. It turns out, in our
hospital, acyclovir 200 mg is five cents; 800 mg is 20 cents. That is the daily cost. But 450 mg of valacyclovir is $17.25, 86
times as much. I think the optimism that
I heard about the utility of this, if you really get down to it, an ordinary
poor person is not going to be able to afford this drug and I think that we
should somehow--if they are going to have this indication, we should somehow
try to suggest that perhaps the cost is a consideration. I deal with patients. Formerly I was primarily a research doctor
but now I deal with patients and cost is a very, very important thing. So, I just wanted to make those comments
regarding the studies.
DR.
GULICK: Thanks. Other comments? Dr. Sherman?
DR.
SHERMAN: I am curious if the sponsor has
any sort of cost-benefit analysis information.
During lunch I was kind of jotting down numbers and calculations on the
back of a piece of paper, looking at the number needed to treat for
effect. Obviously, with a transmission
rate that is in the two to three percent range, reduced to a half percent
range, you have to treat for extended periods of time many patients to get that
benefit. You know, I freely admit that
there is a large number of patients infected but when I looked also at the
numbers related to cost of the product as listed, current retail cost, you
know, again just back of pad calculations came out to some place between
$110,000 and $120,000 per case prevented, which goes beyond the typical
accepted numbers that people use in prevention programs--in evaluation of
vaccines, in other interventional procedures.
So,
I am not questioning the data related to the efficacy of the treatment. I think that the sponsor did a great study on
a difficult population and has presented and satisfied my concerns about
efficacy and safety. But I think that at
some place in this equation has to be the answer to the question that I am
posing.
DR.
GULICK: Would the sponsor like to
respond? Is there any cost-benefit
analysis data?
DR.
COCCHETTO: A couple of comments. Part of the response lies in the patient
population that was selected for the trial, as I am sure you recognize. We selected a patient population who were
candidates for suppressive therapy. Let
me ask Dr. Young to comment further from a cost-benefit perspective and your
comments on numbers needed to treat.
DR.
YOUNG: Just to pick up on Dr.
Cocchetto's comment, I mean, the way that we have actually approached this is
to think of it in terms of an incremental benefit for prevention of
transmission, in addition to the benefit that is already afforded to the person
who is actually receiving suppressive therapy.
So, when we think about the number needed to treat in that circumstance,
it is probably on the order of one or less than one. Certainly what you do see is a reduction in
the frequency of recurrences, again, among those individuals who would be
receiving suppressive therapy.
We
have thought about the number needed to treat in order to prevent a
transmission event, and what we have come up with is an annualized event rate
of about 40 in terms of the number needed to treat but, again, the way we have
thought about this really has to do with thinking about what the incremental
benefit is for someone who is already benefiting from suppressive therapy.
DR.
GULICK: Dr. Englund?
DR.
ENGLUND: Well, I would just like to make
a comment related to that, particularly from the pediatric viewpoint, and that
is that one case of neonatal herpes--there are different estimates as to cost
and I am not the expert on this, but a cost estimate of $500,000 to a million
per case survivor is certainly typical, and that is because the children
survive. Fifty percent have prolonged,
permanent neurologic sequelae. There is
no institutionalization currently available.
They are requiring special ed.
The state is required to send them to school, which costs a lot of
money, even though many of them have very limited potential for learning. So, the cost for the children would be really
high and if any cost-benefit analysis were to be made, I would strongly urge
that the consideration of the children be considered. Particularly in this small study for a small
period of time, it appeared to me there were 18 pregnancies during an
eight-month study period. That is a lot
of potential babies. So, the potential
benefit to prevention of transmission to women of childbearing age really needs
to be considered when anyone is considering doing this. I believe the cost and other things need to
be considered, but I don't want to forget the children out of this analysis,
which is certainly not the primary endpoint of the study but will be a
consideration for people in my clinic and other clinics when there are couples
that want to have children.
DR.
GULICK: Other general comments and then
I am going to try to focus us a little bit? Dr. Fish?
DR.
FISH: I think adding to that the
information that we learned this morning in terms of the potential increased
greater transmission of HIV, if one HIV case is not transmitted there would
also be a huge impact there.
DR.
GULICK: Dr. Guinan?
DR.
GUINAN: I would just like to add that
for HIV patients with herpes simplex infection this is an important
consideration because probably their recurrences are much greater and their
asymptomatic shedding is probably more frequent, although there is limited
data. The possibility that an
HIV-positive person will transmit HSV to a partner who may be negative, you
know, discordant partners for both, and I have seen this in heterosexual
couples with a much younger female partner and the worry is about transmission
of HSV and HIV. I think this
subpopulation, although may be small--it is very important because if the
partner gets HSV infection then they are at higher risk for getting HIV
infection. You see? So, the primary prevention of HSV acquisition
in this discordant relationship is very important. So, there are subpopulations where the cost
effectiveness or cost-benefit analysis would be, I think, quite different
depending on what the values and assumptions are.
DR.
GULICK: Can I ask Dr. Handsfield or Dr.
Corey about information on HIV-infected patients in terms of numbers of
recurrence of HSV and amount of viral shedding, just to clarify that point?
DR.
COREY: Well, it is very variable. Certainly CD4 count and viral load are
factors and, as you would expect, the lower the CD4 count, the higher the viral
load, the more shedding. I think the
most surprising thing, however, that has occurred and in the paper that has
been submitted from our group, is that while therapy decreases the frequency of
genital lesions does not decrease the frequency of total inactivation and
subclinical reactivation. So, it is and
continues to be a problem both in the treated and untreated populations.
DR.
GULICK: Thank you. Dr. DeGruttola?
DR.
DEGRUTTOLA: I would just like to say in
response to this question that I think that the information presented did
support use of valacyclovir to reduce risk of transmission of genital herpes,
but the results are still not quite as reliable as one would hope because of
lingering issues about the high withdrawal rate. Even though I think the study was done under
very difficult conditions and that withdrawal rate may be all that can be hoped
for, there are still some concerns there as with the geographic variation. Despite those concerns, I would still answer
in the affirmative.
But
given that we did see strong evidence for the effect of valacyclovir on viral
shedding, on number of episodes and so on--and this may come later, but some
further research to try to understand transmission better might help increase
the degree of certainty that the question truly has been answered in the
affirmative.
DR.
GULICK: Let me just remind the
committee, we will take a formal vote on this question at the end of this
discussion. Don't feel like you need to
say what your vote is going to be at this point because each person will get
the chance to vote, but comments are welcome.
Let
me try to focus us a little bit. Safety,
let's consider safety for a minute. We
have heard some sort of general comments.
Are there more specific comments to make about safety in terms of what
we saw? Dr. Guinan?
DR.
GUINAN: I would say that it is an
impressive record of safety. The adverse
reactions are headaches for the most part.
Clinically that is what I see.
What we don't know is long-term but, even so--you know, what if you
treat someone for 20 years for example--those data are not available. My suggestion on that would only be that
there needs to be postmarketing surveillance somehow developed for long-term
use of acyclovir and valacyclovir for trying to understand that. In other words, does 20 years of therapy mean
that there is a larger risk, or are there just these rather minor effects that
we see, adverse effects of therapy?
DR.
GULICK: Let me remind the committee that
that is a whole separate question that we are going to answer about the
longer-term side effects. Yes, Dr.
Kumar?
DR.
KUMAR: When acyclovir is used in high
doses I know it crystallizes and causes stones in the kidney, and please
correct me if I am wrong. So, I was a
little intrigued by the one patient that had hematuria that the sponsor said
may have a stone. Do we have any further
information on that patient? There was
one patient with hematuria.
DR.
COCCHETTO: We don't have further
information on that patient. Dr.
Haverkos mentioned it in his case presentation and he may wish to comment.
DR.
HAVERKOS: Well, I have the narratives
and I actually went back to try to find that narrative again last night and I
couldn't find it, but it is one that we need to look at again.
DR.
GULICK: Further comments about
safety? If not, let's turn to
efficacy. We already considered this
somewhat. Are there additional comments
about efficacy? Dr. Washburn?
DR.
WASHBURN: I have a question for Dr.
Smith. I too am fascinated by this
geographic breakdown. To put it bluntly,
I wonder if the differences in the observations in Australia versus eastern
Europe are likely to be by chance alone.
DR.
SMITH: I didn't do a formal comparison
with just Australia compared to eastern Europe but the overall comparison
between all of these, I think six different regions, is statistically
significant. You know, a p value of 0.01
is quite a bit less than 0.05 although they do have multiple comparison issues. You know, that is a good question. I don't know.
DR.
GULICK: Other comments about
efficacy? Could you introduce yourself
to the committee?
DR.
SOON: My name is Greg Soon, FDA. Regarding your question about interactions
that you were asking, is the effect size different between different regions--I
assume that is your question. If that is
your question, then the answer is that the p value for that was fairly
large. I don't remember the exact
numbers but it is somewhere about 0.3 or 0.5 so it is pretty large. So, really we do not have evidence to say the
true differences are different between regions, but we do have evidence to say
that the response rates are different among different regions.
DR.
WASHBURN: Speaking naively, it just
looked like the drug worked in Australia and it didn't work in eastern
Europe. What I am hearing is that
probably wasn't statistically significant, that I should ignore that, that that
is background noise. I can think of it
as a Poisson distribution; it could have been the other way around. Is that right?
DR.
SMITH: Yes, that is probably correct in
terms of the treatment differences. In
terms of the evaluation though, you know, there could be some kind of response
categorization bias or response category bias where they have different ways of
ascertaining the endpoint in eastern Europe and western Europe than then do in
Australia and the United States.
DR.
GULICK: Dr. DeGruttola, would you agree?
DR.
DEGRUTTOLA: Well, I can just comment on
what the FDA statisticians are saying and actually just reviewing the data,
because of the small numbers, it doesn't surprise me that they don't find an
interaction of the treatment effect itself with geographic region, but do find
that geographic region affects the endpoint rate. So, the analysis that the FDA has reported on
seems to me to jive with what I would expect from looking at the numbers.
DR.
GULICK: Dr. Fletcher?
DR.
FLETCHER: My question is for the sponsor
on the efficacy issue, and I am wondering whether you have any information, and
I realize how small the sample size is, but it is to the issue of correlates
with efficacy or with the prevention of transmission. What I am particularly thinking is in terms
of trying to provide information to a physician, to patients--again if there is
a recommendation for approval--that would use this. It would seem to me one dose, for example, is
not likely to be effective so there is probably some duration of time on
therapy before there is efficacy and I am wondering if you have any information
on that issue.
DR.
COCCHETTO: I think we can help to some
extent with that. Let me ask Dr. Wald to
comment.
DR.
WALD: Anna Wald, from University of
Washington. In our shedding studies it
appears that the amount of virus present after initiation of antiviral therapy
decreases in about three to four days, and then achieves sort of a complete low
baseline in five days. The same is also
true when you discontinue therapy. There
is a slow rise over three to four days and then it goes back to baseline levels
at five days.
DR.
GULICK: Additional points about efficacy
to raise? Mr. Ebel?
MR.
EBEL: I wanted to comment from a patient
point of view on the efficacy question and to put it in kind of a real-world
frame of, you know, compared to what.
Obviously, we have heard already some pretty compelling statements from
people to the extent that wanting to protect a sexual partner is a major
concern for people who have genital herpes and the risk reduction measures they
have at their disposal now are very limited.
While condoms are recommended and may be a good option for a lot of
people, I think probably we would all agree there is pretty limited data on
that.
So,
I guess from a patient point of view, it seems to me that this range of
efficacy data we are looking at, whether it is 75 percent or the 50 percent
seroconversion protection, would be regarded by people with herpes as a huge
gain compared to what there is.
DR.
GULICK: Thanks. Dr. Mathews?
DR.
MATHEWS: Two points. I already mentioned the issue about potential
misclassification in terms of the dropout rates. I would suggest that the agency request the
analyses on frequency of sexual intercourse and condom use at least at the baseline
time point to be sure that there was no differential effect in dropouts.
The
other thing with regard to efficacy is that while the point estimate of 75
percent risk reduction is clearly significant and consistent across even the
secondary endpoints, the confidence limits on that point estimate are very
broad. They go from 0.08 to 0.75. So, when you go to craft an efficacy
statement in terms of what the prevention message is and how effective this is,
somehow the uncertainty in that estimate has to be conveyed.
DR.
GULICK: Dr. Birnkrant?
DR.
BIRNKRANT: Building on Dr. Mathews'
statement, we would also like the committee to discuss the relevance of the
other endpoints, namely the overall acquisition, because this will be important
to us with regard to labeling of the product.
So, if we could get a discussion on the importance of including that
type of data in labeling in addition to the primary endpoint, which is the main
focus. We would also like to have input
on the other endpoints as well.
DR.
GULICK: Just to remind us all, the
primary endpoint was clinical episodes of HSV-2, and then seroconversion was a
secondary endpoint. Overall acquisition
would sum those two together. So, what
do we think of the choice of the primary endpoint and the other two
endpoints? Dr. Englund?
DR.
ENGLUND: I personally think that the
serologic or total endpoint is actually much more important. If I were to be asked about future trials,
that is what I am interested in. I am
saying that for several reasons. I think
we know more now than we did perhaps back then about the asymptomatic shedding
and the high prevalence of asymptomatic shedding. I, as a pediatrician, see babies born, like
last week, where the mothers didn't know they had it because it was
asymptomatic shedding. That is, in fact,
very, very common. So from my viewpoint,
I would be interested in the total. And serology, I was trying to get at that in
my earlier question, I think serology is a very good reflection.
Furthermore,
for future studies by relying on serology it might make it easier to do a
study. This study is heroic. This is absolutely heroic to have people
doing as many cultures as they are doing.
I think if it were a simpler study design perhaps, maybe not, you could
get more people involved. But disease as
measured by serology, for me, is important because I think it would really help
couples know what is going on and it certainly would help in terms of the
babies born.
DR.
GULICK: Other comments on
endpoints? Dr. Guinan?
DR.
GUINAN: Yes, I agree with Dr.
Englund. I think that there is a great
deal of asymptomatic infection, not only asymptomatic shedding but asymptomatic
transmission in which the partner does not have any clinical symptoms or
signs. So, this is a very important
aspect of the epidemiology. It is not
terribly important from a clinical point of view of treating people because
they don't know they have it so it is sort of our of the clinician's
purview. But I think if we looked at it
epidemiologically and were interested in prevention or reducing transmission,
that is a more logical and more accurate endpoint about reducing transmission.
DR.
GULICK: Dr. Fish?
DR.
FISH: Yes, I think I would agree with
those comments. When I was first reading
through the briefing document that was the question that came into my mind, why
wouldn't we want to know about overall acquisition and knowing that there is
the risk for shedding and increased risk for potential transmission? It does, however, diminish the apparent
treatment effect when you look at a study that only would have serology-based
data based on the data that was presented here today.
DR.
GULICK: The last special issue to
consider with the question from Dr. Birnkrant is the dropout rate. We have talked a little bit about this
already. Are there additional comments
to make about the dropout rate versus the endpoint rate? Dr. Washburn?
DR.
WASHBURN: Just a quickie, I would assume
that they would be equally distributed through the two arms of the study so
they didn't bother me.
DR.
GULICK: Well, let me try to sum up what
we have said. Consensus of the committee
is that we found the efficacy and safety data impressive and the study well
done. We found that the drug reduces
transmission but would caution not to use the word prevent. It also has some side benefits about reducing
HIV transmission and reducing shedding; the repercussions of the social aspects
of this in terms of reducing anxiety among infected people in terms of
transmitting to their partners.
We
did have some cautions. One was Dr.
Mathews' point about the wide confidence interval around the point estimate
that we saw in terms of the data. The
choice of endpoints generated some recent discussion. People felt that perhaps a serologic endpoint
or overall capturing both clinical and serological endpoints was actually
preferred or would be preferred in future studies. This may be more logical, in the words of Dr.
Guinan. We certainly appreciate more asymptomatic
shedding and transmission and this could be an easier endpoint to assess. That was Dr. Englund's comment on future
studies.
Other
concerns that came up in our discussion are the low number of endpoints
compared to the number of patients treated.
We spoke of the high dropout rates that were observed, although some
people were less concerned than others in terms of the overall effects on the
primary endpoint. Dr. Mathews cautioned
us about differential effects among the dropout populations.
There
are lingering concerns about geographic differences and why those occurred and
how to explain that; some concerns about the demographics of the population
studied. We mentioned earlier today--Dr.
Kumar brought out the point that 90 percent of the population studied were
white and I think the committee felt that we would liked to have seen more
information in other groups as well. We
heard some caution about the duration of therapy. We are going to have another opportunity to
discuss that in terms of long-term safety.
Then,
another issue that we don't often discuss as a committee is cost of medication
but that was raised early, and the cost-benefit analysis and how does this
compare with other interventions that we use, although several cautions about
what is the relative cost of preventing an HIV infection or preventing complications,
for instance, in the pediatric group.
So, that remains an open question but one that generated some interest
among the committee.
With
that, we are going to take a formal vote and read the question one more
time: Does the information presented by
the applicant support the use of valacyclovir to reduce the risk of
transmission of genital herpes among monogamous heterosexual couples? So, a vote "yes" would be for
approval and a vote "no" would be against approval. Mr. Ebel and Dr. Stone, you are not eligible
to vote so I am going to go around the table and ask people to vote yes or no,
and start with you, Dr. Potter.
DR.
POTTER: Yes.
DR.
GULICK: Dr. Guinan? Turn your mike on.
DR.
GUINAN: Yes.
DR.
GULICK: Dr. Pazin?
DR.
PAZIN: Yes.
DR.
GULICK: Dr. Fish?
DR.
FISH: Yes.
DR.
GULICK: Dr. Washburn?
DR.
WASHBURN: Yes.
DR.
GULICK: Dr. Mathews?
DR.
MATHEWS: Yes.
DR.
GULICK: Dr. Fletcher?
DR.
FLETCHER: Yes.
DR.
GULICK: Dr. Stanley?
DR.
STANLEY: Yes.
DR.
GULICK: She is hanging in there! Dr. Kumar?
DR.
KUMAR: Yes.
DR.
GULICK: Dr. Sherman?
DR.
SHERMAN: Yes.
DR.
GULICK: Dr. Englund?
DR.
ENGLUND: Yes.
DR.
GULICK: And Dr. DeGruttola?
DR.
DEGRUTTOLA: Yes.
DR.
GULICK: And the chair votes yes. That is unanimous, 13 votes for
"yes" and no votes for "no." Let's take a five-minute break.
[Brief
recess]
DR.
BIRNKRANT: That was the easy part of the
afternoon.
DR.
GULICK: I know. Thanks for reminding us. Now the working part comes into play. Let's go to question number two: Does the information presented by the
applicant support the use of valacyclovir to reduce the risk of transmission of
genital herpes among populations other than monogamous heterosexual couples? Dr. Mathews?
DR.
MATHEWS: Well, to get it started, the
first thing I would say is that I don't see any reason to restrict it to
monogamous heterosexual couples. I
think, at least to my mind, there is no biological reason why that should have
anything to do with the efficacy of the intervention.
However,
I don't think it should be an indication for immunocompromised heterosexual
couples, whether by HIV or anything else, since that was an exclusion. Although it is likely to have some efficacy,
we don't know anything about whether this would be the appropriate dose, for
example, in immunocompromised populations.
I
also don't think that it should be generalized to non-heterosexual couples for
similar reasons. We just don't know
whether the intervention would have a comparable efficacy, and also the prevalence
of HIV in men who have sex with men would likely attenuate the effect. So, those are my opinions.
DR.
GULICK: Other thoughts? Dr. Potter?
DR.
POTTER: Just a very brief one, the more
different kinds of methods you are using to prevent transmission, the
better. In other words, this and
condoms, although condoms are not used very much, literally because of
compliance issues, the more the better.
DR.
GULICK: Dr. Guinan?
DR.
GUINAN: I don't really know very much
about the quantitative aspects of HSV. I
am just not familiar with the methodology.
But it is clear that if valacyclovir reduces the quantity of virus shed,
and in all infectious diseases we presume that there is a minimal infective
dose for infection and it may vary with host factors so, from a theoretical
point of view, in whatever population you use this there would be a decrease in
quantity of virus and rate of shedding.
So, I believe that that could be extrapolated to all populations. In other words, that the effectiveness, based
on sexual orientation or whether you are monogamous or not, shouldn't be
different.
As
far as whether the social circumstances are different, that is a question that
I think we can't answer, but from an effectiveness point of view, I don't think
you can argue that it is unlikely to decrease the quantity of virus in somebody
who is not monogamous or who is not heterosexual.
DR.
GULICK: Dr. Mathews, a response?
DR.
MATHEWS: Well, I would agree that it is
likely to have some effect but how could we estimate the magnitude of that
effect? Is it 0.75 in an
immunocompromised patient or a gay male who is predominantly having anal
receptive intercourse? I mean, on what
basis would you estimate how protective it would be?
DR.
GUINAN: Well, I certainly wouldn't
estimate that but I would just say that from a logic point of view it would
reduce it. Whether it would reduce it
sufficiently to be protective at the same rates as it is in this study I don't
know. But it would seem logical that it
reduces the rate and magnitude of virus and the shedding. I think that is extrapolatable to gay--I am
not talking about immunocompromised but I would say a non-heterosexual,
non-immunocompromised individual. I
can't see any reason why this wouldn't be translatable.
DR.
GULICK: So, as a committee we have faced
difficult questions like this before. We
have seen data in one population and we have biologic plausibility, but we have
no data in other populations and how do we translate that into what goes into
the label? How do others feel about
that? Dr. Sherman?
DR.
SHERMAN: I think that, as has perhaps
already been said, we can translate this into heterosexual immunocompetent
couples but not beyond that. The
monogamous was a mechanism to do the study appropriately so that certainly
should not be an issue in the equation.
Everything else follows right after that in terms of people who are
immunocompetent and have heterosexual contact.
DR.
GULICK: Dr. Kumar?
DR.
KUMAR: From everything that I have
looked at in the data, I think this data is applicable only to heterosexual
immunocompetent couples. I think to make
the leap of faith, even though biologically it may make sense, especially with
the issues we spoke earlier about, it is efficacious but not the effective
method of decreasing transmission. I
would be very uncomfortable to make that leap of faith to anything other than
immunocompetent heterosexual couples, especially when it comes to
immunocompromised HIV patients.
DR.
GULICK: Dr. Pazin?
DR.
PAZIN: I would just agree with
that. I think immunocompetent
heterosexual is probably as far as you can go on this study data.
DR.
GULICK: Any other thoughts on this or
disagreement?
DR.
GUINAN: Yes, I disagree that you
couldn't in an immunocompetent non-heterosexual--I don't see that the data on
shedding of virus and of reduction in quantity of virus--there is no biologic
known difference between non-heterosexuals and heterosexuals in handling
infections if they are immunocompetent.
So, I would disagree that this should be limited to immunocompetent
heterosexual. I think that
immunocompetent non-heterosexuals would also--it would apply also. I can't find a logical reason why it wouldn't.
DR.
GULICK: Dr. Sherman?
DR.
SHERMAN: I wonder if any of the expert
members on the sponsor's team have an answer to this, but I suspect that
immunosuppressed patients have higher titers and for a given level of reduction
there is probably some threshold level that you see a significant reduction in
risk of transmission below that point.
If that is the case, and it is the case with many other viruses, if we
see an average, just to throw out a number, of a half log decline in virus and
you start two logs higher you may have absolutely no apparent effect in
transmission for this particular virus.
I think that that would really need to be tested.
DR.
GULICK: Dr. Birnkrant?
DR.
BIRNKRANT: Could we also get comments on
use in adolescents and how do we deal with the susceptible partner not being
monogamous?
DR.
GULICK: Let's take adolescents
first. Dr. Englund?
DR.
ENGLUND: Well, adolescents don't use
condoms. We try and try and try and they
don't use condoms even when they are HIV-infected and they know it. They don't tell their partners frequently and
they don't use condoms. I think this HSV
approach might be another way to try and get them up to speed to acknowledge
that there is a problem. There is
certainly double seropositivity in these and I think for my patients and my
clinic that this will be a good approach.
Not that we are ever going to tell them to stop using condoms; we don't
want them pregnant, but they are getting pregnant every day too. So, they obviously aren't using condoms even
when they tell us they are using condoms, which they do tell us but they
aren't.
So,
I think that this is an important adjunct.
I think that people of childbearing age range are where this drug could
be focused from a public health point of view because of the multiple
sequelae--HIV, the childbearing. And, I
see no problem with having this part of an adolescent clinic. We start usually around 11 or 12 years for
this kind of thing. We don't know
long-term effects. I would encourage
that we need to have long-term efficacy and safety but I think it fits right in
with what we are doing and gives us yet another reason to talk with them every
month, which is what we are doing.
DR.
GULICK: Other comments about
adolescents? The other population was?
DR.
BIRNKRANT: When the susceptible partner
is not monogamous. Is that an issue for
any of the members on the committee?
DR.
GULICK: Given our previous discussion
about monogamous couples, I am guessing not.
DR.
BIRNKRANT: Okay. And what about Dr. Stone, being from the CDC,
do you have any additional comments on this question?
DR.
STONE: I think I agree that
immunocompetent heterosexual populations could be included. I have some reservations about men who have
sex with men. I would have no problem
including adolescents.
DR.
GULICK: Dr. Pazin?
DR.
PAZIN: This thought that a susceptible
partner--it is irrelevant. Obviously, it
is not going to provide protection for other people who aren't using the
medication. So, that just goes without
saying as far as I can see.
DR.
GULICK: So, let me summarize what we
said about populations. First of all, a
reminder to us that education about herpes and transmission and the overall
thought that there are other methods of avoiding transmission, including
condoms, continues to be important. What
is recognized here is biological plausibility of an antiviral agent to reduce
the amount of virus. Then, some
differences of opinion about how much one can extrapolate to other populations
because of differences in the amount of virus and how much it may or may not go
down; the differences in effect from population to population and the magnitude
of response.
As
Dr. Sherman pointed out, monogamous was really a requirement for this
particular trial and allowed the study to be done but, as many have echoed, it
is not an important criterion for achieving benefits in immunocompetent
heterosexual couples. That is the best
data we have that we have seen today.
There
was more concern in homosexual couples, although not uniform opinion on whether
one can extrapolate data from heterosexual to homosexual couples, and simply no
data to guide us at all.
There
was endorsement among adolescents for the same reason that adults would
benefit, and perhaps even more of an endorsement in adolescents given problems
with condom use and opportunities to discuss reduction and transmission. Because adolescents are younger, longer-term
data is going to be even more important in this group perhaps.
Then,
a consensus that it is probably not appropriate to extrapolate to the
immunocompromised host because of concerns that viral burden may be higher in
this population and that, again, we simply don't have the data to make those
recommendations.
We
suggested some longer-term studies in the course of our conversation here. Dr. Sherman earlier said that transmission
studies would be of interest, and perhaps relating the amount of HSV or the HSV
titer to transmission is something that we could know about more.
I
guess we would like to see studies in immunocompromised groups. We would like to see studies in gay men and
women. Again, the longer-term safety
issues were something that is of paramount importance. Dr. Mathews?
DR.
MATHEWS: One implication I think of what
we have recommended is that the label should I think somewhere contain a
recommendation that people be encouraged to have HIV testing before this
decision is made to prescribe this. I
mean, the same population should have been HIV tested anyway, I would think,
especially if they are not monogamous.
We should find a way to put that in there.
DR.
GULICK: Just to remind us from the
sponsor point of view, in this study everyone received HIV testing and that was
an exclusion criterion? Is that correct?
DR.
HARDING: There was no HIV testing. They were excluded if they had a history of
HIV. We also went through the case
records after the study had completed to look for any indication of HIV and
there was none, nor were there any medications used for HIV.
DR.
GULICK: So, by history HIV was an
exclusion but serologic testing was not performed on the study?
DR.
HARDING: Right.
DR.
GULICK: Thanks for that correction. Dr. Fletcher?
DR.
FLETCHER: On your list I think you would
want studies in adolescents as well. I
am not saying, you know, a thousand patients.
In this study it only went down to 18 years of age and while I don't
think that the pharmacokinetics of valacyclovir are going to be different in
adolescents, without data--you know, there are always surprises out there. So, I think if you are going to make that
extrapolation to adolescents there needs to be some basis to do that. At least from the most simple point of views,
a pharmacokinetic study of valacyclovir in adolescents would be one way to
understand whether the concentrations at a 500 mg once daily dose are going to
be equivalent to those seen in adults.
DR.
GULICK: Does the sponsor have data on PK
in adolescents with valacyclovir?
DR.
COCCHETTO: I am looking to Dr. Weller
here. Steve? Stephen Weller is in our clinical
pharmacology group and he can comment.
DR.
WELLER: We don't have specific
pharmacokinetic data in adolescents per se since studies have been done in
younger children, much younger children with acyclovir, historically. Children as young as 12, 13 years of age have
been included in some of the Phase III trials for some of the indications but,
again, specifically as pharmacokinetic data in adolescents, we don't have that
at present.
DR.
GULICK: Dr. Pazin?
DR.
PAZIN: Yes, I was thinking it would be
interesting to get the committee to vote on the concept of whether we think it
should be extendable to homosexual couples.
DR.
GULICK: Okay, a non-binding kind of
straw vote.
DR.
PAZIN: Sense of the committee.
DR.
GULICK: Let's just do it--
DR.
GUINAN: Immunocompetent.
DR.
PAZIN: Immunocompetent homosexual
partners. Do you think it should be
extended to them or not?
DR.
GULICK: In other words, extrapolated on
the basis of labeling, whether we would recommend that for labeling or
not. Dr. Handsfield, did you want to
make a comment?
DR.
HANDSFIELD: I would just point out that
in that discussion what has not been raised by any of you is differences in
sexual practices in particular because it is conceivable that at a biological
level it is not just viral load, but what is the level of the kind of exposure
that takes place, for example, during anal intercourse as opposed to vaginal
intercourse and potential microscopic or overt trauma that might affect
transmission rates. So, in thinking
about that vote I would be inclined to factor that into your thinking.
DR.
GULICK: Dr. Guinan?
DR.
GUINAN: Well, in the study was it
determined what types of sexual intercourse these monogamous couples had? Was it restricted to vaginal-penile
intercourse?
DR.
GULICK: Unlikely to be restricted--
[Laughter]
DR.
GUINAN: What I am saying is that it is
very possible that there was rectal intercourse among these couples.
DR.
GULICK: Does the sponsor have any
information on what kind of intercourse occurred on the study?
DR.
HARDING: There was no restriction on
anal intercourse. There was some but it
was a very small number. We do have the
numbers if you require them, but I can't recall them off the top of my
head. The median was zero obviously.
DR.
KUMAR: I think your page 44, table 8,
would that not give us information we are looking for?
DR.
LIDDLE: I think it looks like eight
percent according to the diary data.
DR.
GULICK: Again just to clarify, the way
that this was assessed was by patient diary?
Is that how it was? So, people
were expected to jot down what was going on over the last 24 hours in their
diary?
DR.
COCCHETTO: That is correct. Susceptible partners maintained a diary that
was returned with each monthly clinic.
DR.
GULICK: Additional comments about
extrapolating to the homosexual immunocompetent population before we take a
straw vote? Dr. Mathews?
DR.
MATHEWS: I just one to make one last
comment about this. I don't think it is
a matter of whether it is a good idea or is biologically plausible. It is a matter of is the evidence sufficient
that it should go into a label and my opinion is definitely not. It should be studied and there should be the
same kind of evidence for the MSM population, for the reasons that have been
stated previously as well as what Dr. Handsfield just said.
DR.
GULICK: Dr. Corey, do you want to chime
in?
DR.
COREY: I think everybody is right--
[Laughter]
--but
I would say that there has not been a partners study published in the HIV
literature, and certainly not in the herpes literature that I am aware of, that
has been successful in looking at transmission among gay men solely, monogamous
gay. So, the study design, and we have
thought about this, we don't think is a possible study design to get enough
monogamous gay men. So, you would have
to think of a more unique design or that could be done in a unique
population-based basis, or something.
But it would certainly be a very unique study design as far as I am
aware of in the field of STDs.
DR.
GULICK: Just to be clear, did you say
that previous studies have been attempted or designed and were unsuccessful in
enrolling? Discordant gay couples, those
studies have been largely difficult to perform is what you are saying. Other comments? Dr. Fish?
DR.
FISH: I think that said, I would agree
with Dr. Mathews that I am not sure how we would extrapolate to this patient
population. It is a large leap of faith
and whether the study can or can't be done, it seems to me like the labeling
would better address the information that we have, letting people decide based
on the information that is there and the data that is available, people being
practitioners.
DR.
GULICK: Dr. Guinan?
DR.
GUINAN: I would just like to say I have
worked for the CDC for a long time and was in charge at one time of developing
the STD treatment guidelines, and all that was done on scientific studies, it
was not until very recently that sexual orientation ever entered into the
discussion. In other words, you didn't
know what the sexual orientation of the patient was. It was whether it was effective or not
effective. Do you see what I mean? So, it is very difficult for me to now
differentiate those and say, okay, this is good for heterosexuals and to make a
recommendation, for example, if CDC were incorporating these into the treatment
guidelines, to say, oh, this is good for heterosexuals but we don't recommend
it for homosexuals, or there is no data on homosexuals. Do you see what I mean? So, I understand everybody's concerns but to
think that there are biological differences in the way people process these
drugs because of sexual orientation, to me, is not plausible.
DR.
GULICK: Dr. Stone, could you comment on
implications for guidelines?
DR.
STONE: Let me also just say as regards
the applicability of this to gay people, I think our concerns were more
specifically for MSM--not all MSM but not just HIV co-infection but just the
general sexual practices may be very different.
This
study population did have anal intercourse but it may be with a different
frequency than men who have sex with men.
But when the time comes for us to, you know, update our treatment
guidelines we would--I can't tell you now what we would do but in each section
of our guidelines we have a special section on special populations and we
specifically comment on HIV-infected persons.
To my knowledge, we don't have anything in here about homosexual versus
heterosexual patients or partners.
Another
approach would be to speak of vaginal intercourse versus anal intercourse and
you could get away from the sexual orientation label.
The
other thing about this study, if you were really restricting the applicability,
then it would be applicable almost to very few people because if you look at
the frequency of sex in this group, they really were not very sexually active
but I don't think anyone here wants to limit the indication for people who have
sex six times a month.
[Laughter]
So,
I think it is a fine line between, you know, generalizing too broadly and being
too narrow.
DR.
GULICK: Any Australians in the crowd?
[Laughter]
Dr.
Englund?
DR.
ENGLUND: I just wanted to say that it
was actually the women though who drove the study or the vaginal
intercourse. That is, before the study
the investigators knew that. That is why
the study tried to be stratified, ultimately unsuccessfully. When you look at page 56 and the table, it is
7.5 percent of the women in the placebo group and only 1.0 percent of the
men. So, it is the women, in fact, that
may have benefited the most, which is good news for women, but to be able to
translate that into men only and then men having sex with men in addition, that
is making two leaps of faith instead of just one. So, even though I think biologically it might
be the same, I think the practices vary and I think we, as the advisory group,
need to take that into account.
DR.
GULICK: Dr. Smith?
DR.
SMITH: As I recall, there was no
treatment by gender interaction so the treatment effects in men were basically
similar to the treatment effects in women.
It is just that both treatment groups had a lot of fewer events. So, I would say that the results probably are
generalizable to men among heterosexual monogamous couples.
DR.
GULICK: Then, if we take anatomy as the
likely explanation for differences in transmission, receptive anal intercourse
may be more analogous perhaps to men having an increased risk to transmit to
women, although we don't know. Lots of
leaps of faith here. Dr. Smith?
DR.
SMITH: There is only the median of
zero. You know, the number of anal
sexual contacts is zero for the overall population. So, it is almost all non-anal sex in the
study.
DR.
GULICK: So, we have heard a lot of
differences of opinion and this is kind of a non-binding vote but might be of
interest to the agency if pin people down.
So, let's just raise our hands and Mr. Ebel and Dr. Stone, we will
invite you to vote in this one too since it is just an opinion thing. So, a vote for "yes" is that we
would not recommend restricting the label on the basis of heterosexual versus
homosexual. In other words, that would
simply not be in the label. Is that
phrased okay?
Let
me try this again. You would support the
use of valacyclovir to reduce the risk of transmission of genital herpes,
period. No caveats about monogamous and
no caveats about heterosexual.
DR.
PAZIN: Is that the question?
DR.
GULICK: I thought it was the question.
DR.
PAZIN: I don't think you are stating it
very clearly. I want to make a
distinction between heterosexual couples and homosexual couples. I think that is what the discussion has been
talking about.
DR.
GULICK: That is what I was trying to
do. I am just taking the question and
eliminating the last part. The question to the committee, and this is a straw
vote, is does the information support the use of valacyclovir to reduce the
risk of transmission in genital herpes, period?
Or, if you like, in both homosexual and heterosexual couples. Is that clear? All in favor of including that sentiment in
the label, raise your hand.
[Show
of hands]
Two
votes. All opposed?
[Show
of hands]
So,
you get the idea. It is a straw vote.
MR.
EBEL: Mr. Chairman?
DR.
GULICK: Yes?
MR.
EBEL: To me, I would just like to
reiterate the confusion about calling the question. Are you going to follow-up now with a more
exclusive definition of extending it, in other words, dropping the monogamous
part but keeping the heterosexual part?
DR.
GULICK: Our purpose today is just to
provide some discussion about considerations for the label for the FDA and the
sponsor to go forward with in further discussion. We don't have to sort of hammer out the terms
of the label itself. We have already
voted to say that we would recommend approval of the drug. At this point, all of the other questions
really speak to the fact about what should go into the label. So, I don't think we have to get into the
nitty-gritty of exact wording for the label.
It is helpful I think for the agency--correct me if I am wrong--to hear
that there are differences of opinion on the committee. We were pretty uniform about not including
monogamous and then there was a difference of opinion about stipulating
heterosexual versus not. But I think we
can probably leave it at that and keep going.
MR.
EBEL: I was just concerned that the
monogamous piece was getting lumped in with the sexual orientation piece.
DR.
GULICK: No, I think we have separated
those two issues.
MR.
EBEL: Thank you.
DR.
GULICK: Let's go on to the next
question. In study 3009 over 4,000
couples were screened but only about 1,500 were enrolled. A large number of couples were excluded
because susceptible partners were found to be HSV-2 positive without clinical
symptoms. Please discuss the
implications of screening susceptible partners for HSV prior to initiating therapy
of the source partner with valacyclovir.
Again, this is thinking about the label.
Dr. Mathews?
DR
MATHEWS: Well, here the scenario changes
quite a bit when you broaden the indication to non-monogamous couples because
really the treatment in that setting is not a matter of a discussion between a
source and a specific susceptible. It
really is almost assuming that the source might have sexual contact with more
than one or many people, in which case the education I think becomes very
important for the clinician prescribing or contemplating prescribing the drug
to talk with the patient about, you know, are you sexually active now, or are
you going to be, are you going to discuss your serostatus with your
partners. The question is, if they are
casual partners, it is not really feasible to recommend, oh you know, you
should go out and get tested before you have sex, if you are going to have sex
on a casual basis.
I
am just thinking now. In the context of
an established relationship it might be reasonable to recommend testing the
partner. But if it is not a monogamous
relationship I wouldn't necessarily put that in.
DR.
GULICK: Other thoughts on this? Dr. Kumar?
DR.
KUMAR: I am looking at this a little bit
differently. If the susceptible partner
is positive, then there is no reason for the source person to take the drug. Why would they have to take it for a
prolonged period of time if the benefit is not going to be there?
DR.
MATHEWS: But they might have another
indication for taking it to suppress their own reactivations, which is already
an approved indication.
DR.
KUMAR: That is different but right now
we are looking really for this indication of preventing transmission. In that, if the susceptible person is already
positive, then there is no reason for the source person to take the drug. So, I would recommend that the susceptible
partner needs to be tested.
DR.
GULICK: Would you require it or consider
it?
DR.
KUMAR: I would strongly consider
it. This is not a drug that you are
going to take for a week, two weeks or three weeks. As long as that person is in that
relationship you are going to take it every day.
DR.
GULICK: Dr. Englund?
DR.
ENGLUND: I think we should strongly
recommend it for this indication because there is a great deal of money
involved; there is potential safety and toxicity and if they are taking it you
should know that it is for a reason. A
serologic test costs under $50 which is, whatever--three weeks of pills. It really makes sense medically, socially and
economically.
DR.
GULICK: Dr. Pazin?
DR.
PAZIN: I fully agree that we should
strongly recommend getting tested.
DR.
MATHEWS: But how would that work in the
casual partner setting or adolescents?
What does that mean?
DR.
PAZIN: To be using the drug as a
prophylactic if it is not going to accomplish anything is just a waste, as far
as I am concerned. I just think that you
ought to find out. There is a
substantial possibility that the person already is infected. They may not think so but there is a good
chance. So, it just would be I think
very wasteful.
DR.
GULICK: Dr. Wald, did you have a
comment?
DR.
WALD: Thank you. I guess my feeling is that people should be
tested but not necessarily in the context of considering this added benefit of
valacyclovir therapy. We know from other
studies that clinical history of genital herpes is not always accurate. In fact, in the STD treatment guidelines
laboratory confirmation of all genital herpes cases is currently
recommended. So, it is certainly
recommended for the source partner to have laboratory documentation that they
really do have HSV-2 infection.
In
terms of the susceptible partner, given the experience in this population and
finding that a substantial proportion of people who are concordant, not
discordant, this is a situation which actually brings relief to a lot of
couples, that the susceptible is already infected. Because of that, I think that testing should
be encouraged, maybe not even specifically with the thought of initiating
suppressive therapy but just because of the clinical discordant status.
DR.
GULICK: Can I just make sure I
understand this, the current recommendations for someone who has clinical
symptoms of genital herpes is to undergo serologic testing?
DR.
WALD: It is to undergo laboratory
confirmation of the diagnosis and which test, whether it be a viral detection
test or a serologic test, depends on the clinical presentation.
DR.
GULICK: Okay, but that is for
symptomatic patients.
DR.
WALD: That is correct.
DR.
GULICK: And either Dr. Wald or Dr. Stone,
other populations where it is routinely recommended to obtain an HSV serology
currently?
DR.
WALD: It is routinely recommended to
serologically test those people who present for evaluation of STDs and request
to be also evaluated for HSV.
DR.
GULICK: Dr. Stone?
DR.
STONE: Also, in the current version of
the STD guidelines we say that serologic testing is useful for partners. We don't make a distinction between casual or
regular partners. The thinking is, like
Dr. Wald said, that the partner may already be infected and they are not going
to get infected again so they don't need to worry about becoming infected. Also, they can benefit from counseling and
learning to recognize symptoms and, you know, they themselves may become
candidates for treatment. That is sort
of the clearest indication for serologic testing in our guidelines.
DR.
GULICK: Other comments? Dr. Guinan?
DR.
GUINAN: There is a small problem with
serologic testing in that it is type specific and if you are looking for HSV-2,
then there is a certain percentage of genital herpes that is HSV-1. In other words, it is not exactly that I know
this person is susceptible because they are HSV-2 negative because if the
source has HSV-1 and the partner is HSV-1 positive, then that person wouldn't
need the drug. Do you see what I
mean? Since a certain proportion of
genital herpes is type 1, then doing type-specific antibody to determine a
susceptible if you use only type 2, then you will have some degree of error in
determining susceptibility.
DR.
GULICK: Dr. Pazin?
DR.
PAZIN: It is not nearly as traumatic to
get HSV-1 genital herpes as it is to get HSV-2 genital herpes. So, I think that is not a major concern.
DR.
GUINAN: Maybe not for you.
[Laughter]
DR.
PAZIN: No, I can assure you that you can
reason with those people, with the other ones it is more difficult.
DR.
GULICK: Dr. Guinan, no comment? Your gestures say it all! Other thoughts on the serologic
question? Dr. Fish?
DR.
FISH: I mean, for the patient, they are
not going to know whether they have 1 or 2 and I am not sure I can follow that
argument. What was my other
comment? Oh, a total serology--I believe
there is available serology that can detect both 1 and 2 so that might be a
strategy that could be employed if the susceptible partner were going to be
serologically tested.
DR.
GULICK: Dr. Guinan, can you fill us in
on that?
DR.
GUINAN: I think I am going to say
something controversial.
DR.
GULICK: Good!
DR.
GUINAN: I feel that women are
disproportionately affected by this for lots of reasons, being more susceptible
and having the poor outcomes of risk of transmitting this to a newborn. The male condom is not under the control of
women and the treatment of the source, the male source is not under the control
of women. Do you see what I mean? So, women are still very susceptible and what
I think should be done is women should know their serostatus. In other words, women should know whether
they are HSV positive or negative, especially for type 1 infection, and then
let them know that they are susceptible and their partners, if they have known
herpes infection, should be. But this is
what I have done and I have recommended off-label, and I am sure I will be put
in jail some day but what I have done is to give young women valacyclovir who
are in a relationship with someone because their male partner won't take
it. So, I give it to the women to
protect them. In other words, there is
no data but it gives them something because they have nothing. They are madly in love and they can't
resist. It is expensive and that is a
big part, but the safety--so from my point of view, this is something that
needs to be addressed in some way. In
other words, women are susceptible and in trying to prevent perinatal herpes
infection you need to prevent it in the woman.
So, women's knowledge of their serostatus I think is extremely important
and trying then to give them information about protecting themselves against
acquisition of infection.
DR.
GULICK: I think you are making important
points. I don't want us to get too far
away from where we are, which is what should be required in the label for
valacyclovir for this indication.
DR.
PAZIN: Clearly that is another study if
you are going to be giving it to prevent acquisition.
DR.
GUINAN: It will never be done.
DR.
GULICK: So, that was my point. So, interesting and provocative but maybe we
should steer clear of it now. Dr. Kumar?
DR.
KUMAR: Dr. Gulick, isn't the indication
right now to prevent transmission to a susceptible person? Isn't that the indication for this drug?
DR.
GULICK: Or to reduce transmission.
DR.
KUMAR: To reduce transmission. So, that is why I am so confused. If the susceptible person is not susceptible,
then the source person should not be taking the drug. So, I just find this whole question extremely
unclear because that is the indication.
It says we are giving it to prevent or reduce transmission. So, I think the susceptible person should be
tested.
DR.
GULICK: What I am hearing is consensus
on this point but the practical world that Dr. Mathews describes is that not
everyone has one partner that we can bring in for testing, and that is the
clinical reality of this situation. So,
I think most people around the table agree that serologic testing, if there is
an appropriate person to test, would be of great benefit and might actually
exclude the need for this drug but there are many people in the real world
where you will not be able to apply that.
So, I guess that is our feeling on this issue. Okay?
DR.
MATHEWS: Let me just give one example to
make it very concrete. If a commercial
sex worker who is HSV-2 seropositive has to require that their partners be
tested in order to get this drug, you know it is not going to happen. So, I think or I would hope the sense of the
committee is that, yes, it should be recommended to be done when it can be done
but certainly not required, otherwise the people at greatest risk of
transmission will not get access to the treatment.
DR.
GULICK: I think that sums up the
consensus very well. Let's move on,
question number four, in your opinion--in your opinion, underlined--will
marketing of valacyclovir for reduction of genital herpes transmission have an
impact on the use of condoms and abstinence from sex during clinical HSV-2
outbreaks? Dr. Fletcher?
DR.
FLETCHER: Well, I don't know is the easy
answer but--
DR.
GULICK: Question number five!
DR.
FLETCHER: You said you wanted to get out
early! But I do have two points. I guess one has to say I hope not, and I
think that goes to Dr. Mathews' point about the confidence interval in the
effectiveness in the reduction of transmission which, if my math is right, is
24 percent to 94 percent. So, the
message needs to get out very strongly that, you know, yes, it works but the
extent to which it works is really uncertain.
I
think the second point that I want to make is that the benefit is not
immediate. It seems from the data that
Dr. Wald mentioned, it seems that one dose really does not convey a benefit. So, being on therapy, staying on therapy and
using additional methods to prevent transmission seems to be the message that
needs to get out. I think, great, to the
extent possible efforts, aggressive efforts need to be made to ensure that
people understand that other forms of protection need to be taken.
DR.
GULICK: Dr. Sherman?
DR.
SHERMAN: Does the sponsor have that
slide that showed--I mean, we have data on this and it looked like condom use
did go down. Was that statistically
meaningful?
DR.
GULICK: Or was that the agency that
showed it? Dr. Smith?
DR.
SMITH: We have that in our
presentation. I think the applicant also
showed a slide with the transmission.
DR.
GULICK: Could we see that again? What slide?
DR. SMITH: It was towards the middle, right at the end
of efficacy. I think it is 26. Well, it is actually 27 and 28.
DR.
HAVERKOS: Also 54.
[Slide]
Is
that the one?
DR.
GULICK: Can you walk us through this
again, please?
DR.
HAVERKOS: Basically, if you look at the
reports of condom use in the month before study or baseline, remember, there
are three groups, there is "never," "sometimes" and
"always." As you see, we only
have data on 725 of the 743 valacyclovir patients. It probably reflects the fact that they
didn't actually collect some of this data until amendment I which was a couple
of months into the study. But 32 percent
said they nearly always used condoms and 51 percent said they never used
condoms. That is 83 percent of the
total. For the other 17 percent, there
was either no data or "sometimes."
This was just for vaginal sex, 90-100 percent for "nearly
always."
During
the study itself you can actually calculate number of sex acts per month, and
then each month you can calculate the condom use. If it is "nearly always" it is
90-100 percent. If it is zero, if they
never used condoms for vaginal sex, anal sex or oral sex, it is never. Then, there is a group that gives you some
data in between.
Then
they take a median. So, in other words,
there is eight months of data from many patients; there is five months of data
for others if you take the middle month, so if it is all "nearly
always" it is nearly always. If it
is four "never" and two "sometimes" and one "nearly
always" it is never. So you can
actually go back and calculate these numbers.
So, it doesn't actually translate into 90-100 percent across the whole
study. It is a unique way of calculating
condom use. But if you look at the
baseline data and the vaginal use data from baseline through the study, you get
a slight drop in "nearly always" and you get a slight increase in
"never."
DR.
GULICK: The denominator is changing.
DR.
HAVERKOS: The denominators change,
right.
DR.
GULICK: Let's go to the sponsor on the
same point and then I will take a couple more comments.
DR.
COCCHETTO: Just a methodology caution on
this. As you recognize, at baseline the
information that is reported is the individual participant's recollection of
activity from the prior month, whereas during the study it is actually diary
card data that is being captured on a sexual contact by contact basis.
DR.
GULICK: Thank you. Dr. Potter?
DR.
POTTER: My one question was wasn't this
during clinical outbreaks as opposed to during the full cycle?
DR.
GULICK: It was assessed all throughout
the study.
DR.
POTTER: This was assessed but I meant
the question. Wasn't it have an impact
on the use of condoms and abstinence from sex during clinical outbreaks?
DR.
GULICK: Oh, I am sorry, you are focusing
on the question here.
DR.
POTTER: Yes.
DR.
GULICK: We have been a bit too broad,
although that is also perhaps of interest.
So, we have been considering generally in terms of looking at this data
and the concern expressed here is currently during a clinical HSV-2 outbreak
the recommendation is to be abstinent from sex, and will the marketing of
valacyclovir actually impact that. So,
let's focus on that specific question.
Thanks for that. Dr. Englund?
DR.
ENGLUND: I would just like to say that
in my relatively limited by intense work with adolescents the answer is clearly
no because they don't use condoms. They
are not going to use condoms very much.
We are trying hard, we really are but it is not going to change.
DR.
GULICK: Dr. Stone?
DR.
STONE: I would like to reiterate Dr.
Englund's comment, common use is very low.
Maybe I am a dreamer but actually the marketing could have a beneficial
effect. Who knows about condoms, but the
part on abstinence from sex when lesions are present, it could be that people
haven't gotten this message that it is very important to not have sex when
lesions are present. In a study alluded
to by Dr. Corey and Dr. Wald, in the vaccine study, during the course of that
study people were counseled on condom use and also to avoid having sex when
lesions were present and they actually reported that that declines over the
course of the study, having sex with lesions.
So, the effect could be, you know, in a good direction.
DR.
GULICK: That is interesting. Dr. Guinan?
DR.
GUINAN: I think it is really difficult
to interpret these data without information on birth control practices of the
women because some people do use condoms for birth control. In fact, the most committed users of condoms
are those that don't want to get pregnant rather than for protection from
disease. If these women changed their
contraceptive us during the study they would maybe not do condoms. Do you see what I mean? So, it may have nothing to do with the study
but something to do with the contraceptive practices. So, I think you can't interpret that data
that Dr. Haverkos presented without knowing what the other contraceptive
practice was.
DR.
GULICK: Mr. Ebel?
MR.
EBEL: Yes, I would like to comment on
the communications aspect of it because I think one of the things we know about
counseling patients with herpes is that one of the areas where it is hardest
for clinicians to spend time and do the counseling is precisely on impact on
patient's sex life, and on risk reduction, and those kinds of things. I think the marketing of this and the
increased awareness about the need for prevention and the awareness of a new
intervention potentially could really have a positive effect in giving
clinicians a more positive way to discuss this, in turn enabling patients to be
more able to discuss it with their partners, and we know that that is a
problem. So, the whole prevention thing
at some point revolves around communication and this might help with that.
DR.
GULICK: Dr. Pazin?
DR.
PAZIN: When I look at these data, it suggest
to me that these people put all their eggs in the pill basket. Really, when they go on a study, you know, if
they didn't use condoms before they don't use them when they are on the study. Conversely, if they did use them almost all
the time, they continue to do that. I
think that it really doesn't have that much impact but I think that having the
availability of the pill will have the impact of making them disregard that
other possibility of using the condom.
DR.
GULICK: Let me try to summarize what we
said here in terms of valacyclovir for prevention decreasing the use of condoms
and abstinence during outbreaks. The
consensus was that it could but recognizing that condom use tends to be low
among people in general. We all agree I
think, and would like to emphasize, that education is essential as part of the
prescribing of this drug, putting valacyclovir in the context of other ways of
avoiding transmission of HSV-2 and also recognizing the limitations based on
the wide confidence interval once again.
The fact that we are uncertain about the amount of benefit, that
reduction is anywhere from 24-94 percent.
Then Dr. Stone's point that this added education could actually be a
benefit to tell people that active lesions are a time when they should be
abstinent or use condoms.
Let's
go on to the next question. Number five,
although patients ion the registrational trial were treated for eight months,
valacyclovir for suppression of transplantation of genital herpes will likely
be used for significantly longer periods of time. What additional studies would you suggest to
evaluate the potential for longer-term adverse events, including resistance to
valacyclovir?
We
have touched on this several times over the course of the day. I think it was the consensus of the committee
that this is a concern of ours, about the long-term safety, and the fact that
duration, as was raised earlier in the day, is really not stipulated right now
in terms of the indication.
Let's
take that point first, duration of use here.
What would we suggest as appropriate?
Dr. Pazin?
DR.
PAZIN: People are going to use it as
long as they are at risk. I don't think
that there should be that much of a duration emphasis--I think till their money
runs out.
[Laughter]
DR.
GULICK: Well, we heard a couple of
interesting scenarios earlier today.
Change of relationship, should that prompt a change in drug here? Or, what if the susceptible partner does
seroconvert for HSV-2?
DR.
PAZIN: Then you don't take it anymore.
DR.
GULICK: There you go! Maybe this is painfully obvious here.
Specific
studies to look at long-term adverse events?
Dr. Englund?
DR.
ENGLUND: I really think we need a
pregnancy registration. We are used to
using acyclovir in pregnant women. I
personally don't know how much Valtrex is being used in pregnant women but I
think that needs to be followed up because although I think there is no good
data about immunocompetent adults ever getting resistant virus, I would be
concerned potentially about a baby being infected with resistant virus, on a
theoretical basis not based on what I see.
I think that there is an obligation to follow the use of this through
registration as opposed to a study.
DR.
GULICK: Does the sponsor have data on
valacyclovir in pregnancy?
DR.
COCCHETTO: We do have some
information. In concert with CDC and
others we had a pregnancy registry that was initiated in 1984 with acyclovir
and then subsequently expanded to include valacyclovir once that product was
initially approved within the United States.
Dr. Alice White is the head of our epidemiology group who collaborated
with Dr. Stone and others on that effort.
I would be happy to ask her to comment on that briefly if you like.
DR.
GULICK: Sure, that would be great.
DR.
WHITE: Hi, I am Dr. Alice White, vice
president of the epidemiology department at GlaxoSmithKline. As Dr. Cocchetto mentioned, we did initiate
the pregnancy registry in 1984. It was
really designed to look at major birth defects and compare the risk that might
be observed with acyclovir used prenatally with risk of birth defects observed
in the general population, through the CDC's birth defects surveillance
system. As the first one approved that
would be used widely in women of childbearing age, we felt it was important to
look at major malformations. It was a
short-term registry. Generally by the
six-week visit we followed up to get birth outcome information. We have some results from that study on
slides if you would like to see them. We
terminated the registry in 1999 on the advice of our independent advisory
committee because it was felt that the body of evidence about safety with
respect to major malformations was sufficient.
Our enrollments had dropped off as clinicians and patients became more
comfortable with use of the drug in pregnancy.
So, we stopped it. Of course, at
that point we weren't looking for things like resistance..
DR.
GULICK: Would we be interested in seeing
the data?
DR.
ENGLUND: It is the acyclovir data, I
don't need to see it; I have seen some of it.
No.
DR.
GULICK: Okay. Then, your other point I guess was about
resistance in newborns as well.
DR.
ENGLUND: Right. As we have said, I am not concerned about the
transmission of resistant virus in the patients that we specify for use. I am concerned about the development of
resistance in patients for whom this relatively low dose of drug is being used
for a long period of time and who may have partners who are not who we want to
give the drug to or who are themselves unrecognized as being
immunocompromised. So, I would have some
concerns about resistance for follow-up, not necessarily to change what we are
doing today.
DR.
GULICK: Is it fair to say--and this came
up earlier too--that follow-up of susceptible partners who seroconvert is
pretty key, and it would have been helpful to see that in the study that was
presented to know the clinical outcomes?
We heard the resistance data I guess for ten of them, but also the
clinical outcomes because of this concern that resistance could be a problem
long-term, particularly as this gets into the population with widespread
use. Dr. Wald, a comment on that?
DR.
WALD: When we were designing the study
we actually did not feel that that information to be very important because
immunocompetent people heal their primary herpes whether or not they are given
antiviral therapy. So, following
somebody for a single episode and seeing it heal or not heal without any
comparison really would not have, I believe, have provided us with any
additional useful information to this point.
DR.
GULICK: May I suggest that it would have
been quite easy to put together and quite reassuring to know that the partners
all had a normal course after receiving valacyclovir?
DR.
WALD: That is correct but they didn't
have susceptible isolates.
DR.
GULICK: That is helpful. Dr. Fish?
DR.
FISH: I think that the package insert
could just relate the fact of how long the trial lasted; that the experience
was eight months, or whatever it is; and leave it to the provider and the
patient to make the decision beyond that.
I think it also adds to Dr. Mathews' point earlier about a
recommendation for HIV testing because that is where we do see a not infrequent
occurrence of resistance to acyclovir or the other agents that we have used
historically. So, in that patient
population we wouldn't necessarily want to be inadvertently treating them for
suppression or otherwise and have the resistance issue come up.
DR.
GULICK: Okay. I think we have covered that. Let's move to our last question. The primary endpoint in 3009 was the
proportion of couples with clinical evidence of a first episode of genital
HSV-2 in the susceptible partner. Would
you recommend that primary endpoint in future studies? If not, what primary endpoint would you
recommend?
We
have really already considered this, haven't we? I guess the feeling was that because of
asymptomatic shedding and transmission seroconversion is a valuable endpoint,
or the composite endpoint of both serological and clinical would be--I am
trying to speak for everyone--it would be our consensus that that would be even
a better endpoint than clinical alone.
Comments? Dr. Pazin?
DR.
PAZIN: I think they should be sort of
co-equal endpoints in the sense that I am interested in how many people develop
clinical disease, recognizable and documented, confirmed. I am also interested in serologic
conversions. I think, you know, pretty
much the way this study did it, should be sort of co-equal endpoints, that they
should both be incorporated.
DR.
GULICK: Well, co-endpoints is
tough. You could have a composite
including both or you could make one your primary and one your secondary. But you are saying that they both tell you
important information.
DR.
PAZIN: Yes, important information.
DR.
GULICK: Any other thoughts about
that? Yes, Dr. Englund?
DR.
ENGLUND: I would just say I think the
primary should be serologic and the secondary could be the clinical.
DR.
GULICK: It certainly would make studies
easier to do.
DR.
ENGLUND: Well, it would also give
uniformity. You know, with frequent
serology it would give uniformity to Australia and eastern Europe, things like
that.
DR.
GULICK: We are all for uniformity in
Australia and eastern Europe. Dr.
Mathews?
DR.
MATHEWS: I had a comment on a different
matter.
DR.
GULICK: Okay. Any other comments on endpoints? We have pretty much covered that I
think. So, last couple of matters to
think about.
DR.
MATHEWS: I have a concern about the dose
appropriateness for this indication.
Because the risk reduction, depending upon what the endpoint was, varied
from 0.5 to 0.75, it is clearly not zero.
If you were to restrict this analysis to people who are at high risk of
transmission, namely, some of those characteristics would be recently acquired
infection, relationships of short duration, very frequent intercourse and other
factors, a lack of use of condoms, all of these, what do we know about how well
the drug at this dose works in the high risk setting? That is to say nothing about other
populations, for example the dose in immunocompromised or where the predominant
form of contact is not vaginal intercourse, and so on. So, I think this is an area for additional
study to examine the dose and to try and identify settings in which people at
high risk for transmission can be studied because, this population, really the
way it was constructed to make the study feasible was skewed towards relatively
lower risks of transmission I think.
DR.
GULICK: Other comments on other issues
that people would like to make? Dr.
Birnkrant, how did we do?
DR.
BIRNKRANT: Very well today. We got a lot of useful information.
DR.
GULICK: Great! So that brings us to the end of the
meeting. I would like to thank the
sponsor and the agency for their presentations today, the committee for a
lively, provocative and far-ranging discussion, and we will close the meeting
now. Thanks.
[Whereupon,
at 3:15 p.m.., the proceedings were adjourned.]
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